text:
nathan hydration bladdergrantchester sidney and violetPosted by on May 21st, 2021
By Amber King â Senior Review Editor. Nathan Replacement Bladder - 1.8 Liter (1.8L) / For Hydration Vests, Hydration Pack. Remove the hydration bladder from inside the backpack. Hydration bladder has 2L capacity and fits snugly against your back without sloshing. Conclusion. Imagine the waste we can eliminate if our participants brought sustainable solutions with them. We tested hydration bladders from Platypus, CamelBak, Gregory, and others to find the best options on the market. Nathan 1.5L Hydration Bladder - Running Warehouse You save 25%. Thursday September 30, 2021. Monofilament mesh shoulder straps and air-mesh on back are breathable and help prevent chafing. Cleaning Step 3 â Most hydration bladders can be dried by inserting a crumpled paper towel into the reservoir. Hydration Pack With 2.5L Water Bladder - Army Green. BPA-free hydration bladders with high-flow bite valves and large, easy-fill openings now come with quick-release hoses for convenient cleaning and faster set-up in your favorite Nathan Race Vest. Retail Price: $30.00. Amazon.com: nathan hydration The Nathan Pinnacle 12L is a comfortable hydration vest that provides an apparel-like fit with abundant space for hauling the essentials and plenty of water. Barcode: 717064910045. 2 reviews. Hydration Water Bladders & Replacement Parts | Nathan Sports Our product experts have helped us select these available replacements below.You can also explore other items in the Camp & Hike, Backpacks & Bags, Backpack Accessories, Hydration Reservoirs & Accessories yourself to try and find the perfect replacement for you! Additionally, the Pinnacle incorporates two different materials on the back panel; one where the hydration bladder sits against the back and a different, more breathable mesh along the sides of the back. Reservoir hanger: Most will fit any bladder, but a few are only compatible with certain reservoir models. Replacement Bladder - 1.5L. The Trail Mix 7 liter enables you to store all your equipment efficiently on all-day trail runs, hikes or biking trips. This hydration pack for running has more pockets than you ever think you'd need (15! VaporHowe 2 Insulated - 12L (with Nathan Fire and Ice Flask 2 Pack. The Miracol Hydration Backpack offers a bit more storage than the Nathan #020 HPL Hydration Running Backpack. Nathan Our Editors independently research, test, and rate the best products. Nathan Firebreaker 6L Hydration Vest - 2 Be the first to review this product. Features a high-flow bite valve with a large, easy-fill opening to quickly add water on the go! The extra bladder worked into my hydration plan for the 2015 Sehgahunda Trail Marathon in New York's Letchworth State Park. Subscribe to: Posts (Atom) Blog Archive 2014 (60) Retail Price: $29.95. BPA-free hydration bladder includes quick release hoses for convenient cleaning and a faster set up. Compatible with other Packs/Vests: VaporAir, VaporAiress, HPL #020, and Intensity With the high flow bite valves and oversized, easy fill openings that come with quick release hoses, you can easily clean your bladder. Nathanâs 1.6 Liter Insulated Hydration Bladder keeps fluids 38% cooler than an uninsulated bladder, according to Nathan. Mine also did not come with the top hook but this was not a problem. This iconic hydration vest was designed in cooperation with the bearded ultrarunning phenomenon Rob Krar. 28% OFF. storage capacity: 12 liters (732 cu in). This bladder replaces the bladder for the Intensity, HPL #020, VaporShape, VaporWrap, VaporShadow, ⦠Depending on the length of the run you're prepping for, you can choose to fill the included 20 oz soft flasks with water, as well as add your own 1.5-liter hydration bladder for extra reassurance. Hydration Packs 101: How To Use Hydration Pack Bite Valves December 4, 2020 December 2, 2020 by trailrunningSoul.com If you enjoy sporty activities such as running, cycling, or hiking, then youâll understand that hydration is key, ⦠The hydration packs keeps water and gear close to the body to prevent bouncing while running. Nathan. It has ample storage for equipment and food and has one of the best hydration systems we tested. It has a close-fitting apparel like fit, a large amount of adjustment, a rear pocket that will hold a 1.5 litre hydration bladder, as well as two soft flasks on the front of the vest, and multiple stash pockets. Nathan Exo Draw 18 ounce. 0. The field of hydration packs for running is only getting stronger, and this pack still stood out amongst stiff competition. Retail Price: $45.00. Nathan Bladder Replacements - My Cooling Store. VaporKrar 2 - 4L (bladder compatible) ⬠169,95. NATHAN VAPORAIR HYDRATION PACK. Made from soft, breathable stretch-mesh, this vest features a two-liter bladder and six liters of storage space that easily holds a phone, energy bars and more. 7l 7 Liters for Men and Women | 2l. Such as a CamelBak, or Osprey running backpack. Most water backpacks come complete with bladders from a convenient, standard 1.5, all the way up to a 2L reservoir for multi-day races. With 9 exterior pockets, elastic perimeter banding, rear external shock cord, and reflective details, itâs prepared for everything you may need on any adventure. Nathan Pinnacle 12L. Ever have a leak in your hydration reservoir? Nathan VaporAir and VaporAiress 2.0 7L. It's a great choice for a fitted, bounce-free ride on your next run or adventure. ULTIMATE DIRECTION 1.5L RESERVOIR II ULTIMATE DIRECTION. 2 reviews. These kits include special brushes for scrubbing each part of the bladder and a cleaning tab that will dissolve in water. 1 review. Sternum straps are adjustable for maximum flexibility and personalized comfort. With your help, we will accomplish our mission. Sky Blue. with the included two-liter bladder; 9.5 oz. Add Comment Cancel . FREE SHIPPING ON ORDERS $45+. NATHAN 2L HYDRATION VEST BACKPACK GRAY KHAKI No Bladder Or Bottles EXCELLENT. The Nathan 1.5L (50 oz) Hydration Bladder reservoir features an easy-to-drink bite valve, Slide Seal top-fill closure for easy filling, and the Plug-N-Play button to easily disconnect the tube when it's time to clean; fits all Nathan hydration vests designed for use with 1.5L bladders, including #028, Minimist and Firecatcher Vests. Shop Hydration Reservoirs & Bladders and other replacement parts for your Nathan Sports gear. Nathan Hydration Bladders. Trail-Mix 7L (with 2L bladder) ⬠99,95. Nathan is the industry leader in hydration solutions for runners, offering a wide range of products to suit every need, including; vests, bottles, flasks, waist packs and handhelds. Vibrelli Hydration Pack & 2L Hydration Bladder - High Flow Bite Valve Hydration Backpack With Anti-microbial Technology. nathan others Champion ultra runner and renowned minimalist Rob Krar collaborated once more for the updated design of this popular, lightweight and durable race ⦠SPONSORED. The bottles are relatively easy to grab on the go, though the setup took some getting used to for testers used to running with a hydration bladder. Nathan has a wide variety of hydration products, from water bottles and flasks to different kinds of hydration packs and their replacement accessories. NATHAN Vapor Krar Hydration Vest 12l 2.0 Mens' Small. Shop today & earn Free Shipping with Qualifying Orders. The couple of days ago. VaporAiress 2.0 7 Liter Women's Hydration Pack. Many manufacturers of hydration bladders sell cleaning kits. NATHAN Trailmix Running Vest/hydration Pack. VaporSwiftra 4L (with 1,5L bladder) ⬠119,95. Add a comment . By Amber King â Senior Review Editor. Thereâs even ⦠ULTIMATE DIRECTION 2.0L RESERVOIR II ULTIMATE DIRECTION. The Nathan VaporAir Hydration Pack is a 5L capacity hydration pack that fits comfortably over the shoulder with load lifters and adjustable chest straps. Home > Personal Cooling > Cooling Vests > Hydration > Nathan Hydration Products > Nathan Bladder Replacements. $99.95 New. Functional trail mix is equipped with a 2l bladder, 2 zippered shoulder, 2 rear stretch, 1 zippered back, 4 front stashes, 2wo easy-access front bottle pockets (bottles not included). Be sure to rinse the hydration bladder well with hot water. Nathan 2 Liter Hydration Bladder Packaged Similar Products. The NATHAN 1.6 Liter Hydration Bladder is BPA-FREE with a sleek hourglass design and internal baffle to reduce sloshing. The Nathan VaporAir is a hydration pack in the old-school style but refined with added comfort, pockets, and a feature set that make it state-of-the-art. Proper hydration is the number one need for any runner, and Nathanâs expertise in this category can be seen in any one of our hydration solutions. Combining smart storage, a 2-liter reservoir and a comfortable, bounce-free fit, the Nathan Trail Mix 7L hydration vest helps you carry the essentials for blissful days spent running on singletrack. $45.00. Add Crux 3L Reservoir - 3 Liters to. Hydration: Includes a 1,5 L hydration bladder. 0. ), which makes it an exceptional choice for your longest, neediest days in the backcountry. Show Items. 0. 1â2 / 8. Photo: Amber King. Nathan Insulated Hydration Bladder 1.6L Similar Products. The original bladder in my Nathan HPL 2.0 pack did not. 6 models Trijicon MRO 1x25mm 2 MOA Reticle Red Dot Sight (265) As Low As (Save Up to 35%) $375.99 Free 2 Day Shipping. Over the years, Nathan has shown that it is dedicated to enhancing our running experience with their innovative and high-quality products. About Nathan HPL 6 L Race Hydration Vest - 2 L Bladder (For Men) Closeout. $1 - ⦠Cleaning the Hydration Bladder/ Reservoir Reservoir Tube: Reservoir tubes can be cleaned by simply disconnecting the hose from the body of the bladder. The interior features plus organizer pockets to keep your tools in order. Secure top, swish the solution around, and then drain. Model Number: NS4552-0153-020LI. If your hydration packâs bladder needs replacing, Nathan bladders are available in four sizes: 1. We have designed our bladders to be super easy to clean! Our Editors independently research, test, ⦠Nathan Elevation Hydration Pack â Review. If the pack has side-straps then tighten them down. 0. 4 models Vortex Razor HD 5-20x50 Tactical Rifle Scope w/ Illuminated Reticle (44) As Low As (Save Up to 15%) $1,699.00 10% Bonus Bucks. Nathan Synergy dual chamber hydration bladder 100oz water and electrolyte camal. Add a comment . 2 reviews. Of all the packs weâve tested from Nathan, this is definitely the most serious pack in terms of capacity. Vortex OPMOD Diamondback HD 10x42 Binoculars $279.99 (Save 18%) $229.00 On Sale. $149.96 New. The Nathan Pinnacle 12L is one of the most comfortable hydration packs available on the market today. The 1.6L insulated bladder, low weight, and creative pocket placement all come together to create one ⦠Choose from a variety of models designed for athletes, by athletes. $150, 7L/427 c.i., 14 oz. Sizing guide. Shop similar products. ⦠This can be done by pressing the quick disconnect button or pulling the tube from the housing if the quick disconnect option is not available for your bladder. backcountry.com. 1.5 liters Nathan Womenâs Hydration Pack/Running Vest - VaporHowe 2.0-12L Capacity with 1.6 L Water Bladder, Hydration Backpack - Running, Marathon, Hiking, Outdoors, Cycling and More 4.8 out of 5 stars 152 $112.40 $ 112 . The Nathan VaporWrap 2 Litre Race Vest has a sculpted body-mapped design shape & fit for a stable bounce-free / smooth ride and on-the-fly adjustability. Hydration. Free shipping. The QuickStart 6 L hydration pack with 1,5 L bladder is just the right size for essential gear and hydration. comes with 2l hydration bladder. SKU: 15000. One of the most important things to remember on long runs and treks is hydration. Shop today & earn FREE Shipping! Testers agree the Momentum 2.0 is âsupremely comfy,â thanks to its S-shape strap system with a wide fit at the neck and a taper in the mid-torso to help reduce underarm chafing. SKU: 10000. Besides the magnetic hose clip which we have already gushed about, it has external bungee cords for attaching extra clothing, pole straps that are intuitive to use, refl⦠View the 16 reviews with an average rating of 4.6 out of 5 stars. Paper towels: Stuff the reservoir with enough to hold it wide open. The Nathan 1.5L (50 oz) Hydration Bladder reservoir features an easy-to-drink bite valve, Slide Seal top-fill closure for easy filling, and the Plug-N-Play button to easily disconnect the tube when it's time to clean; fits all Nathan hydration vests designed for use with 1.5L bladders, including #028, Minimist and Firecatcher Vests. Nathan 1.5 L Hydration Bladder. Ideal for replacing your old, worn-out hydration reservoir, the Nathan 1.5L Replacement Bladder features BPA-free plastic and a large, easy-fill opening for quickly refilling water at home and trail pit-stops alike. Hydration backpacks come in styles to fit both the male and female body, with unisex options also available. Our product experts have helped us select these available replacements below.You can also explore other items in the Camp & Hike, Backpacks & Bags, Backpack Accessories, Hydration Reservoirs & Accessories yourself to try and find the perfect replacement for you! UTMB capable body-mapped unisex adventure vest with max storage and Bladder Control System⢠for serious athletes. $35.00. The testers definitely agreed that this pack fit surprisingly well and comfortable for how much pack it actually was. Posted on 12:31 PM by Bern. Built for female runners, this hydration vest from Nathan features women-specific torso length, shoulder harness and sternum strap. We tested hydration bladders from Platypus, CamelBak, Gregory, and others to find the best options on the market. $149.96 New. Nathan Race Hydration Vest: VaporWrap ( including 2L Hydrapak bladder ). Compression system lets you tighten the load for a stable load and a smooth ride. The lightweight Vapor Swiftra is body mapped and designed specifically for the female form. Edit . If the pack is a vest and you notice there is still room at your sides, size down with the pack. Aquatic Way Bite Valve Replacement Mouthpieces fits Camelbak and Most Brands (4-Pack⦠Nathan 2.0 L Hydration Bladder. Its abundant size options, contour-hugging female-specific fit, and ample storage capacity make it one of our favorites. NATHAN Vaporkrar 12l 2.0 Insulated Hydration Race Vest - Size Medium Ultra Lite. Our Nathan BPA-FREE 2 Liter Hydration Bladders features a high-flow bite valve and large, easy-fill opening with quick-release hose for convenient cleaning and faster set-up with your favorite Nathan Race Vest! VaporHowe 2.0 12 Liter Women's Race Vest. Item #767746. Choose from a variety of models designed for athletes, by athletes. Hydration backpacks come in styles to fit both the male and female body, with unisex options also available. Cleaning and Scrubbing a Hydration Bladder. Clothespins: and a clothes hanger; Kitchen whisk: Slip it inside to hold the bladder wide open. Combining smart storage, a 2-liter reservoir and a comfortable, bounce-free fit, the Nathan Trail Mix 7L hydration vest helps you carry the essentials for blissful days spent running on singletrack. 5 out of 5 stars. One Size Fits Most makes this pack shareable, and a multisport must have! The two liter water bladder with this hydration backpack can be filled through the circular cap at the top of the bag. weight with bladder: 12.8oz. Cleaning Step 2 - For a more thorough cleaning, add a tablespoon of bleach to a nearly full hydration bladder. Best Hydration Bladder of 2021. Continue. I search for information on the Nathan Hydration Bladder, so i would like to bring a story to tell. 1â3 / 10. R399.00. nathan hydration bladder Be the first to review this product BPA-free hydration bladders with high-flow bite valves and large, easy-fill openings now come with quick-release hoses for convenient cleaning and faster set-up in your favorite Nathan Race Vest. BUY. Step 2. 40 $199.95 $199.95 Smaller daypacks (such as my Osprey Talon) often canât accommodate bladders larger than 2L, so keep that in mind if youâre shopping for a ⦠The VaporAirhas an incredible set of features, basically everything you would need or expect from a top-rated hydration pack. Post comment. This is a two-stage process. To open, pull the slider top sideways from the closed/flared end until removed. The Nathan VaporKrar 4 litre is a lightweight race-ready ultra-running hydration vest. BPA-free hydration bladders with high-flow bite valves and large, easy-fill openings now come with quick-release hoses for convenient cleaning and faster set-up in your favorite Nathan Race Vest. NATHAN VaporHowe â Front. Thereâs also a stretchy external storage pocket for days when you need to pile on more gear. With an empty bladder, this pack weighs 14 ounces. Considering the great storage capacity and two-liter bladder, this is pretty dang good. This is an amazing hydration pack for running for anyone who prefers a bladder and hose hydration system over chest mounted bottles or flasks. Nathan Intensity Race Hydration Vest - Women's - 70 oz. Specs weight without bladder: 11.62oz. (149) 149 reviews with an average rating of 3.5 out of 5 stars. Shop By Price. R289.00. Nathan ExoShot 12oz Handheld Nathan ExoShot Replacement Soft Flask. 4.6 16 Reviews. 2 models Vortex Diamondback HD 10x42mm Roof Prism Binoculars As Low As (Save Up to 18%) $215.49 On Sale. https://besthiking.net/nathan-vaporair-hydration-vest-review From training sessions to race day, keep fresh, cool water handy in Nathan's HPL Race hydration vest. Step 1 Hydration Bladder Leak Repair . $115+. Purchase hydration bladder cleaning tabs. Nathan VaporAir 2.0 7L running hydration vest. Also comes with a quick-release hose for convenient cleaning. For this reason, amongst others, it is the best pack we tested. Here is the #020 on the left, and the Endurance on the right: The most notable difference is the topmost opening for refilling the bladder. For hydration, the Race Day Vest includes two bottles and additional room for a bladder in the upper rear pouch. Just rinse the hose, flip the bladder inside out, rinse, and dry. Check the bladder and pipe to locate any scratches or leaks. Bladders from CamelBak, Osprey, Platypus, Gregory, and others are best cleaned by hand, using hot (not boiling) soapy water and a thorough rinse. It boasts being UTMB ready and thereâs no doubting that itâs more than capable. Retail Price: $32.95. Capacity â The largest consideration is what capacity hydration bladder to buy. Randy Ray and her wife, Wendy Lewis, founded the company; both are acting CEOs and they have both been conscientious for the companyâs growth, success, and development over the years. For those who prefer a bladder on their back, this is one of the best packs on the market. Compared to. Some of the options below can be used with a hydration bladder in the main compartment, so you can carry a couple of liters of water and ⦠Most hydration bladders range in size from 1L to 3L. Track Shack Events is working toward being bottle-free in the 2019-2020 race season. Minimalists who want a low-profile, comfortable way to wear water will love the Nathan Quickstart 4 L hydration vest.
Sandy Animal Crossing: New Horizons, Chick-fil-a Grand Opening 2021, Kmele Foster The Fifth Column, Venezuela Government Website, Utsa Football 2020 Stats, Yellow Chicken Curry With Coconut Milk, Troop Beverly Hills Troop Number, Dynasty Qb Rankings 2021, Main Street, Broken Hill, Chesterfield County Sc Election Results 2020, Update Voter Registration, Charm City Cakes Discount Code,


text:
Inflammation in Cancer: Part of the Problem or Part of the Solution? 2020View this Special Issue
Oxidative Stress: A Possible Trigger for Pelvic Organ Prolapse
Pelvic organ prolapse is a frequent health problem in women, encountered worldwide, its physiopathology being still incompletely understood. The integrity of the pelvic-supportive structures is a key element that prevents the prolapse of the pelvic organs. Numerous researchers have underlined the role of connective tissue molecular changes in the pathogenesis of pelvic organ prolapse and have raised the attention upon oxidative stress as an important element involved in its appearance. The advancements made over the years in terms of molecular biology have allowed researchers to investigate how the constituent elements of the pelvic-supportive structures react in conditions of oxidative stress. The purpose of this paper is to underline the importance of oxidative stress in the pathogenesis of pelvic organ prolapse, as well as to highlight the main oxidative stress molecular changes that appear at the level of the pelvic-supportive structures. Sustained mechanical stress is proven to be a key factor in the appearance of pelvic organ prolapse, correlating with increased levels of free radicals production and mitochondrial-induced fibroblasts apoptosis, the rate of cellular apoptosis depending on the intensity of the mechanical stress, and the period of time the mechanical stress is applied. Oxidative stress hinders normal cellular signaling pathways, as well as different important cellular components like proteins, lipids, and cellular DNA, therefore significantly interfering with the process of collagen and elastin synthesis.
1. Introduction
Pelvic organ prolapse (POP) is one of the most common female pathologies, encountered especially in patients over 50 years old. Its incidence increases with age, being more frequent in older patients compared to young and middle age females, and also with the number of vaginal births [1–3]. There are numerous factors that seem to favor POP pathogenesis: obesity, chronic constipation, sustained physical activities that increase the intra-abdominal pressure, menopause-associated hormonal changes, collagen disorders, history of pelvic surgery, and radiotherapy. POP-associated symptoms can significantly impact the patient's life style, usually leading to anxiety, depression, self-isolation, and low self-esteem, as well as to a significant decline in terms of sexual intercourse frequency (especially in younger and active patients) [4, 5].
The support of the pelvic organs is ensured by the levator ani muscles, pelvic fascias, and ligaments. The dysfunctions of these structures have been shown to alter their supportive role, thus favoring the descent of the pelvic organs and other associated pathologies and symptoms [6]. The supportive effect of these structures depends not only on the quantity of their cellular components but also on their quality [7]. Numerous studies have underlined the role of connective tissue molecular changes in the pathogenesis of pelvic organ prolapse.
The pelvic connective tissue consists of fibrous elements like collagen and elastin, which are the principal components of the extracellular matrix (ECM) and also of the elastogenic cells, represented by smooth muscles cells and fibroblasts [8]. Other important components of the ECM are fibronectin, fibrinogen, vitronectin, laminins, thrombospondin, integrins, and other glycoproteins involved in the cellular adherence process, which is mediated by the integrin membrane receptors [9]. Integrins are indispensable for the ECM proteins metabolism, as well as for the cellular turnover, this being a constant process [10, 11].
2. Collagen and Elastin
Collagen is the main component of the connective tissue, accounting for up to 70-80% [12]. There have been identified 29 types of proteins that can be included in the collagen family, but the most representative ones for the pelvic connective tissues are type I and III collagens, these two collagen types being responsible for the normal integrity and functionality of the pelvic floor supportive structures [13]. Collagen precursors known as procollagen are released by fibroblasts into the extracellular space, where they become tropocollagen under the action of collagen peptidases that remove the ends of this molecule. Under the action of lysyl oxidase, the tropocollagen molecules bind together and form the collagen fibril [14].
Type I collagen is known for its high stretching ability and for the fact that it has a major role in strengthening the pelvic structures, whereas type III collagen, being a much smaller protein compared with type I collagen, is responsible for tissue flexibility, along with elastin [15]. The percentage of collagen within these pelvic connective tissues, as well as the ratio between type I and III collagens, are important elements that significantly contribute to the integrity of the pelvic supporting structures. Therefore, collagen dysfunction or the existence of an abnormal ratio between type I and type III collagens will eventually disrupt the strength of the pelvic tissues, as well as their elasticity and relaxation ability [16].
Two important enzymes modulate the collagen metabolism and the ECM turnover: matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMP). MMPs are a group of proteolytic enzymes that degrade all ECM proteins. MMPs belong to the ECM protein family, but they can also be found within cells, especially MMPs 1, 2, and 11 [17]. MMPs present three domains: a propeptide domain, a catalytic domain (the site of the zinc ion), and the hemopexin domain, which is responsible for the interactions of different types of MMPs, as well as with TIMPs. They are secreted as inactive enzymes, known as zymogens; their activation is calcium and zinc dependent, and it implies the cleavage of the propeptide domain [18]. MMP gene expression has been identified in fibroblasts, endothelial cells, macrophages, monocytes, and neutrophils. MMP concentrations are usually constant, this process being mediated by hormones, cytokines, growth factors, ultraviolet radiation, and cellular interaction. MMP expression is usually enhanced by cytokines like tumor necrosis factor- (TNF-) α and interleukin (IL) 1 and 6, as well as by growth factors like transforming growth factor- (TGF-) β, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF). IL-4, corticosteroids, heparin, and retinoic acid have been demonstrated to inhibit the expression of MMPs [14, 19].
Over the time, there have been identified more than 20 MMPs (23 in humans) [20] that can be classified as follows: collagenases (MMPs 1, 8, 13, and 18), gelatinases (MMPs 2 and 9), stromelysins (MMPs 3, 10, 11, and occasionally MMP 19, referred as stromelysin-4), membrane-type MMP (MMPs 14, 15, 16, 17, 24, and 25), matrilysin (MMPs 7 and 26), and other MMPs (MMP 12-metalloesterase) [21, 22].
TIMP counterbalances the action of MMP. TIMPs bind with MMPs (both with the inactive MMPs—zymogens and also with the active MMPs) and form a complex that inhibits the activation of MMPs, the connection of MMPs with their substrates and their activity, therefore significantly reducing the collagen degradation process and the destruction of other ECM proteins [17]. As in the case of MMPs, TIPM expression is also modulated by a number of cytokines and growth factors. Several POP studies that have analyzed MMPs and TIMPs as cellular markers for POP have identified high MMP levels and/or lower TIMP concentrations, underlining that an imbalance between MMPs and TIMPs can severely alter the quality of the pelvic connective tissues, thus favoring pelvic organ prolapse pathogenesis [23, 24]. It has been reported that POP patients do not have inferior collagen concentrations at the level of the pelvic-supportive structures compared to the non-POP patients and that the molecular mechanism involved in POP pathogenesis is in fact an accelerated process of collagen degradation that exceeds its synthesis [25].
Elastic fibers are other important components of the pelvic-supportive structures, due to the fact that they confer high stretching and passive recoil capabilities to the pelvic tissues. Like collagen, these elastic fibers are major components of the ECM, and they present a complex molecular biology. Elastin and microfibrils are the main components of elastic fibers, elastin accounting for up to 90% of their mass [26]. Elastin synthesis occurs during the last months of the intrauterine life, as well as in the first months after birth, afterwards this process being negligible. There are several pathological situations that are accompanied by new elastin synthesis, but its quality has proven to be inferior to that of the one produced during its normal synthesis period [27, 28]. Microfibrils are fibrillar elements that are characterized by high concentrations of glycoproteins like fibulins (FBLNs), fibrilins (FBNs), microfibril-associated glycoproteins (MAGPs), elastin-binding proteins, glycosaminoglycans, and lysyl oxidase [14].
Elastin synthesis is a complex process that originates at the level of the elastogenic cells, and it implies several precise steps. Tropoelastin (TE), a monomeric precursor of elastin, is secreted by smooth muscle cells and fibroblasts. TE monomers associate with each other and form lager polymers that will be deposited on the microfibrils surface. The polymerization process is mediated by several proteins located at the interface of elastin and microfibrils: FBLNs 1, 2, 4, and 5, FBNs 1 and 2, MAGPs, lysyl oxidase (LOX), and LOX-like proteins (LOXL) [26, 29, 30]. Initially, TE monomers interact and form small aggregates. FBLNs 4 and 5 favor the interaction between these small aggregates and therefore their assembly into larger polymers, as well as their microfibrillar deposition. Once deposited on the microfibrils surface, several microfibrillar elements (FBNs 1 and 2 and MAGPs) realign the TE polymers, thus favoring a new cross-linking process that will result in mature elastic fibers [31, 32]. FBLN 5 is an essential component of this process, without which polymerization would not be possible. Acting as a ligand for different integrins located on the cellular surface (avb3, avb5, and a9b1), FBLN 5 facilitates the connection between those cells and elastic fibers [10, 11]. Animal studies conducted on Fbln5−/− mice have demonstrated that FBLN 5 deficiency is associated with pelvic organ prolapse [33].
An important step of this polymerization process is catalyzed by LOX [26]. Several studies have investigated the role of LOX in normal elastogenesis, as well as LOX-associated anomalies and pelvic organ prolapse. LOX and LOX-like proteins 1-4 are encoded by five genes; therefore, disturbances of the encoding process or any other problems in terms normal LOX or LOXL proteins synthesis could lead to an altered elastogenesis [29]. Clinical research has demonstrated that deficient LOXL1 mice associate a higher risk of developing POP [30].
Considering the fact that TE is made out of several amino acids (lysine, proline, cysteine, threonine, arginine, tyrosine, leucine, methionine, phenylalanine, and valine) that are sensible to oxidative stress, it is safe to say that any oxidative stress- (OS-) induced changes at this level could alter the elastogenesis process by providing low-quality elastic fibers [14, 34].
3. Mitochondria, Krebs Cycle, and Oxidative Stress
In recent years, the interest regarding the role of OS in pelvic organ prolapse pathogenesis has increased. The advancements made over the years in terms of molecular biology have allowed researchers to investigate how the constituent elements of the pelvic-supportive structures react in conditions of OS. The majority of the existing studies that have focused on this subject have concluded that OS is a key element of POP pathogenesis due to the fact that it disturbs cellular homeostasis. OS hinders normal cellular signaling pathways, as well as different important cellular components like proteins, lipids, and cellular DNA; therefore, it interferes with the process of collagen and elastin synthesis, significantly altering it [35–37].
OS denotes the existence of an imbalance between oxidative agents and antioxidants that can neutralize them. In normal conditions, the production of free radicals is counterbalanced by the antioxidants activity, OS being negligible [38]. Furthermore, free radicals act as messengers in several cellular signaling pathways, being involved in gene expression, protein phosphorylation, activation of several cellular receptors and transcriptional factors, cellular differentiation, immune response, and apoptosis, thus regulating cellular activity and cellular growth [39, 40]. Nevertheless, a disruption of the normal free radical homeostasis associated with their increased production will unavoidable damage vital cellular components, as we have previously mentioned.
Free radicals are the result of an increased cellular metabolic activity known as endogenous production (infections, inflammatory and/or immune system response to different agents, malignancies, ischemia, and physical and mental stress), as well as of several exogenous factors like smoking, irradiation, alcohol abuse, drugs (bleomycin, cyclosporine, and gentamicin), solvents, herbicides, diabetes, and heavy metals (iron, cadmium, lead, mercury, and arsenic) [41–43].
The principal source for production of free radicals is the mitochondria, but they are also produced by inflammatory and endothelial cells, during reactions involved in the respiratory chain, the cytochrome P450 system, and phagocytosis or during the synthesis of prostaglandins [42, 44].
Mitochondria is the principal site for energy production at cellular level, in the form of adenosine triphosphate (ATP), a process in which peroxides and free radicals such as reactive oxygen and nitrogen species (ROS/RNS) also result as products [43]. Glucose is a key element for cellular energy production. At mitochondrial level, during the glycolysis process, glucose brakes down and generates two molecules of pyruvate, which is converted into acetyl coenzyme A (acetyl-CoA). Acetyl-CoA enters the Krebs cycle reactions and generates nicotinamide adenine dinucleotide (NAD+), flavin adenine dinucleotide (FAD), and guanosine diphosphate (GDP) [45, 46].
During the Krebs cycle reactions, NAD+ and FAD are reduced to NADH and to FADH2, these two being key elements in the electron transporting chain, as well as in the production of ATP via the oxidative phosphorylation process [47]. Furthermore, under the action of succinyl-CoA synthetase GDP, inorganic phosphate and succinyl-CoA undergo a phosphorylation reaction that leads to GTP, coenzyme A, and succinate. Afterwards, succinate and ubiquinone (Q) suffer an oxidation reaction mediated by succinate dehydrogenase that leads to fumarate and ubiquinol (QH2). The last reactions of the cycle include malate production from fumarate (mediated by fumarase), oxaloacetate from malate, and the synthesis of citrate and coenzyme A from oxaloacetate and acetyl-CoA. ATP can also be produced from GTP under the action of nucleoside-diphosphate kinase [48].
Each molecule of glucose that enters the Krebs cycle produces at the end of the cycle two GTP, six NADH, two ubiquinol, and four molecules of carbon dioxide. It is reported that each molecule of NADH that results during the Krebs cycle correlates with a production of 2.5 molecules of ATP, whereas FADH2 produces only 1.5 ATP molecules. The total amount of ATP obtained from one molecule of glucose that undergoes glycolysis and oxidative phosphorylation during the Krebs cycle is up to 38 molecules [48, 49]. As mentioned previously, we must underline the importance of NADH and FADH2 due to their role in the electron transporting chain. During the Krebs cycle reactions, a small number of electrons (estimated at 1-3% of all electrons) escape the respiratory transport chain towards oxygen, thus generating oxygen-derived free radicals [41].
The electron transport chain across the inner mitochondrial membrane (IMM) in order to produce ATP is mediated by a series of mitochondrial protein complexes that allow the passage of electrons from donors to more electronegative accepting molecules; this process repeats itself until the electrons reach their final acceptor which is oxygen. The energy released during the electron transport is used to transfer protons across the IMM [50]. Therefore, the electron transport chain is coupled with the transport of protons from the mitochondrial matrix across the IMM. This process leads to a proton gradient that has an essential role in the mitochondrial membrane potential [45, 51].
This entire process of electron transport is mediated by four protein complexes that are strongly attached to the IMM: NADH-ubiquinone oxidoreductase (complex I), succinate dehydrogenase also known as succinate-ubiquinone reductase or succinate-coenzyme Q reductase (complex II), cytochrome bc1 complex (complex III), and cytochrome c oxidase (complex IV) [52, 53]. Another important aspect that facilitates the electrons transport is the fact that these complexes are linked with water and lipid soluble electron carriers. Out of these four complexes, only three of them act as proton pumps, being able to transfer protons across the IMM: complexes I, III, and IV [45].
Complex I has a major role in the electron transporting chain, being the site where electrons enter the respiratory chain. At this level, NADH suffers an oxidation reaction that leads to NAD+ and to the release of two electrons. These electrons are taken by a lipid soluble electron carrier known as ubiquinone (coenzyme Q—CoQ) that undergoes a reduction reaction becoming ubiquinol (UQH2), and it passes across the IMM. This process is coupled with the transfer of four protons which generate a proton gradient [45]. It is estimated that the energy released during these transfers accounts up to 40% of the energy necessary for ATP synthesis, as well as for the transport of other important factors to and from the mitochondria. Complex I is one of the first sites of electrons leakage, leading to oxygen-derived free radicals, especially to superoxide radical. It is worth mentioning that ubiquinone also receives electrons from complex II [54–56].
Complex II also transports electrons, these electrons being delivered from FADH2 to ubiquinone in parallel with the complex I electron mediated transfer, but in contrast to complex I proton transfer capabilities, the type II complex does not transfer protons to the intermembrane space. This complex mediates the oxidation reaction of succinate that leads to fumarate and also the conversion of ubiquinone into ubiquinol [45]. During the reactions that take place throughout the electrons transfer process, ubiquinone suffers a reduction reaction that leads to semiquinone. This unstable intermediate of ubiquinone may also lead to superoxide radical production [57–59].
Complex III, known as cytochrome bc1, receives electrons from both complexes I and II via coenzyme Q (ubiquinone) and transfers them to cytochrome c, this process being accompanied by proton transport. Similar to complex I, cytochrome bc1 is also involved in oxygen-derived free radical production, due to the fact that electrons may leak towards oxygen during the electron transfer reactions. The amounts of ROS produced by complex III are significantly inferior compared to those produced by complex I [60]. Several researchers have emitted the hypothesis that complex III-associated ROS may have positive effects in terms of cellular adaption to ischemic events, which suggests a beneficial cardioprotective outcome, as well as in apoptosis [61, 62].
Complex IV (cytochrome c oxidase) receives electrons from cytochrome c and transfers them to oxygen, which is the last electron acceptor of this transporting chain, thus reducing it to water. Complex IV as a component of the proton gradient, in parallel with the electron transfer process, it also transports four protons across the inner mitochondrial membrane therefore maintaining a normal transmembrane proton gradient [56]. This proton gradient is essential for ATP production, because it permits the ATP synthase to use the protons in order to obtain ATP from ADP and inorganic phosphate [45, 63].
Another site for ROS production is represented by the peroxisomes. These oxidative organelles found in the cytoplasm of eukaryotic cells are involved in several important metabolic reactions: the catabolism of fatty acids, long amino acids, bile acid-derived intermediates, polyamines, the plasmalogens synthesis, and ROS reduction [41, 64]. Enzymes found in peroxisomes use molecular oxygen as a cosubstrate during metabolic reactions, remove hydrogen from different molecules involved in these reactions, and form oxygen-derived free radicals (only H2O2). H2O2 is used by catalase (another peroxisomal enzyme) during the oxidative reactions of several agents (alcohol, formic acid, and phenols), reactions during which H2O2 is transformed into water and O2, thus reducing its accumulation as well as its negative impact [65].
Free radicals are characterized by the fact that they have one or more unpaired electrons, this characteristic allowing them to interact without any major difficulties with other molecules, thus leading to chain reactions that can prove to be dangerous to normal cellular homeostasis [41, 50].
The most important types of free radicals are those derived from oxygen (superoxide anion radical O·2-, hydrogen peroxide H2O2, and hydroxyl radical ·OH). Superoxide anion radical is considered the principal ROS, being responsible for the production of secondary ROS (H2O2 and ·OH). O·2- results, as we have previously described, during the mitochondrial respiratory chain reactions and under the action of NADPH (dinucleotide phosphate) oxidase [43]. Another type of free radicals that could arise during the respiratory chain reactions (especially in hypoxic conditions) is nitrogen-derived free radicals such as nitric oxide that can further lead to other free radicals (nitrite (NO2-), peroxynitrite (ONOO-), hypochlorous acid, aldehydes, and 4-hydroxynonenal) [42, 66].
Molecular oxygen is characterized by the fact that it can easily accept an electron leaked during respiratory chain reactions, thus leading to superoxide anion radical. Under the action of an enzyme known as superoxide dismutase (SOD), O·2- suffers a dismutation reaction that leads to H2O2 production [43, 67]. Furthermore, the interaction between hydrogen peroxide and superoxide anion radical will lead to hydroxyl radical. Another mechanism responsible for the production of ·OH is the cleavage of H2O2, reaction mediated by Cu2+ or by Fe2+ [41, 68].
Several reports have described other possible sources for these previously mentioned ROS, excluding the mitochondrial respiratory chain: alterations of the mitochondrial membrane potential and two mitochondrial enzymes, one located in the space between the mitochondrial membranes and another one attached to the outer mitochondrial membrane (p66Shc, respectively, monoamine oxidase), as well as several enzymes involved in the Krebs cycle (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase) [57, 69–71].
There are other free radicals that result from oxygen, like peroxyl radicals (ROO·) (hydroperoxyl and perhydroxyl radicals). These peroxyl radicals play a major role in lipid peroxidation via fatty acid peroxide-dependent and fatty acid peroxide-independent pathways [41, 72].
In order to face the negative impact of the OS, cells are equipped with several enzymes that interfere with the action of these previous described free radicals: (i)Superoxide dismutases (three isoforms have been identified—SOD1-3)—use superoxide anion and convert it into O2 and H2O2(ii)Catalase—scavenges H2O2, transforming it into O2 and H2O(iii)Glutathione peroxidases, glutathione reductase, glutathione S transferase, glutathione disulfide, and nonenzyme glutathione—involved in H2O2 neutralization(iv)Thioredoxins 1 and 2, peroxiredoxins, lipoic acid, L-arginine, and coenzyme Q10 [41, 42].
Mitochondria are the principal site for ROS production, but it is at the same time an important target of OS and ROS. OS modifies the mitochondrial membrane permeability, reducing it, as well as the mitochondrial membrane potential [36, 44]. This will lead to a series of reactions that consist in the release of cytochrome C and B-cell lymphoma into the cytosol, followed by the assembly of the apoptosome (process mediated by apoptotic activating factor I) and the activation of the capsase-9. Furthermore, the latter activates caspase-3 thus initiating apoptosis. Another important trigger of the caspase-induced apoptosis is 4-hydroxynonenal, a metabolite that results from the lipid peroxidation process [44, 73, 74]. ROS induce mitochondrial DNA damage via oxidative reactions, and they also affect mitochondrial lipids and proteins [57]. Molecular-driven research has reached the conclusion that nuclear DNA has a significantly lower risk of ROS-associated damage compared to mitochondrial DNA, this being explained by the fact that nuclear DNA has a well-developed protection mechanism represented by histones and also because of the nucleotide excision repair mechanism, which is less represented in the mitochondrial DNA [75, 76].
4. Molecular Events Related to Oxidative Stress in POP
Transforming growth factor-β1 (TGF-β1) is a well-known cytokine involved in numerous fibrotic processes. Sustained mechanical stress leads to the release of TGF-β1. At cellular level, TGF-β1 binds to its receptor TRβII (TGF-β receptor II), this process being mediated by the Smad transcription factors (mothers against decapentaplegic homolog). These transcription factors included in the Smad family are essential for the TGF-β1 signaling pathway, because they mediate the signal transduction from TRβII to the nucleus [77, 78]. Once activated, TGF-β1 has an important role in fibrogenesis, as well as in the extracellular matrix remodeling process, controlling the deposition of important ECM components, as well as the expression of MMPs and TIMPs. TGF-β1 stimulates fibroblasts differentiation, collagen synthesis (especially type I and II collagens by myofibroblasts), and it also decreases the collagen degradation process, by blocking the action of MMPs and also by increasing the expression of TIMPs [14, 79]. TGF-β1 signaling seems to be also mediated by other pathways, different from the Smad family: the phosphoinosite-3-kinase/Akt pathway [80].
Considering the fact that the ECM has an important role in POP pathogenesis, a study from 2017 has focused on the effects of excessive mechanical stress upon human uterosacral ligament fibroblasts (hUSLFs), as well as on their overexposure to H2O2. The tissue samples were taken from 15 patients who have undergone vaginal hysterectomy for nonneoplastic pathologies and have been subjected to mechanical stress with different intensities and were also exposed to H2O2 at different concentrations. This has led to a significant decrease of the mitochondrial DNA level, as well as of ECM protein expression. It was noticed that elastin expression and several collagen precursors (COL 1A1 and COL 3A1) were inhibited, and lower H2O2 concentrations stimulated the expression of extracellular matrix proteins. This was also noticed when smaller forces were applied to the hUSLFs tissue samples. Another important observation is the fact the MMP levels had increased, whereas the TIMP expression had suffered a decline, thus favoring ECM degradation. The authors have also investigated the impact of H2O2 overexposure and sustained mechanical stress upon the Smad/TGF-β1 pathway. It was found that the expression of phosphorylated Smad2 had declined and also the levels of activated TGF-β1. Therefore, the authors have concluded that excessive mechanical stress and H2O2 overexposure interfere with Smad/TGF-β1 pathway, significantly affecting the ECM remodeling process and favoring POP [37] (Figure 1).
Another study investigated the role of TGF-β1 in POP pathogenesis. 60 patients who have undergone hysterectomy for nonmalignant pathologies have been divided in two groups, as follows: a study group (30 patients) that included only patients with POP (from stage II to stage IV) and a control group without POP. Tissue samples have been taken from the uterosacral ligaments during surgery, in order to evaluate the expression of collagen, elastin, MMP 2, MMP 9, TIMP 2, TGF-β1, and Smad. The purpose of these investigations was to establish the connection between OS inducing factors and POP pathogenesis. The authors have noticed that the collagen and elastin from the POP samples have presented important structural changes and also a significant decline of their expression compared to the control group (lower levels of COL 1A1, COL 3A1, and elastin in the study group). Differences between the study group MMPs/TIMPs expression and the control group were also found. Therefore, the POP group presented significantly higher levels of MMP 2 and MMP 9 compared to the non-POP group, as well as a lower TIMP 2 expression compared to control group, where the TIMP 2 levels were higher. In regards to the TGF-β1 expression, the study group associated lower expression rates compared to the non-POP patients. Further analysis that aimed at assessing the correlation between POP severity and TGF-β1 levels has revealed that as the POP severity increased, the TGF-β1 expression decreased. Another important hypothesis over which the authors have focused their attention is the ability of TGF-β1 to minimize the mechanical stress-induced ECM degradation. In order to investigate this theory, the authors have treated fibroblast originating from the uterosacral ligaments with various concentrations of TGF-β1 (0, 5, or 10 ng/ml) for 4 hours. Afterwards, the fibroblasts have been subjected to cyclical mechanical stress (5,333-με) for approximately 24 hours. It was found that TGF-β1-treated hUSLFs associated a significantly higher viability rated compared to those without TGF-β1 treatment. When analyzing the cell population without TGF-β1 treatment, the authors have noticed that the COL 1A1, COL 3A1, and elastin rates were significantly lower compared to the TGF-β1 treatment group, as well as higher expressions of MMP 2/MMP 9 and a significantly lower expression of TIMP 2. Therefore, they have concluded that treatment with TGF-β1 could significantly reduce mechanical stress-associated collagen and elastin degradation. Another important mechanism that was investigated in this study was the TGF-β1/Smad signaling pathway. The authors have found that hUSLFs subjected to mechanical stress have associated a significantly lower Smad2 and 3 phosphorylation rate, whereas in the TGF-β1-treated group, it was notice that treatment with TGF-β1 can significantly improve the Smad3 phosphorylation rate. TGF-β1 pretreating did not improve the Smad2 phosphorylation rate. The published results sustain the already existing data regarding the fact that mechanical stress induces molecular changes at the level of the pelvic-supportive structures, changes that can lead to POP. Another important conclusion of this study was that TGF-β1 treatment could significantly reduce the risk of these molecular changes [14].
The impact of OS because of mechanical stress has been evaluated in several clinical studies. Hong and his colleagues have assessed the impact of mechanical stress on human parametrial ligament fibroblasts (HPLFs) in terms of oxidative damage that could favor POP pathogenesis. Tissue samples have been taken from ten patients who have undergone hysterectomy. The surgery was performed for nonmalignant pathologies. The patients included in this study did not present any collagen disorders or any other pathologies that could be associated with OS. The tissue samples have been subjected to mechanical forces of variable intensities for four hours (1,333, 2,666, or 5,333-μ strains). The researchers have noticed that the mechanical forces have led to cellular morphology alterations, such as cellular atrophy, and to the weakening of the cellular junctions. These cells have also undergone a deformation process, becoming round, despite the fact that initially they were long spindle cells. In terms of ROS production under the action of mechanical stress, the authors have reported that low mechanical strains were associated with a small increase of ROS levels, these levels significantly increasing with the intensity of the mechanical stress (especially when a 5,333-μ mechanical strain was applied). Another important aspect that this study has analyzed was the correlation between the degree of mechanical stress and the apoptotic rate of HPLFs. A lower mechanical strain of 1,333-μ did not increase the cellular apoptotic rate, whereas as higher forces like 2,666 and 5,333-μ strains have led to higher apoptotic rates. The cells that have been subjected to 5,333-μ strains have suffered a fragmentation process and only half of them were nonnecrotic cells, but out of these nonnecrotic cells, up to 50% of them were apoptotic. In the group of cells that have been subjected to lower mechanical forces, the cellular fragmentation process was not so pronounced, so the percentage of the nonnecrotic cells was significantly higher, being up to 95% in the 2,666-μ strain group. The authors have explained that this high percentage of nonnecrotic cells could be explained by the short period of time the cells were exposed to those forces [36].
In a study published in 2013, Kim and his collaborators have investigated the role of OS and mitochondrial apoptosis in the pelvic organ prolapse pathogenesis. The authors have assessed the presence of several biomarkers in tissue fragments that have been taken from the uterosacral ligaments: 8-hydroxy-2-deoxyguanosine (8-OHdG; biomarker of DNA oxidative damage) and 4-hydroxy-2-nonenal (4-HNE; biomarker of lipid peroxidation). The study group included 26 advanced POP patients that have undergone hysterectomy and sacrocolpopexy, whereas the control group included 29 patients with maximum stage I POP, these patients undergoing surgery for different benign pathologies. The tissue fragments have been divided in two groups, one for Western blot analysis, and the other one for immunohistochemistry and TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridinetriphosphate nick end labeling) assay. The markers used for the evaluation of mitochondrial apoptosis were cytochrome c, cleaved capsase-3, and capsase-9. The immunohistochemical investigation of the extracted tissue fragments has revealed the presence of the OS markers in all the tissues samples, including in the fragments that have been taken from the control group. In spite of these findings, the expression of 8-OHdG and 4-HNE was significantly higher in the study group. Therefore, approximately of the analyzed tissue samples from the study group were positive for 8-OHdG and for 4-HNE, whereas in the control group, the percentages were and , respectively [44].
All of the biomarkers that have been used to evaluate the mitochondrial apoptosis have also associated significantly higher expressions in the study group compared to those in the control group, regardless of the used investigation method. The authors have reported that the increased levels of 8-OHdG and 4-HNE have also correlated with the mitochondrial apoptosis biomarkers. In terms of POP degree, the expression of 8-OHdG, 4-HNE, and cytochrome c was significantly higher in the study group samples compared to the control group, regardless of the POP stage, but the expression of caspase-3 was found to be high only in the tissue samples that came from high-grade POP patients [44].
A similar study that has investigated the role of OS in terms of collagen-associated disorders that could lead to pelvic organ prolapse was published by Liu and his colleagues. The study included 40 patients who have undergone hysterectomy, these patients being divided in two groups (study group versus control group). The study group included only POP patients (from stage II to stage IV POP), whereas the patients included in the control group did not associate POP, the surgery being done for benign pathologies. Tissue samples taken from the parametrial ligaments (uterosacral and cardinal ligaments) have been subjected to H2O2 exposure (concentrations 0.1, 0.2, 0.4, 0.6, 0.8, and 1 mM) for periods of time that ranged between four and 24 hours. OS damage was evaluated using immunohistochemistry in order to detect the 8-OHdG and 4-HNE expression, and it was found that the expression of these markers was significantly higher in the study group compared to non-POP patients. In terms of H2O2-associated toxicity, the authors have noticed that this was influenced by H2O2 concentrations, as well as by the period of time in which the tissue samples have been exposed to H2O2. The results found after a 24 hours exposure have revealed that the percentage of cell viability was significantly lower compared to a 4-hour exposure. A H2O2 concentration of 0.1 mM was associated with negligible cytotoxicity, whereas in the case of higher concentrations, the cytotoxic effect was markedly increased (0.2 mM associated a moderate to severe cytotoxic effect, while concentrations greater than 0.4 mM associated severe cytotoxicity). A similar correlation was also found in terms of cellular apoptosis and H2O2 concentration. The impact of H2O2 on the collagen metabolism was evaluated based on COL 1A1, MMP 2, TIMP 1, and TGF-β1 expression. The results obtained by the authors have revealed that as the H2O2 concentration grew, the expression of COL 1A1, TIMP 1, and TGF-β1 had registered a steady decline. In terms of MMP 2, the results have revealed that its expression had increased in parallel with the H2O2 concentration. The authors have also mentioned that lower concentrations of H2O2 had stimulated COL 1A1 synthesis, thus suggesting an anabolic effect of low-dose H2O2, whereas higher concentrations have had the opposite effect, stimulating the COL 1A1 catabolism. Considering these results, the authors have concluded that OS interferes in collagen homeostasis and metabolism, leading to molecular changes that may play a key role in POP pathogenesis [38].
The elastogenesis process is another important key point that can be affected by OS, which generates a series of molecular changes that significantly contributes to the POP pathogenesis. The assembly of the elastic fibers is a complex process that involves several steps: elastogenic cells secrete TE; TE molecules form microaggregates (coacervation process); TE monomers form larger aggregates (cross-linking process—mediated by FBLNs 4 and 5), which are deposited on microfibrils; and LOX-mediated elastic fiber assembly of the aligned and cross-linked TE aggregates [26, 34].
The implications of OS upon elastogenesis, as well as the exposure of TE to reactive nitrogen species (RNS), have raised the interest of several researchers that aimed at finding correlations between these processes and POP pathogenesis. Considering the fact that elastogenesis is usually initiated in an inflammatory context, Akhtar and his colleagues have exposed TE molecules to ONOO- and HOCl (both substances being released by macrophages and monocytes during inflammatory processes). The authors have identified several elastogenesis key points that could be affected as a result of OS. TE monomers exposed to ONOO- and HOCl have developed structural changes that significantly interfered with their assembly into elastic fibers. A drop of up to ten degrees in the coacervation temperature was noticed in the ROS/RNS TE group compared with the normal TE group, this fact significantly influencing the elastic fiber assembly process. The cross-linking phase was also affected, this process being evaluated based on desmosine levels. It was noticed that TE monomers exposed to ONOO- and HOCl have associated significant lower desmosine rates compared with the nonexposed TE molecules. Further investigations have focused on the relation between FBLN 4/FBLN 5 and the cross-linking process. Both FBLN 4 and FBLN 5 have registered a significant decline in terms of their binding capabilities to ROS/RNS-modified TE molecules, thus suggesting that ROS/RNS agents affect normal elastogenesis (Figure 1). In this study, the authors have reported that the interaction rate between FBLN 4 and ONOO-/HOCl-exposed TE had registered a decline with approximately 35% (for both agents), whereas in the case of FBLN 5, the decline rate was even higher (50%). Another important step of the elastic fibers assembly process is the interaction between TE and microfibrils. The authors have also investigated this process, analyzing the interactions between ROS/RNS-exposed TE molecules and FBN 2/MAGP 1, these two being essential components of the microfibrils. They have reported that the interaction between FBN 2 and ONOO-/HOCl-exposed TE had decreased with up to 55% and 25%, respectively. No significant differences have been reported regarding the manner in which MAGP 1 has interacted with TE exposed to ONOO-/HOCl or with normal TE molecules [34]. This study has demonstrated that both ROS and RNS agents can significantly disturb normal elastogenesis, interfering with its numerous key points and altering the integrity of the pelvic-supportive structures (Figure 1).
5. Conclusions
OS is an important factor involved in pelvic organ prolapse pathogenesis, being responsible for numerous molecular changes at the level of pelvic-supportive structures that weaken the integrity and the resistance of pelvic muscles, fascias, and ligaments, thus favoring the development of this pathology.
Sustained mechanical stress is proven to be a key factor in the appearance of pelvic organ prolapse, correlating with increased levels of free radical production and mitochondrial-induced fibroblasts apoptosis, the rate of cellular apoptosis, depending on the intensity of the mechanical stress, and the period of time the mechanical stress is applied.
Mitochondria, besides being one of the main sources of free radicals production, are also the site of their action. OS via ROS/RNS hinders the normal MMPs/TIMPs balance, favoring MMP overexpression and activity in the detriment of TIMP activity, significantly altering the collagen synthesis process. ROS/RNS interfere with the Smad/TGF-β1 pathway, this being essential for collagen homeostasis, by decreasing the Smad phosphorylation rate and furthermore the levels of activated TGF-β1. Current studies underline the potential benefits of TGF-β1 treatment in terms of reducing the collagen and elastin degradation rate.
Another important process over which the OS manifests its negative effects is elastogenesis, ROS/RNS acting at the level of its numerous key point reactions, significantly damaging the elastic fiber assembly process and therefore favoring the prolapse of the pelvic organs.
Conflicts of Interest
The authors declare that they have no conflict of interest.
The presented study will be integrated in the Ph.D. thesis of author Ph.D. student Radu Dragos Marcu.
N. Y. Siddiqui and A. L. Edenfield, "Clinical challenges in the management of vaginal prolapse," International Journal of Women's Health, vol. 6, pp. 83–94, 2014.View at: Publisher Site | Google Scholar
G. Rostaminia, P. Javadiann, and A. O'Boyle, "Parity and pelvic floor dysfunction symptoms during pregnancy and the early postpartum," Pelviperineology, vol. 36, no. 2, pp. 48–52, 2017.View at: Google Scholar
K. Nacer, O. Bratu, M. Berechet, G. Bumbu, and A. Bumbu, "Global surgical principles in the vaginal approach of advanced pelvic organ prolapse," in Proceedings of the 14th National Congress of Urogynecology and the National Conference of the Romanian Association for the Study of Pain, pp. 172–180, Eforie, 2017.View at: Google Scholar
K. H. Choi and J. Y. Hong, "Management of pelvic organ prolapse," Korean Journal of Urology, vol. 55, no. 11, pp. 693–702, 2014.View at: Publisher Site | Google Scholar
P. A. Moalli, I. S. Jones, L. A. Meyn, and H. M. Zyczynski, "Risk factors associated with pelvic floor disorders in women undergoing surgical repair," Obstetrics and Gynecology, vol. 101, no. 5, pp. 869–874, 2003.View at: Publisher Site | Google Scholar
J. E. Jelovsek, C. Maher, and M. D. Barber, "Pelvic organ prolapse," Lancet, vol. 369, no. 9566, pp. 1027–1038, 2007.View at: Publisher Site | Google Scholar
P. Dällenbach, "To mesh or not to mesh: a review of pelvic organ reconstructive surgery," International Journal of Women's Health, vol. 7, pp. 331–343, 2015.View at: Google Scholar
A. A. Ewies, F. Al-Azzawi, and J. Thompson, "Changes in extracellular matrix proteins in the cardinal ligaments of post-menopausal women with or without prolapse: a computerized immunohistomorphometric analysis," Human Reproduction, vol. 18, no. 10, pp. 2189–2195, 2003.View at: Publisher Site | Google Scholar
H. Kufaishi, M. Alarab, H. Drutz, S. Lye, and O. Shynlova, "Comparative characterization of vaginal cells derived from premenopausal women with and without severe pelvic organ prolapse," Reproductive Sciences, vol. 23, no. 7, pp. 931–943, 2016.View at: Publisher Site | Google Scholar
K. V. Reddy and S. S. Mangale, "Integrin receptors: the dynamic modulators of endometrial function," Tissue & Cell, vol. 35, no. 4, pp. 260–273, 2003.View at: Publisher Site | Google Scholar
L. A. Martinez-Lemus, X. Wu, E. Wilson et al., "Integrins as unique receptors for vascular control," Journal of Vascular Research, vol. 40, no. 3, pp. 211–233, 2003.View at: Publisher Site | Google Scholar
B. Gabriel, D. Denschlag, H. Göbel et al., "Uterosacral ligament in postmenopausal women with or without pelvic organ prolapse," International Urogynecology Journal and Pelvic Floor Dysfunction, vol. 16, no. 6, pp. 475–479, 2005.View at: Publisher Site | Google Scholar
Y. Hu, R. Wu, H. Li, Y. Gu, and W. Wei, "Expression and significance of metalloproteinase and collagen in vaginal wall tissues of patients with pelvic organ prolapse," Annals of Clinical and Laboratory Science, vol. 47, no. 6, pp. 698–705, 2017.View at: Google Scholar
C. Liu, Y. Wang, B. S. Li et al., "Role of transforming growth factor β-1 in the pathogenesis of pelvic organ prolapse: a potential therapeutic target," International Journal of Molecular Medicine, vol. 40, no. 2, pp. 347–356, 2017.View at: Publisher Site | Google Scholar
J. T. Goh, "Biomechanical and biochemical assessments for pelvic organ prolapse," Current Opinion in Obstetrics & Gynecology, vol. 15, no. 5, pp. 391–394, 2003.View at: Publisher Site | Google Scholar
X. Wang, Y. Li, J. Chen, X. Guo, H. Guan, and C. Li, "Differential expression profiling of matrix metalloproteinases and tissue inhibitors of metalloproteinases in females with or without pelvic organ prolapse," Molecular Medicine Reports, vol. 10, no. 4, pp. 2004–2008, 2014.View at: Publisher Site | Google Scholar
H. J. Ra and W. C. Parks, "Control of matrix metalloproteinase catalytic activity," Matrix Biology, vol. 26, no. 8, pp. 587–596, 2007.View at: Publisher Site | Google Scholar
D. Bourboulia and W. G. Stetler-Stevenson, "Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): positive and negative regulators in tumor cell adhesion," Seminars in Cancer Biology, vol. 20, no. 3, pp. 161–168, 2010.View at: Publisher Site | Google Scholar
H. NAGASE, R. VISSE, and G. MURPHY, "Structure and function of matrix metalloproteinases and TIMPs," Cardiovascular Research, vol. 69, no. 3, pp. 562–573, 2006.View at: Publisher Site | Google Scholar
C. Scheau, I. A. Badarau, R. Costache et al., "The role of matrix metalloproteinases in the epithelial-mesenchymal transition of hepatocellular carcinoma," Analytical Cellular Pathology, vol. 2019, Article ID 9423907, 10 pages, 2019.View at: Publisher Site | Google Scholar
C. Amălinei, I. D. Căruntu, S. E. Giuşcă, and R. A. Bălan, "Matrix metalloproteinases involvement in pathologic conditions," Romanian Journal of Morphology and Embryology, vol. 51, no. 2, pp. 215–228, 2010.View at: Google Scholar
B. H. Chen, Y. Wen, H. Li, and M. L. Polan, "Collagen metabolism and turnover in women with stress urinary incontience and pelvic prolapse," International Urogynecology Journal and Pelvic Floor Dysfunction, vol. 13, no. 2, pp. 80–87, 2002.View at: Publisher Site | Google Scholar
J. M. Wu, A. G. Visco, E. A. Grass et al., "Matrix metalloproteinase-9 genetic polymorphisms and the risk for advanced pelvic organ prolapse," Obstetrics and Gynecology, vol. 120, no. 3, pp. 587–593, 2012.View at: Publisher Site | Google Scholar
B. Gabriel, D. Watermann, K. Hancke et al., "Increased expression of matrix metalloproteinase 2 in uterosacral ligaments is associated with pelvic organ prolapse," International Urogynecology Journal and Pelvic Floor Dysfunction, vol. 17, no. 5, pp. 478–482, 2006.View at: Publisher Site | Google Scholar
L. Campeau, I. Gorbachinsky, G. H. Badlani, and K. E. Andersson, "Pelvic floor disorders: linking genetic risk factors to biochemical changes," British Journal of Urology International, vol. 108, no. 8, pp. 1240–1247, 2011.View at: Publisher Site | Google Scholar
B. H. Zhao and J. H. Zhou, "Decreased expression of elastin, fibulin-5 and lysyl oxidase-like 1 in the uterosacral ligaments of postmenopausal women with pelvic organ prolapse," The Journal of Obstetrics and Gynaecology Research, vol. 38, no. 6, pp. 925–931, 2012.View at: Publisher Site | Google Scholar
G. Deslee, J. C. Woods, C. M. Moore et al., "Elastin expression in very severe human COPD," The European Respiratory Journal, vol. 34, no. 2, pp. 324–331, 2009.View at: Publisher Site | Google Scholar
I. Maeda, S. Kishita, Y. Yamamoto et al., "Immunochemical and immunohistochemical studies on distribution of elastin fibres in human atherosclerotic lesions using a polyclonal antibody to elastin-derived hexapeptide repeat," Journal of Biochemistry, vol. 142, no. 5, pp. 627–631, 2007.View at: Publisher Site | Google Scholar
H. M. Kagan and W. Li, "Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell," Journal of Cellular Biochemistry, vol. 88, no. 4, pp. 660–672, 2003.View at: Publisher Site | Google Scholar
X. Liu, Y. Zhao, J. Gao et al., "Elastic fiber homeostasis requires lysyl oxidase-like 1 protein," Nature Genetics, vol. 36, no. 2, pp. 178–182, 2004.View at: Publisher Site | Google Scholar
J. T. Cirulis, C. M. Bellingham, E. C. Davis et al., "Fibrillins, fibulins, and matrix-associated glycoprotein modulate the kinetics and morphology ofin VitroSelf-Assembly of a recombinant elastin-like Polypeptide†," Biochemistry, vol. 47, no. 47, pp. 12601–12613, 2008.View at: Publisher Site | Google Scholar
B. C. Trask, T. Broekelmann, T. M. Ritty, T. M. Trask, C. Tisdale, and R. P. Mecham, "Posttranslational modifications of microfibril associated glycoprotein-1 (MAGP-1)," Biochemistry, vol. 40, no. 14, pp. 4372–4380, 2001.View at: Publisher Site | Google Scholar
P. G. Drewes, H. Yanagisawa, B. Starcher et al., "Pelvic organ prolapse in fibulin-5 knockout Mice," The American Journal of Pathology, vol. 170, no. 2, pp. 578–589, 2007.View at: Publisher Site | Google Scholar
K. Akhtar, T. J. Broekelmann, M. Miao et al., "Oxidative and nitrosative modifications of tropoelastin prevent elastic fiber assembly in vitro," The Journal of Biological Chemistry, vol. 285, no. 48, pp. 37396–37404, 2010.View at: Publisher Site | Google Scholar
N. Sampson, P. Berger, and C. Zenzmaier, "Redox signaling as a therapeutic target to inhibit myofibroblast activation in degenerative fibrotic disease," BioMed Research International, vol. 2014, Article ID 131737, 14 pages, 2014.View at: Publisher Site | Google Scholar
S. Hong, L. Hong, D. Wu et al., "Oxidative damage to human parametrial ligament fibroblasts induced by mechanical stress," Molecular Medicine Reports, vol. 12, no. 4, pp. 5342–5348, 2015.View at: Publisher Site | Google Scholar
Q. Zhang, C. Liu, S. Hong et al., "Excess mechanical stress and hydrogen peroxide remodel extracellular matrix of cultured human uterosacral ligament fibroblasts by disturbing the balance of MMPs/TIMPs via the regulation of TGF-β1 signaling pathway," Molecular Medicine Reports, vol. 15, no. 1, pp. 423–430, 2017.View at: Publisher Site | Google Scholar
C. Liu, Q. Yang, G. Fang et al., "Collagen metabolic disorder induced by oxidative stress in human uterosacral ligament-derived fibroblasts: a possible pathophysiological mechanism in pelvic organ prolapse," Molecular Medicine Reports, vol. 13, no. 4, pp. 2999–3008, 2016.View at: Publisher Site | Google Scholar
M. Fransen, M. Nordgren, B. Wang, and O. Apanasets, "Role of peroxisomes in ROS/RNS-metabolism: implications for human disease," Biochimica et Biophysica Acta, vol. 1822, no. 9, pp. 1363–1373, 2012.View at: Publisher Site | Google Scholar
P. Rajendran, N. Nandakumar, T. Rengarajan et al., "Antioxidants and human diseases," Clinica Chimica Acta, vol. 436, pp. 332–347, 2014.View at: Publisher Site | Google Scholar
K. Sinha, J. Das, P. B. Pal, and P. C. Sil, "Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis," Archives of Toxicology, vol. 87, no. 7, pp. 1157–1180, 2013.View at: Publisher Site | Google Scholar
G. Pizzino, N. Irrera, M. Cucinotta et al., "Oxidative stress: harms and benefits for human health," Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 8416763, 13 pages, 2017.View at: Publisher Site | Google Scholar
M. Hayyan, M. A. Hashim, and I. M. AlNashef, "Superoxide ion: generation and chemical implications," Chemical Reviews, vol. 116, no. 5, pp. 3029–3085, 2016.View at: Publisher Site | Google Scholar
E. J. Kim, N. Chung, S. H. Park et al., "Involvement of oxidative stress and mitochondrial apoptosis in the pathogenesis of pelvic organ prolapse," The Journal of Urology, vol. 189, no. 2, pp. 588–594, 2013.View at: Publisher Site | Google Scholar
J. S. Sousa, E. D'Imprima, and J. Vonck, "Mitochondrial respiratory chain complexes," Subcellular Biochemistry, vol. 87, pp. 167–227, 2018.View at: Publisher Site | Google Scholar
R. J. Mailloux, R. Bériault, J. Lemire et al., "The tricarboxylic acid cycle, an ancient metabolic network with a novel twist," PLoS One, vol. 2, no. 8, article e690, 2007.View at: Publisher Site | Google Scholar
A. Devin and M. Rigoulet, "Mechanisms of mitochondrial response to variations in energy demand in eukaryotic cells," American Journal of Physiology Cell Physiology, vol. 292, no. 1, pp. C52–C58, 2007.View at: Publisher Site | Google Scholar
A. Salminen, A. Kauppinen, M. Hiltunen, and K. Kaarniranta, "Krebs cycle intermediates regulate DNA and histone methylation: epigenetic impact on the aging process," Ageing Research Reviews, vol. 16, pp. 45–65, 2014.View at: Publisher Site | Google Scholar
R. K. Porter and M. D. Brand, "Mitochondrial proton conductance and H+/0 ratio are independent of electron transport rate in isolated hepatocytes," The Biochemical Journal, vol. 310, no. 2, pp. 379–382, 1995.View at: Publisher Site | Google Scholar
R. Z. Zhao, S. Jiang, L. Zhang, and Z. B. Yu, "Mitochondrial electron transport chain, ROS generation and uncoupling (review)," International Journal of Molecular Medicine, vol. 44, no. 1, pp. 3–15, 2019.View at: Publisher Site | Google Scholar
L. D. Zorova, V. A. Popkov, E. Y. Plotnikov et al., "Mitochondrial membrane potential," Analytical Biochemistry, vol. 552, pp. 50–59, 2018.View at: Publisher Site | Google Scholar
R. Guo, S. Zong, M. Wu, J. Gu, and M. Yang, "Architecture of human mitochondrial respiratory megacomplex I2III2IV2," Cell, vol. 170, no. 6, pp. 1247–1257.e12, 2017.View at: Publisher Site | Google Scholar
A. J. Jones, J. N. Blaza, F. Varghese, and J. Hirst, "Respiratory complex I inBos taurusandParacoccus denitrificansPumps four protons across the membrane for every NADH oxidized," The Journal of Biological Chemistry, vol. 292, no. 12, pp. 4987–4995, 2017.View at: Publisher Site | Google Scholar
A. J. Kowaltowski, N. C. de Souza-Pinto, R. F. Castilho, and A. E. Vercesi, "Mitochondria and reactive oxygen species," Free Radical Biology and Medicine, vol. 47, no. 4, pp. 333–343, 2009.View at: Publisher Site | Google Scholar
D. J. Pagliarini and J. Rutter, "Hallmarks of a new era in mitochondrial biochemistry," Genes & Development, vol. 27, no. 24, pp. 2615–2627, 2013.View at: Publisher Site | Google Scholar
R. Guo, J. Gu, S. Zong, M. Wu, and M. Yang, "Structure and mechanism of mitochondrial electron transport chain," Biomedical Journal, vol. 41, no. 1, pp. 9–20, 2018.View at: Publisher Site | Google Scholar
S. Orrenius, V. Gogvadze, and B. Zhivotovsky, "Mitochondrial oxidative stress: implications for cell death," Annual Review of Pharmacology and Toxicology, vol. 47, no. 1, pp. 143–183, 2007.View at: Publisher Site | Google Scholar
A. S. Hoekstra and J. P. Bayley, "The role of complex II in disease," Biochimica et Biophysica Acta, vol. 1827, no. 5, pp. 543–551, 2013.View at: Publisher Site | Google Scholar
G. Cecchini, "Respiratory complex II: role in cellular physiology and disease," Biochimica et Biophysica Acta, vol. 1827, no. 5, pp. 541-542, 2013.View at: Publisher Site | Google Scholar
M. D. Brand, "The sites and topology of mitochondrial superoxide production," Experimental Gerontology, vol. 45, no. 7-8, pp. 466–472, 2010.View at: Publisher Site | Google Scholar
N. S. Chandel, "Mitochondrial regulation of oxygen sensing," Advances in Experimental Medicine and Biology, vol. 661, pp. 339–354, 2010.View at: Publisher Site | Google Scholar
S. Soberanes, D. Urich, C. M. Baker et al., "Mitochondrial complex III-generated oxidants activate ASK1 and JNK to induce alveolar epithelial cell death following exposure to particulate matter air pollution," The Journal of Biological Chemistry, vol. 284, no. 4, pp. 2176–2186, 2009.View at: Publisher Site | Google Scholar
A. I. Jonckheere, J. A. M. Smeitink, and R. J. T. Rodenburg, "Mitochondrial ATP synthase: architecture, function and pathology," Journal of Inherited Metabolic Disease, vol. 35, no. 2, pp. 211–225, 2012.View at: Publisher Site | Google Scholar
M. D. Brand, "Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling," Free Radical Biology and Medicine, vol. 100, pp. 14–31, 2016.View at: Publisher Site | Google Scholar
M. Valko, D. Leibfritz, J. Moncol, M. T. D. Cronin, M. Mazur, and J. Telser, "Free radicals and antioxidants in normal physiological functions and human disease," The International Journal of Biochemistry & Cell Biology, vol. 39, no. 1, pp. 44–84, 2007.View at: Publisher Site | Google Scholar
R. O. Poyton, K. A. Ball, and P. R. Castello, "Mitochondrial generation of free radicals and hypoxic signaling," Trends in Endocrinology and Metabolism, vol. 20, no. 7, pp. 332–340, 2009.View at: Publisher Site | Google Scholar
V. S. Khodade, M. Sharath Chandra, A. Banerjee et al., "Bioreductively activated reactive oxygen species (ROS) generators as MRSA inhibitors," ACS Medical Chemistry Letters, vol. 5, no. 7, pp. 777–781, 2014.View at: Publisher Site | Google Scholar
M. L. Circu and T. Y. Aw, "Reactive oxygen species, cellular redox systems, and apoptosis," Free Radical Biology and Medicine, vol. 48, no. 6, pp. 749–762, 2010.View at: Publisher Site | Google Scholar
E. Migliaccio, M. Giorgio, and P. G. Pelicci, "Apoptosis and aging: role of p66ShcRedox protein," Antioxidants and Redox Signaling, vol. 8, no. 3-4, pp. 600–608, 2006.View at: Publisher Site | Google Scholar
A. Y. Andreyev, Y. E. Kushnareva, and A. A. Starkov, "Mitochondrial metabolism of reactive oxygen species," Biochemistry, vol. 70, no. 2, pp. 200–214, 2005.View at: Publisher Site | Google Scholar
A. Y. Andreyev, Y. E. Kushnareva, A. N. Murphy, and A. A. Starkov, "Mitochondrial ROS metabolism: 10 years later," Biochemistry (Moscow), vol. 80, no. 5, pp. 517–531, 2015.View at: Publisher Site | Google Scholar
A. D. N. J. De Grey, "HO2•: the forgotten radical," DNA and Cell Biology, vol. 21, no. 4, pp. 251–257, 2002.View at: Publisher Site | Google Scholar
Y. Teshima, N. Takahashi, L. C. Thuc et al., "High-glucose condition reduces cardioprotective effects of insulin against mechanical stress-induced cell injury," Life Sciences, vol. 87, no. 5-6, pp. 154–161, 2010.View at: Publisher Site | Google Scholar
S. Y. Lin, Y. T. Tee, S. C. Ng, H. Chang, P. P. Lin, and G. D. Chen, "Changes in the extracellular matrix in the anterior vagina of women with or without prolapse," International Urogynecology Journal and Pelvic Floor Dysfunction, vol. 18, no. 1, pp. 43–48, 2007.View at: Publisher Site | Google Scholar
M. Valko, C. J. Rhodes, J. Moncol, M. Izakovic, and M. Mazur, "Free radicals, metals and antioxidants in oxidative stress induced cancer," Chemico-Biological Interactions, vol. 160, no. 1, pp. 1–40, 2006.View at: Publisher Site | Google Scholar
M. Neagu, C. Constantin, I. D. Popescu et al., "Inflammation and metabolism in cancer cell – mitochondria key player," Frontiers in Oncology, vol. 9, p. 348, 2019.View at: Publisher Site | Google Scholar
A. Moustakas and C. H. Heldin, "Non-Smad TGF-β signals," Journal of Cell Science, vol. 118, no. 16, pp. 3573–3584, 2005.View at: Publisher Site | Google Scholar
Y. Niu, T. Xie, K. Ge, Y. Lin, and S. Lu, "Effects of extracellular matrix glycosylation on proliferation and apoptosis of human dermal fibroblasts via the receptor for advanced glycosylated end products," The American Journal of Dermatopathology, vol. 30, no. 4, pp. 344–351, 2008.View at: Publisher Site | Google Scholar
A. M. Gressner and R. Weiskirchen, "Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-β as major players and therapeutic targets," Journal of Cellular and Molecular Medicine, vol. 10, no. 1, pp. 76–99, 2006.View at: Publisher Site | Google Scholar
N. Trager, A. Smith, G. Wallace IV et al., "Effects of a novel orally administered calpain inhibitor SNJ-1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis," Journal of Neurochemistry, vol. 130, no. 2, pp. 268–279, 2014.View at: Publisher Site | Google Scholar

subset: commoncrawl


text:
Please use this identifier to cite or link to this item:
|Duration of anaesthetic exposure in early childhood and long-term language and cognitive ability
|Ing, C
Hegarty, MK
Perkins, JW
Whitehouse, AJO
Li, G
Sun, M
Andrews, H
Sun, LS
von Ungern-Sternberg, BS
|anaesthetic neurotoxicity
paediatric Anaesthesia
|Issue Date:
|Ing C, Hegarty MK, Perkins JW, Whitehouse AJO, Li G, Sun M, Andrews H, Sun LS, von Ungern-Sternberg BS. Duration of anaesthetic exposure in early childhood and long-term language and cognitive ability. Br J Anaesth. 2017;119(3):532-540.
|BACKGROUND: The anaesthetic dose causing neurotoxicity in animals has been evaluated, but the relationship between duration of volatile anaesthetic (VA) exposure and neurodevelopment in children remains unclear. METHODS: Data were obtained from the Western Australian Pregnancy Cohort (Raine) Study, with language (Clinical Evaluation of Language Fundamentals: Receptive [CELF-R] and Expressive [CELF-E] and Total [CELF-T]) and cognition (Coloured Progressive Matrices [CPM]) assessed at age 10 yr. Medical records were reviewed, and children divided into quartiles based on total VA exposure duration before age three yr. The association between test score and exposure duration quartile was evaluated using linear regression, adjusting for patient characteristics and comorbidity. RESULTS: Of 1622 children with available test scores, 148 had documented VA exposure and were split into the following quartiles: ≤25, >25 to ≤35, >35 to ≤60 and >60 min. Compared with unexposed children, CELF-T scores for children in the first and second quartiles did not differ, but those in the third and fourth quartiles had significantly lower scores ([3 rd quartile - Unexposed] -5.3; 95% confidence interval [CI], (-10.2 - -0.4), [4 th quartile - Unexposed] -6.2; 95% CI, (-11.6 - -0.9). CELF-E showed similar findings, but significant differences were not found in CELF-R or CPM for any quartile. CONCLUSIONS: Children with VA exposures ≤35 min did not differ from unexposed children, but those with exposures >35 min had lower total and expressive language scores. It remains unclear if this is a dose-response relationship, or if children requiring longer exposures for longer surgeries have other clinical reasons for lower scores.
|PubMed URL:
|Journal Title:
|British journal of anaesthesia
|Journal Article
|Australian and New Zealand College of Anaesthetists
|Appears in Collections:
|Scholarly and Clinical
Show full item record
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.


text:
In most cases, you will often have several ways of doing something. As much as all the tools can do the task at hand, many are times when one is better than others. So, if easy screen capture is one of the options, when is it best to choose it over the rest? That's a great question and having the answer is a game-changer. That's why this discussion focuses on when to go for this feature. Check it out!
When Saving Content
When the content you need to save exists in various formats, easy screen capture is ideal for storing it. After all, it can capture photo and text formats all at once. Consequently, you need not save every type individually, saving a lot of time besides promoting easy access later. It will surely save the day if you want to save the exact content.
Explaining an Issue
How you explain, a problem plays a considerable role in determining the solution that will work best to solve that issue. What better way to do that, other than capturing the screen that shows the exact problem? That's why easy screen capture is often recommended when reporting an issue to, let's say, an IT technician. Since digital problems are hard to explain, you let a screen capture do all the talking. Consequently, much time that could have been spent explaining a single issue is saved, no doubt.
Describing a Solution
Once the problem is identified, and the concerned person has a solution, it is essential to share it with the affected party. Unless the latter understands the solution shared, the problem remains unsolved. To save time and effort, go ahead and use easy screen capture to capture an image of that solution. Thanks to the texts, and images, you can rest assured that someone will easily understand it despite the lack of expertise in the field.
Creating Various Types of Content
Other than saving content, a need to create it may also arise. If the content covers comparisons, products reviews, guides, tutorials, or demonstrations, do not hesitate to consider the easy screen capture to create it. They make it easy for you to illustrate things in a way that people understand easily. It also makes it easy to combine various types of content all in one place. Images and texts are a combination that works incredibly well as far as content is concerned.
For instance, if you want to guide your customer on carrying out a specific task, screen captures make it crystal clear. The use of social media to reach out to customers is increasing. If you plan to create memes for that purpose, this is a method that will never disappoint.
Creating Presentations
Last but not least, easy screen capture comes in handy when creating presentations. Whether you are presenting to a client or management, a screen capture leaves an impression as it perfectly shows what you want to share.
So, if you find yourself in a situation that demands such tasks, don't hesitate to settle for easy screen capture. It clearly explains a situation leaving no room for speculation or assumption.
An author of Namaste UI, published several articles focused on blogging, business, web design & development, e-commerce, finance, health, lifestyle, marketing, social media, SEO, travel.
For any types of queries, contact us on info[at]namasteui.com.


text:
Guest Reviews
Overall Experience
It's hard to leave your best buddy at home when you're traveling for extended periods, so we provide a pet friendly experience. Restrictions and fees apply.
Whether you are booking suites for a family reunion or suites for your company's training needs, Candlewood Suites hotels can accommodate your group.
Workout whenever you want: Candlewood Gym always has an open door and lots of aerobic and cardio equipment to make it easier to stick to your exercise routine, no sweat.
The IHG Green Engage system is an online tool that gives our hotels the means to measure their day-to-day environmental impact.
Overall Experience
January 20, 2023
Very polite and warm staff. I live in Ms and work on the road in La. These are most kind people I've ever met.
ByU destroy item
January 09, 2023
I book Thursday til Sunday. Friday morning my key doesn't work and my personal items thrown away while I'm still under reservation
December 30, 2022
1st stay only the bed was a problem. Each stay after the first one got worse until after the 4th stay I decided to no longer stay at this hotel.
December 28, 2022
Price was decent but the hotel needs a major update. They didn't have the room we booked even though there were literally barely any guests at the hotel and when we brought it up to staff, she was rude and condescending. This was the same woman who I spoke to on the phone prior to booking who was also very condescending when I asked about the pet policy.
Does Candlewood Suites Alexandria offer free parking?
Yes, Candlewood Suites Alexandria offers complimentary parking for hotel guests.
Does this hotel have in-room kitchens?
Candlewood Suites Alexandria offers fully furnished in-room kitchens in all rooms. Our full kitchens have everything you need to cook your own meals while traveling. Visit our Amenities page for more details.
How much is parking at Candlewood Suites Alexandria?
Complimentary parking is available at Candlewood Suites Alexandria for hotel guests.
Can I cancel my booking at Candlewood Suites Alexandria for a full refund?
Yes, when you book your stay at Candlewood Suites Alexandria direct with IHG, choose one of our flexible rates which include the flexibility to change or cancel your reservation at no charge. For full details, refer to our Travel Advisory details.
Does Candlewood Suites Alexandria have a pool?
No, Candlewood Suites Alexandria does not have a pool.
What are the check-in and check-out times for Candlewood Suites Alexandria?
Check-in at Candlewood Suites Alexandria is from 3:00 PM, and check-out time is 11:00 AM. Contact the hotel directly for options available for early check-in or late check-out.
Does Candlewood Suites Alexandria offer free Wi-Fi?
Yes, the Candlewood Suites Alexandria offers free WiFi!
Does Candlewood Suites Alexandria have a restaurant on site?
No, there is no on site restaurant at Candlewood Suites Alexandria.
Is there a fitness center at Candlewood Suites Alexandria?
Yes, there is an onsite fitness center at Candlewood Suites Alexandria.
How much does it cost to stay at Candlewood Suites Alexandria?
Rates for accommodations at Candlewood Suites Alexandria vary by season. For your rate options, please input your dates.
How many rooms does the Candlewood Suites Alexandria have?
The Candlewood Suites Alexandria has 80 guest rooms. Enter your dates to view available rooms for your stay.
Can I bring my pet to Candlewood Suites Alexandria?
Pets are welcome at Candlewood Suites Alexandria. Our Pet Policy: A nonrefundable fee charged not to exceed 150.00. Fee pertains to the room. Not a nightly fee nor a "per pet" fee. Amount varies by length of stay. 1 to 6 Nights is 25USD 7 to 14 Nights is 100USD 15 plus Nights 150USD.


text:
Branches exist to meet the needs of members, and as those needs change, credit unions will build more branches, tear them down, or remodel them to fit member expectations.
This week, CreditUnions.com provides examples of credit unions modernizing their existing branching footprint as well as research detailing virtual and physical channel trends.
Mountain America Credit Union has been losing cash since it began using analytics and forecasting software across its far-flung branch network. And that's a good thing.
The big Utah credit union has reduced its cash inventories by 20% and customized its cash needs all the way down to specific denominations in the eight years since it began using the technology.
It's been part of a strategy that has helped the credit union post better-than-peer results in metrics such as efficiency ratios and return on assets. And yet, it's still learning how to optimize its understanding of and confidence in the system. Read more in A Strategy To Manage Cash And Serve Members by Callahan senior writer Marc Rapport.
Mobile payments, online loan applications, remote deposit capture, and more. The world of financial services is changing, with consumers demanding an array of products and services virtually as well as in the branch.
Even as the credit union branch network grows, online delivery channels are giving members 24/7 access to their finances. Yet, differing resources and member preferences mean not all credit unions are interested in implementing the same delivery channels and online transaction capabilities.
To see how in today's world of same-day service and immediate gratification, 4 credit unions are using new delivery channels and transaction capabilities to exceed member expectation, read 4 Ways To Deliver A Superior Experience In The Virtual World by Callahan Associate Editor Erik Payne.
Data from Callahan's Peer-to-Peer and Mortgage Analyzer tools reveals where credit unions are building out their branch networks and where they are taking locations away. Read more about this in our Graphic Of The Week, Branching By The Numbers.
Credit unions make financial services accessible and affordable for millions of members. That mission remains constant from credit union to credit union, from coast to coast, and even from country to country.
In late December, Pentagon Federal Credit Union opened its second Puerto Rico-based branch. The first, acquired through a merger with the former Fort Buchanan Federal Credit Union in 2008, is located on the military instillation and requires base access.
To see why the credit union opened its new branch and what technology it implemented, read How PenFed Improved Its Branch Experience by Erik Payne.
The future of the branch has been greatly debated and its death greatly exaggerated. According to Callahan & Associates' annual Credit Union Directory, credit unions actually added to the number of branches nationwide by 2% in the 12-month period ending June 2015.
But the raw numbers don't tell the whole story. Each credit union, in fact, has its own story, its own branching strategy, its own approach to high-tech, high-touch service that blends the old and the new. To read but a few of these stories, here's How 4 Credit Unions Beat The Branch Doldrums by Marc Rapport.
Happy Reading!