Induced Tissue Injury Research Articles

Unveiling advanced strategies for therapeutic stem cell interventions in severe burn injuries: a comprehensive review.

This comprehensive review explores the complex terrain of stem cell therapies as a potential therapeutic frontier in the healing of complicated burn wounds. Serious tissue damage, impaired healing processes, and possible long-term consequences make burn wounds a complex problem. An in-depth review is required since, despite medical progress, existing methods for treating severe burn wounds have significant limitations. Burn wounds are difficult to heal because they cause extensive tissue damage. The challenges of burn injury-induced tissue regeneration and functional recovery are also the subject of this review. Although there is a lot of promise in current stem cell treatments, there are also some limitations with scalability, finding the best way to transport the cells, and finding consistent results across different types of patients. To shed light on how to improve stem cell interventions to heal severe burn wounds, this review covers various stem cell applications in burn wounds and examines these obstacles. To overcome these obstacles, one solution is to enhance methods of stem cell distribution, modify therapies according to the severity of the burn, and conduct more studies on how stem cell therapy affects individual patients. Novel solutions may also be possible through the combination of cutting-edge technologies like nanotechnology and biotechnology. This review seeks to increase stem cell interventions by analyzing present challenges and suggesting strategic improvements. The goal is to provide a more effective and tailored way to repair serious burn wounds.

Damage sensing through TLR9 Regulates Inflammatory and Antiviral Responses During Influenza Infection.

Host response aimed at eliminating the infecting pathogen, as well as the pathogen itself, can cause tissue injury. Tissue injury leads to the release of a myriad of cellular components including mitochondrial DNA, which the host senses through pattern recognition receptors. How the sensing of tissue injury by the host shapes the anti-pathogen response remains poorly understood. In this study, we utilized mice that are deficient in toll-like receptor-9 (TLR9), which binds to unmethylated CpG DNA sequences such as those present in bacterial and mitochondrial DNA. To avoid direct pathogen sensing by TLR9, we utilized the influenza virus, which lacks ligands for TLR9, to determine how damage sensing by TLR9 contributes to anti-influenza immunity. Our data show that TLR9-mediated sensing of tissue damage promotes an inflammatory response during early infection, driven by the epithelial and myeloid cells. Along with the diminished inflammatory response, the absence of TLR9 led to impaired viral clearance manifested as a higher and prolonged influenza components in myeloid cells including monocytes and macrophages rendering them highly inflammatory. The persistent inflammation driven by infected myeloid cells led to persistent lung injury and impaired recovery in influenza-infected TLR9-/- mice. Further, we show elevated TLR9 activation in the plasma samples of patients with influenza and its association with the disease severity in hospitalized patients, demonstrating its clinical relevance. Overall, we demonstrate an essential role of damage sensing through TLR9 in promoting anti-influenza immunity and inflammatory response.

#2884 Dose-dependent EGR1 expression in the rat renal medulla after chronic NSAID treatment

Abstract Background and Aims Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in clinical medicine. Chronic use of NSAIDs is associated with reduced renal medullary blood flow, potentially causing severe and irreversible damage including papilla necrosis. We have previously demonstrated that chronic hyperosmolar injury in the renal medulla induces the expression of pro-fibrotic TGF-beta1 and EGR1. However, the impact of chronic NSAID treatment on EGR1 and pro-fibrotic factors in renal cortex and medulla remains unexplored. Thus, we aimed to analyze the effects of chronic NSAID treatment in the rat renal medulla. Method Male Wistar rats (250-260 grams) were orally treated twice daily for two weeks with various NSAIDs: indomethacin (IND, 2 mg/kg), naproxen (NAP, 10 or 20 mg/kg), celecoxib (CEL, 10 and 30 mg/kg), or vehicle (1% hydroxyethylcellulose). Left kidney was removed for histology and immunohistochemistry, the right kidney medulla was separated for mRNA analysis. Kruskal-Wallis test was performed for statistical analysis. Results NSAIDs caused significant tubular dilatation in all treated groups except IND. CEL (10, 30 mg/kg) and NAP (10 mg/kg) markedly increased epithelial atrophy. NAP 10 and 30 mg/kg induced a dose-dependent, 2-fold and 3.2-fold TIMP1 mRNA over-expression, respectively. Only NAP 20 mg/kg induced significant, 2.5-fold EGR1 mRNA expression. Both IND and CEL increased a 2-fold EGR1 protein expression in the medulla, but NAP induced a dose-dependent 5- and 10-fold increase of EGR1 protein. Conclusion Our study show that EGR1 and TIMP1 might play an important role in the development of NSAID induced tissue injury in the rat renal medulla. Further studies are needed to shed light on the molecular pathogenesis.

End-ischemic pharmacological cocktail treatment to mitigate rewarming/reperfusion injury

Increasing shortage of donor organs leads to the acceptance of less than optimal grafts for transplantation, up to and including organs donated after circulatory standstill of the donor.Therefore, protective strategies and pharmacological interventions destined to reduce ischemia induced tissue injury are considered a worthwhile focus of research.The present study evaluates the potential of a multidrug pharmacological approach as single flush at the end of static preservation to protect the liver from reperfusion injury.Livers were retrieved from male Wistar rats 20 min after cardiac standstill. The organs were cold stored for 18 h, flushed with 20 ml of saline, kept at room temperature for 20 min, and reperfused at 37 °C with oxygenated Williams E solution. In half of the cases, the flush solution was supplemented with a cocktail containing metformin, bucladesine and cyclosporin A.Upon reperfusion, treated livers disclosed a massive mitigation of hepatic release of alanine aminotransferase and aspartate aminotransferase, along with a significant approximately 50 % reduction of radical mediated lipid peroxidation, caspase activation and release of TNF-alpha.Even after preceding cold preservation, a pharmacological cocktail given as single flush is capable to mitigate manifestations of reperfusion injury in the present model.

Serum Proteins Infer Molecular Protection Against Inflammation in Weddell Seal (Leptonychotes weddellii) Blood

Weddell seals ( Leptonychotes weddellii) are elite divers able to dive up to 900 meters deep and remain submerged for over 90 minutes. Weddell seals have a dramatic dive response to allow for longer, deeper dives including intense bradycardia and constriction of blood vessels, especially those supplying peripheral or visceral organs. Vasoconstriction, hypo-perfusion and subsequent re-oxygenation upon surfacing is known to induce tissue injury in terrestrial mammals via inflammation. Previous work interrogating the Weddell seal’s innate immune system suggested a component in the seal’s blood serum that protects against inflammation. We are using a mouse macrophage (RAW 264.7) cell model to characterize components of the seal’s blood that are anti-inflammatory to lipopolysaccharide (LPS). When exposed to 10 ng/mL LPS, RAW cells supplemented with deproteinated serum from adult Weddell seals lose their protection against inflammation, having 11-fold greater induction of interleukin-6 (IL-6) mRNA expression after a 6-h exposure compared to RAW cells supplemented with intact seal serum (T=3.29, p=0.01). To determine whether anti-inflammatory capacity of serum is innately present in Weddell seals or whether it is acquired in conjunction with development of diving capacity, we compared the protective effects of adult Weddell seal serum against serum from Weddell seal pups collected at approximately their age of weaning, when they had begun diving activities but do not yet dive deep. Following exposure to 10 ng/mL LPS, IL-6 expression was 69% lower in RAW cells supplemented with serum from adult seals compared to those supplemented with serum from pups (T=8.41, p=0.002), suggesting that ontogeny or diving behavior contributes to the development of anti-inflammatory serum. Analysis of adult (n=12) and pup (n=11) serum proteomes revealed a single protein, colony stimulating factor 2 receptor subunit beta (CSF2RB), with a 24-fold higher abundance in adults (PFDR<0.0001). CSF2RB is a pleiotropic cell surface receptor subunit with known functions in innate immunity, erythropoiesis, as well as tissue protection. Therefore, we hypothesize that it plays a role in the anti-inflammatory protection observed in adult seals. Defining the mechanism of action for this protein in seal serum could identify a protective adaptation that facilitates deep and long dives. In a broader context, lessons learned from an extreme diving mammals may identify anti-inflammatory strategies with new clinical relevance. NSF #1921491; #1853326; #2337400. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of prior axonal injury on subsequent injury during brain tissue stretching – A mesoscale computational approach

Epidemiology studies of traumatic brain injury (TBI) show individuals with a prior history of TBI experience an increased risk of future TBI with a significantly more detrimental outcome. But the mechanisms through which prior head injuries may affect risks of injury during future head insults have not been identified. In this work, we show that prior brain tissue injury in the form of mechanically induced axonal injury and glial scar formation can facilitate future mechanically induced tissue injury. To achieve this, we use finite element computational models of brain tissue and a history-dependent pathophysiology-based mechanically-induced axonal injury threshold to determine the evolution of axonal injury and scar tissue formation and their effects on future brain tissue stretching. We find that due to the reduced stiffness of injured tissue and glial scars, the existence of prior injury can increase the risk of future injury in the vicinity of prior injury during future brain tissue stretching. The softer brain scar tissue is shown to increase the strain and strain rate in its vicinity by as much as 40% in its vicinity during dynamic stretching that reduces the global strain required to induce injury by 20% when deformed at 15 s−1 strain rate. The results of this work highlight the need to account for patient history when determining the risk of brain injury.

Serum amyloid A contributes to radiation-induced lung injury by activating macrophages through FPR2/Rac1/NF-κB pathway.

Patients who receive thoracic radiotherapy may suffer from radiation-induced lung injury, but the treatment options are limited as the underlying mechanisms are unclear. Using a mouse model of right thorax irradiation with fractionated doses of X-rays for three consecutive days (8 Gy/per day), this study found that the thoracic irradiation (Th-IR) induced tissue injury with aberrant infiltration of macrophages, and it significantly increased the secretion of TNF-α, IL-1β, IL-6, TGF-β1 and serum amyloid A (SAA) in mice. Interestingly, SAA could activate macrophages and then induce epithelial-mesenchymal transition (EMT) of lung epithelial cells and fibrosis progression in lung tissue. Mechanistically, SAA enhanced the transient binding of FPR2 to Rac1 protein and further activated NF-κB signaling pathway in macrophages. Inhibition of FPR2 significantly reduced pulmonary fibrosis induced by SAA administration in mice. In addition, cimetidine could reduce the level of SAA release after irradiation and attenuate the lung injury induced by SAA or Th-IR. In conclusion, our results demonstrated that SAA activated macrophages via FPR2/Rac1/NF-κB pathway and might contribute to the Th-IR induced lung injury, which may provide a new strategy to attenuate radiation-induced adverse effects during radiotherapy.

An unexpected role of neutrophils in clearing apoptotic hepatocytes in vivo.

Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here, we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term perforocytosis, and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver, and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease.

An unexpected role of neutrophils in clearing apoptotic hepatocytes in vivo

Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here, we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term perforocytosis, and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver, and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease.

Aqueous extract of Daucus carota exerts a protective effect on the Renal, Hepatic and Duodenal mucosal histology in Diclofenac Induced Tissue Injury

Objective: The use of ethnobiology in treatment of many diseases especially in rural residents with limited access to medical technology, treatment and equipment is beneficial and necessary. Daucus carota (DC) root extract was used as pre-treatment in adult Wistar rats exposed to diclofenac sodium (DF) to investigate a protective effect on the histology of liver, kidney and duodenum. Materials and Method: Twenty-five adult Wistar rats were used for this study and were randomly divided into 5 groups of 5 rats each, which included: Group A - Normal control; Group B – 50mg/kg DF control; Group C – 50mg/kg DC + 50mg/kg DF, Group D – 100mg/kg DC + 50mg/kg DF; and, Group E – 140mg/kg DC + 50mg/kg DC. Results and Discussion: The results showed a reduction in damage to the hepatocytes, maintenance of sinusoidal integrity and reduction in the number of inflammatory cells in the hepatic parenchyma, In the kidney tissue, the extract preserved the glomerular capillary tuft, renal tubular epithelial cells, conserved Bowman’s space and lining epithelium of the capsule in a dose dependent manner. The intestinal mucosa in groups treated with higher doses of the extract were completely preserved and intact with minimal erosion of epithelial lining along with preservation of lamina propria and intestinal glands. Conclusion: Pre-administration of DC, preferably at concentrations of 100mg/kg and 140mg/kg reduced hepatotoxicity, renal tissue and mucosal layer damage in the duodenum following administration of DF. This preservation of tissues improved as concentration of the extract increased verifying that its efficiency was dose dependent.

Atezolizumab Retains Cellular Binding to Programmed Death Ligand 1 Following Aerosolization via Mesh Nebulizer.

Cytotoxic inhalable drugs were shown to be advantageous in treating malignancies of the respiratory tract. However, these drugs have not always presented a safe profile and were reported to induce local adverse events. Protein-based anticancer drugs, such as immune checkpoint and vascular endothelial growth factor inhibitors, do not induce tissue injury, nor do they exhibit vesicant properties upon direct contact with tissues. Protein drugs are susceptible to the heat and stress encountered during droplet generation for delivery by nebulization. The aim of this study was to investigate the capacity of atezolizumab, an antibody to programmed death ligand 1, to bind target cells after nebulization with a vibrating mesh (VM) nebulizer. We compared Fourier-transformed infrared (FTIR) and Raman spectra of native atezolizumab (60 mg/ml) and its nebulized form following 10-min nebulization in a piezoceramic VM nebulizer. The binding of atezolizumab to DU-145 prostate cancer cells was evaluated using competitive blocking of anti-CD274 staining. Nebulization did not induce Raman or FTIR spectral modification nor did it affect the binding capacity of atezolizumab. Conversely, heat-inactivated atezolizumab lost its cell-binding capacity and did not reduce anti-CD274 immunostaining. Native and nebulized atezolizumab displayed identical spectra, whereas the FTIR spectra of the heat-inactivated drug was significantly altered. VM nebulization does not obliterate the functionality of the drug atezolizumab. The integrity of a nebulized form can be rapidly assessed by FTIR and Raman spectrometry.

Machine-learning prediction model for acute skin toxicity after breast radiation therapy using spectrophotometry.

Radiation-induced skin toxicity is a common and distressing side effect of breast radiation therapy (RT). We investigated the use of quantitative spectrophotometric markers as input parameters in supervised machine learning models to develop a predictive model for acute radiation toxicity. One hundred twenty-nine patients treated for adjuvant whole-breast radiotherapy were evaluated. Two spectrophotometer variables, i.e. the melanin (IM) and erythema (IE) indices, were used to quantitatively assess the skin physical changes. Measurements were performed at 4-time intervals: before RT, at the end of RT and 1 and 6 months after the end of RT. Together with clinical covariates, melanin and erythema indices were correlated with skin toxicity, evaluated using the Radiation Therapy Oncology Group (RTOG) guidelines. Binary group classes were labeled according to a RTOG cut-off score of ≥ 2. The patient's dataset was randomly split into a training and testing set used for model development/validation and testing (75%/25% split). A 5-times repeated holdout cross-validation was performed. Three supervised machine learning models, including support vector machine (SVM), classification and regression tree analysis (CART) and logistic regression (LR), were employed for modeling and skin toxicity prediction purposes. Thirty-four (26.4%) patients presented with adverse skin effects (RTOG ≥2) at the end of treatment. The two spectrophotometric variables at the beginning of RT (IM,T0 and IE,T0), together with the volumes of breast (PTV2) and boost surgical cavity (PTV1), the body mass index (BMI) and the dose fractionation scheme (FRAC) were found significantly associated with the RTOG score groups (p<0.05) in univariate analysis. The diagnostic performances measured by the area-under-curve (AUC) were 0.816, 0.734, 0.714, 0.691 and 0.664 for IM, IE, PTV2, PTV1 and BMI, respectively. Classification performances reported precision, recall and F1-values greater than 0.8 for all models. The SVM classifier using the RBF kernel had the best performance, with accuracy, precision, recall and F-score equal to 89.8%, 88.7%, 98.6% and 93.3%, respectively. CART analysis classified patients with IM,T0 ≥ 99 to be associated with RTOG ≥ 2 toxicity; subsequently, PTV1 and PTV2 played a significant role in increasing the classification rate. The CART model provided a very high diagnostic performance of AUC=0.959. Spectrophotometry is an objective and reliable tool able to assess radiation induced skin tissue injury. Using a machine learning approach, we were able to predict grade RTOG ≥2 skin toxicity in patients undergoing breast RT. This approach may prove useful for treatment management aiming to improve patient quality of life.

Myomaker and Myomixer Characterization in Gilthead Sea Bream under Different Myogenesis Conditions

Skeletal muscle is formed by multinucleated myofibers originated by waves of hyperplasia and hypertrophy during myogenesis. Tissue damage triggers a regeneration process including new myogenesis and muscular remodeling. During myogenesis, the fusion of myoblasts is a key step that requires different genes' expression, including the fusogens myomaker and myomixer. The present work aimed to characterize these proteins in gilthead sea bream and their possible role in in vitro myogenesis, at different fish ages and during muscle regeneration after induced tissue injury. Myomaker is a transmembrane protein highly conserved among vertebrates, whereas Myomixer is a micropeptide that is moderately conserved. myomaker expression is restricted to skeletal muscle, while the expression of myomixer is more ubiquitous. In primary myocytes culture, myomaker and myomixer expression peaked at day 6 and day 8, respectively. During regeneration, the expression of both fusogens and all the myogenic regulatory factors showed a peak after 16 days post-injury. Moreover, myomaker and myomixer were present at different ages, but in fingerlings there were significantly higher transcript levels than in juveniles or adult fish. Overall, Myomaker and Myomixer are valuable markers of muscle growth that together with other regulatory molecules can provide a deeper understanding of myogenesis regulation in fish.

Amelioration of injury-induced tissue acidosis by a nonsteroidal analgesic attenuates antinociceptive effects of the pH-dependent opioid agonist NFEPP

Opioid agonists are powerful drugs for managing pain. However, their central side effects are limiting their use and drugs with similar potency, but a lower risk profile are needed. (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP) is a novel opioid agonist that preferentially activates opioid receptors at acidic extracellular pH. NFEPP was designed to activate peripheral opioid receptors in injured tissue, therefore precluding side effects elicited at normal pH in brain or intestinal wall. Considering the common combination of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) in multimodal analgesia, we investigated the interaction between NFEPP and a widely prescribed prototypical NSAID, diclofenac (DCF), in a rat model of unilateral hindpaw inflammation induced by complete Freund’s adjuvant. We evaluated the effects of systemically applied DCF on the paw tissue pH, on the expression of inflammatory mediators in immune cells from inflamed paws and on the expression of opioid receptors in dorsal root ganglia. Additionally, we investigated the antinociceptive efficacy of NFEPP injected into the inflamed paws after DCF treatment. We found that DCF reduced inflammation-induced nociceptive responses and tissue acidosis, but did not change the mRNA expression of IL-1β, TNF-α, IL-6, IL-4, NGF, or of mu-, delta-, or kappa-opioid receptors. The treatment with DCF moderately reduced the antinociceptive efficacy of NFEPP, suggesting a correlation between an increase in local tissue pH and the decreased antinociceptive effect of this pH-sensitive opioid agonist.

Persistent activation of Nrf2 in a p62-dependent non-canonical manner aggravates lead-induced kidney injury by promoting apoptosis and inhibiting autophagy

IntroductionLead (Pb) is an environmental toxicant that poses severe health risks to humans and animals, especially renal disorders. Pb-induced nephrotoxicity has been attributed to oxidative stress, in which apoptosis and autophagy are core events. ObjectivesNuclear factor erythroid 2-related factor 2 (Nrf2) acts as a major contributor to counteract oxidative damage, while hyperactivation or depletion of Nrf2 pathway can cause the redox imbalance to induce tissue injury. This study was performed to clarify the function and mechanism of Nrf2 in Pb-triggered kidney injury. Methods and resultsFirst, data showed that Pb exposure activates Nrf2 pathway in primary rat proximal tubular cells. Next, Pb-induced Nrf2 activation was effectively regulated by pharmacological modulation or siRNA-mediated knockdown in vitro and in vivo assays. Notably, Pb-triggered cytotoxicity, renal injury and concomitant apoptosis were improved by Nrf2 downregulation, confirming that Pb-induced persistent Nrf2 activation contributes to nephrotoxicity. Additionally, Pb-triggered autophagy blockage was relieved by Nrf2 downregulation. Mechanistically, we found that Pb-induced persistent Nrf2 activation is attributed to reduced Nrf2 ubiquitination and nuclear-cytoplasmic loss of Keap1 in a p62-dependent manner. ConclusionsIn conclusion, these findings highlight the dark side of persistent Nrf2 activation and potential crosstalk among Pb-induced persistent Nrf2 activation, apoptosis and autophagy blockage in Pb-triggered nephrotoxicity.

Complement induces podocyte pyroptosis in membranous nephropathy by mediating mitochondrial dysfunction

Podocyte damage mediated by in situ complement activation in the glomeruli is a key factor in the pathogenesis of membranous nephropathy (MN), but the molecular mechanism has not been fully elucidated. Pyroptosis is a special type of programmed cell death, mediate inflammatory response and induce tissue injury. However, it is not clear whether pyroptosis is involved in the development and progression of MN. Here, we report that pyroptosis plays an important role in promoting podocyte injury in MN. We first observed the occurrence of pyroptosis in the kidneys of MN patients and validated that complement stimulation triggered pyroptosis in podocytes and that inhibiting pyroptosis reversed complement-induced podocyte damage in vitro. In addition, stimulation of complement caused mitochondrial depolarization and reactive oxygen species (ROS) production in podocytes, and inhibition of ROS reversed complement-induced pyroptosis in podocytes. Interestingly, inhibition of pyroptosis in turn partially alleviated these effects. Furthermore, we also found the involvement of pyroptosis in the kidneys of passive Heymann nephritis (PHN) rats, and inhibitors of pyroptosis-related molecules relieved PHN-induced kidney damage in vivo. Our findings demonstrate that pyroptosis plays a critical role in complement-induced podocyte damage in MN and mitochondrial dysfunction is an important mechanism underlying this process. It provides new insight that pyroptosis may serve as a novel therapeutic target for MN treatment in future studies.

Adhesion stabilization in the early postoperative period in a rat model

Introduction:Adhesion formation is a complex series of events that results from cellular and molecular processes where, in contrast to the normal case, events that support adhesion genesis dominate over adhesion lysis. Tissue injury, haemorrhage, tissue desiccation and inflammatory processes, among others, play a role in its induction. Since the presence of adhesions can be associated with a number of negative complications, the primary aim is to prevent their development. There are several preventive targets for the process, but in many cases therapy is only provided immediately after the procedure. In this study, we present an experimental rat model of adhesion, where the aim is to understand the stabilization period of adhesion. All animals underwent the same surgical procedure, inducing tissue injury, minor haemorrhage and tissue desiccation, differing only in the timing of reoperations and sampling. On postoperative days 1–7, we assessed macroscopically and histopathologically the type of adhesions formed, the adhesive tissue, the stability of the adhesion. We found that stabilization was a process lasting several days, with unstable and moderately stable adhesions predominating by postoperative day 4. Knowing this allows to broaden the therapeutic window, targeting the most appropriate period in the early postoperative period, possibly combining treatments, to make adhesion prevention even more effective.

Molecular Evidence of the Inhibitory Potential of Melatonin against NaAsO2-Induced Aging in Male Rats.

Arsenic (As) poisoning is widespread due to exposure to pollution. The toxic level of (As) causes oxidative stress-induced aging and tissue damage. Since melatonin (MLT) has anti-oxidant and anti-aging properties, we aimed to evaluate the protective effect of MLT against the toxicity of sodium arsenite (NaAsO2). Healthy male NMRI mice were divided into eight different groups. The control group received a standard regular diet. Other groups were treated with varying diets, including MLT alone, NaAsO2, and NaAsO2 plus MLT. After one month of treatment, biochemical and pathological tests were performed on blood, heart, and lung tissue samples. NaAsO2 increased the levels of TNF-α, 8-hydroxy-2-deoxy guanosine (8OHdG), malondialdehyde (MDA), reactive oxygen species (ROS), and high mobility group box 1 (HMGB1), increased the expression of TNF receptor type 1-associated death domain (TRADD) mRNA and telomerase reverse transcriptase, and decreased the expression of Klotho (KL) mRNA in both plasma and tissues. In contrast, MLT reduced MDA, ROS, HMGB1, lactate, and TNF-α enhanced the mRNA expression of KL, and suppressed the mRNA expression of the TERT and TRADD genes. Thus, MLT confers potent protection against NaAsO2- induced tissue injury and oxidative stress.

Effect of a Novel Hybrid Nanocomposite of Cisplatin-Chitosan on Induced Tissue Injury as a Suggested Drug by Reducing Cisplatin Side Effects.

The self-assembly of cisplatin (Cis-Pt) and chitosan nanoparticles (Cs NPs) has been synthesized and characterized successfully by different analyses and techniques, such as scanning electron microscopy, ultraviolet-visible spectrophotometry, and Fourier transform infrared spectroscopy. The efficiency of loading Cis-Pt on Cs NPs for decreasing the side effects of Cis-Pt by loading it on Cs NP surface was revealed through histopathological and physiological measurements for the liver, testis, and kidney cells. Self-assembly hybrid nanocomposite (Cis-Pt@Cs) could improve spermatogenic cells, seminiferous tubules, and Leydig cells in the interstitial tissue. Kidney examination showed intact glomeruli with a mild increase in capsular space in addition to the intact renal tubular epithelial lining, and liver findings showed improvement in dilation and congestion of the central vein besides mild dilation of blood sinusoids in addition to a mild degree of hepatocyte vacuolation. The serum levels of hepatic, renal, and testicular marker analysis were measured, where Cis-Pt increased the serum levels of alanine aminotransferase, aspartate aminotransferase activity, urea, creatinine, and decreased testosterone levels, while synthesized self-assembly appeared normalized levels. From the results, the self-assembly hybrid nanocomposite decreases and improves the side effects of Cis-Pt.

Persistent activation of Nrf2 promotes a vicious cycle of oxidative stress and autophagy inhibition in cadmium-induced kidney injury

Nuclear factor erythroid 2-related factor 2 (Nrf2) serves as the master regulator of antioxidant signaling and inhibition or hyperactivation of Nrf2 pathway will result in the redox imbalance to induce tissue injury. Herein, we established cadmium (Cd)-exposed rat kidney injury model by intraperitoneal injection with CdCl2 (1.5 mg/kg body weight) and cytotoxicity model of NRK-52E cells by CdCl2 (5 μM) exposure to reveal the role of Nrf2 hyperactivation in Cd-induced nephrotoxicity. Data from the in vitro and in vivo study showed that Cd caused Nrf2 nuclear retention due to nuclear-cytoplasmic depletion of Kelch-like ECH-associated protein 1 (Keap1) and Sequestosome-1(SQSTM1/p62) accumulation, leading to the persistent activation of Nrf2. Moreover, we established inhibited models of Cd-induced prolonged Nrf2 activation using siRNA-mediated gene silencing in vitro and pharmacological inhibition in vivo for subsequent assays. First, Cd-induced cytotoxicity, renal injury and concomitant oxidative stress were markedly alleviated by Nrf2 inhibition. Second, Cd-induced autophagy inhibition was notably alleviated by Nrf2 inhibition. Further, we revealed underlying molecular mechanisms of the crosstalk between persistent activation of Nrf2 and autophagy inhibition in Cd-induced nephrotoxicity. Data showed that Cd-induced lysosomal dysfunction evidenced by impaired lysosomal biogenesis and degradation capacity was markedly recovered by Nrf2 inhibition. Meanwhile, Cd-impaired autophagosome-lysosome fusion was obviously restored by Nrf2 inhibition. In conclusion, our findings revealed that persistent activation of Nrf2 promoted a vicious cycle of oxidative stress and autophagy inhibition in Cd-induced nephrotoxicity.