Histological Damage Research Articles

Non-HLA Autoantibodies Against Angiotensin II Receptor 1 (AT1R) and Endothelin A Receptor (ETAR) in Pediatric Kidney Transplantation

Antibody-mediated rejection (AMR) is the leading cause of premature kidney transplant failure. The role of alloantibodies against Human Leukocyte Antigens (HLA) has been a primary focus in AMR. More recently autoantibodies and alloantibodies against the angiotensin II receptor type 1 (AT1R) and the endothelin A receptor (ETAR) have been linked to poor allograft outcomes in kidney transplantation. Nevertheless, evidence supporting routine testing remains insufficient. ELISA testing for anti-AT1R and anti-ETAR antibodies was performed in a pediatric renal transplant cohort. We selected 12 pediatric recipients who had undergone protocol biopsies and antibody measurements at 6 and 24 months post-transplant. Immunohistochemistry was performed on biopsies for AT1R and ETAR as well as the adhesion molecules ICAM-1 and VCAM-1. The analysis showed that ICAM-1 and VCAM-1 expression was significantly increased, along with the presence of circulating antibodies, in patients at 24 months post-transplant compared to patients without circulating antibodies. The presence of anti-AT1R and anti-ETAR antibodies does not seem to influence the expression of their receptors in the transplanted organ. Instead, the increase in adhesion molecules may precede the development of histological damage. Therefore, enlarging the cohort and extending long-term observation would help to understand the impact of anti-AT1R and anti-ETAR antibodies after transplantation.

Decabromodiphenyl ethane (DBDPE) inhibited the growth and feeding by disrupting the gut and digestive gland homeostasis in octopus Amphioctopus fangsiao (Mollusca: Cephalopoda)

A novel brominated flame retardant decabromodiphenyl ethane (DBDPE) poses a potential threat to animals, but its effects on cephalopods remain unknown. In this study, Amphioctopus fangsiao, a common octopus in China, was exposed to DBDPE (0, 1, 50, 100, 300 μg/L) for 28 days. Chemical analysis revealed that the digestive gland bore a greater burden of DBDPE compared with other tissues. In addition, accumulated DBDPE could curb the growth and feeding performance of A. fangsiao. The potential effects on the “gut-digestive gland axis” were also elucidated. Specifically, DBDPE in the gut shifted the microorganisms toward a Bacteroidetes-dominated composition, and impaired the intestinal epithelial barrier, thereby triggering oxidative stress and inflammation. Excessive DBDPE also threatens the digestive gland function, including histological damage, immune reaction, oxidative stress, glucolipid metabolism dysfunction, and neurotoxicity. Metabolome plasticity enabled A. fangsiao to develop a DBDPE stress-adaptive metabolic profile via alteration of glucolipid metabolism, immunity, oxidative stress, and signaling molecules. Taken together, we identified a new detoxification mechanism linking the microbiota-gut-digestive gland axis with the growth and food intake of A. fangsiao, which is the first time it has been demonstrated in mollusks. These findings provided important clues for a further mechanism study and risk assessment of DBDPE.

Influence and distinctions of particulate matter exposure across varying etiotypes in chronic obstructive pulmonary disease (COPD) mouse model

BackgroundAir pollution, notably particulate matter (PM), significantly impacts chronic respiratory disease such chronic obstructive pulmonary disease (COPD). Although asthma-COPD overlap (ACO), considered one of the COPD etiotype, is associated with greater severity in both symptoms and outcomes, effects of PM exposure remain unclear. Thus, this study aimed to evaluate impact of PM on chronic airway disease animal models.MethodsWe established two distinct COPD etiotypes, cigarette smoking-related COPD (COPD-C) and COPD with asthma (COPD-A), using porcine pancreatic elastase (PPE) for COPD-C and a combination of PPE with ovalbumin for COPD-A. To reflect smoking influence, cigarette smoking extract was administered to both disease models. To assess impact of PM exposure, bronchoalveolar lavage fluid (BALF), proinflammatory cytokines, lung histology, and cellular damage mechanisms were analyzed.ResultsIn the COPD-A model, cell counts and type 2 cytokines were elevated in BALF independent of PM exposure. All models exhibited increased lung inflammation and emphysema due to PM exposure. Expression levels of apoptosis-related protein B-cell lymphoma protein 2 (Bcl-2) associated X (Bax) showed an inclination to increase with PM exposure. In the COPD-A model, decreased expression of basal nuclear factor erythroid-derived 2-like 2 (Nrf-2) and increased production of reactive oxygen species (ROS) due to PM exposure were noted.ConclusionWe developed two distinct models for the etiotypes of COPD and found increased vulnerability to cell damage in COPD-A after PM exposure. Moreover, the control group displayed escalated airway inflammation and emphysema due to PM exposure, substantiating the risk of respiratory diseases.

Phosphodiesterase inhibitors and testicular torsion: A systematic review and meta-analysis of animal studies.

Testicular torsion is a common urological emergency in children and teenagers that, in most cases, requires surgical exploration and detorsion. However, even after a successful intervention, a high number of patients still develop irreversible damage. To investigate whether the administration of phosphodiesterase inhibitors (PDE) in animal models of testicular torsion can reduce damages caused by the ischemia-reperfusion syndrome. A systematic search of the Medline, Web of Science, Embase, and Ovid databases for studies up to December 2023 was performed using PRISMA guidelines. A detailed search was conducted using the following key terms: "testicles," "ischemia," "reperfusion," and "phosphodiesterase inhibitors." There was no restriction regarding language or year of publication. We investigated spermatogenesis by the Johnsen's biopsy score (JTBS) and histological damage by the Cosentino's biopsy score (CBS). Malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione peroxidase (GPx) testicular levels were also analyzed. Initially, 296 articles were identified. However, only 20 studies met the inclusion criteria. PDE inhibitors improved JTBS (MD=2.53, CI=1.94 to 3.13), CBS (MD=-1.11, CI=-1.25 to -0.97) and SOD (SMD=3.27, CI=1.59 to 4.95) outcomes. PDE did not improve MDA (SMD=-0.93, CI=-2.19 to 0.34), NO (SMD=-0.54, CI=-1.56 to 0.48), and GPx (SMD=0.77, CI=-0.38 to 1.92) outcomes. A higher dose of PDE inhibitors only improved CBS outcome. This review indicates that the administration of PDE inhibitors in rats ameliorated the outcomes, representing a promising complementary strategy for spermatogenesis recovery following testicular torsion. Our review suggests that JTBS and CBS could be translated into future human studies, validating and extending these findings within the context of human physiopathology, while providing applicability of interventions in real clinical practice.

Potential of Fiber and Probiotics to Fight Against the Effects of PhIP + DSS-Induced Carcinogenic Process of the Large Intestine.

We determined the in vivo counteracting effect of fiber and probiotic supplementation on colonic mucosal damage and alterations in gut microbiota caused by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) and sodium dextran sulfate (DSS). Male Fischer-344 rats were randomly divided into 4 groups: control (standard diet), PhIP + DSS group (standard diet + PhIP + DSS), fiber (fiber diet + PhIP + DSS), and probiotic (probiotic diet + PhIP + DSS). The intake of PhIP + DSS for 3 weeks induced colonic mucosal erosion, crypt loss, and inflammation, and the distal colon was more severely damaged. Fiber alleviated colonic mucosal damage by reducing crypt loss and inflammation, while the probiotic increased colon length. The intake of PhIP + DSS increased the fecal relative abundance of Clostridia UCG014 along the intervention, in contrast to the lower abundances of these taxa found after PhIP + DSS administration in the rats supplemented with probiotics or fiber. Fiber supplementation mitigated the histological damage caused by PhIP + DSS shifting the gut microbiota toward a reduction of pro-inflammatory taxa.

Lead Toxicity and Maternal Exposure: Characterisation of Alveolar Bone Changes on Offspring Rats.

Lead poisoning is a global public health concern. Maternal exposure during intrauterine and lactational periods can present a higher susceptibility of harm to the offspring. Thus, pregnant female Wistar rats (Rattus norvegicus) were randomly divided in two experimental groups: control group and Lead group. The animals were exposed to 50mg/kg of Lead Acetate daily for 42days (21days of gestational period + 21days of lactational period). After the exposure period, the mandibles of the offspring were collected for lead quantification, Raman spectroscopy analysis, micro-CT, morphometric e histochemical analysis. Lead exposure altered the physical-chemical composition of alveolar bone and caused histological damage associated with a reduction in osteocyte density and collagen area fraction, increase in collagen maturity, as well as a reduction in bone volume fraction. An increase in trabecular spaces with anatomical compromise of the vertical dimensions of the bone was observed. Thus, the results suggest that developing alveolar bone is susceptible to toxic effects of lead when organisms are exposed during intrauterine and lactation periods.

Evaluation of Bioactive Compounds, Antioxidant Capacity, and Anti-Inflammatory Effects of Lipophilic and Hydrophilic Extracts of the Pericarp of Passiflora tripartita var. mollissima at Two Stages of Ripening.

Chronic disease inflammation requires safe complementary treatments. The pericarp of Passiflora tripartita var. mollissima (PTM) contains potential anti-inflammatory metabolites. This study aimed to evaluate the bioactive components, antioxidant capacity, and anti-inflammatory effects of PTM extracts at two ripening stages. The bioactive compounds in the hydrophilic and lipophilic extracts of mature and green pericarps were identified by GC-MS and UV-VIS, while the antioxidant capacity was measured by free radical reduction. Anti-inflammatory effects were tested using a rat paw edema model with carrageenan-induced edema, indomethacin, or PTM extracts (100, 250, and 500 mg/kg). The effect of mature hydrophilic extract was further evaluated in an air pouch model, where rats received the placebo, carrageenan, indomethacin, or the extract (500 and 1000 mg/kg). Leukocytes, cytokines, and markers of oxidative stress were evaluated. The results showed the presence of organic compounds, total phenols, and flavonoids. The mature hydrophilic extract exhibited the highest antioxidant activity. At 500 mg/kg, it reduced edema, leukocyte migration, and levels of IL-1β, IL-6, and TNF-α while managing oxidative stress and preventing histological damage. In conclusion, PTM contains bioactive compounds with potential pharmacological properties. The hydrophilic extract of the mature pericarp, at a dose of 500 mg/kg, exhibits an enhanced antioxidant and anti-inflammatory effect.

Long-term consumption of aspartame & cancer risk

Artificial sweeteners, specifically aspartame, are present in everyday modern diets due to their low-calorie content and high level of sweetness. They are often used as sugar substitutes to promote weight loss and manage diabetes. Despite their widespread use and approval by regulatory bodies such as the U.S. Food and Drug Administration (FDA), concerns about the safety and potential carcinogenicity of artificial sweeteners persist. This research paper delves into the controversy surrounding aspartame, which was classified as possibly carcinogenic to humans by the International Agency for Research on Cancer (IARC) in 2023. By reviewing literature and analyzing studies published between 2000 and 2024, this paper explores aspartame’s metabolism in the human body, its by-products, and its biological effects. The article also delves into a notable experimental study involving male Wistar albino rats that demonstrated significant biochemical changes, histological liver damage, and gene expression alterations at high doses of aspartame, indicating potential cancer risks. The findings underscore the need for further research to clarify the biochemical and molecular mechanisms linking artificial sweeteners to cancer while emphasizing cautious consumption and reevaluation of safety guidelines.

Potential protection of resveratrol-tempeh against nephrotoxic and hepatotoxic histological damage in mice induced by aluminum

Aluminum is a widely distributed metal that, while generally safe at low levels, can become toxic when accumulated in the body. Its exposure is daily through various sources, including food, water, and medications. High levels of aluminum have been shown to adversely affect the kidneys and liver, leading to significant organ damage. Resveratrol-tempeh is a safe protective agent against organ damage caused by aluminum. Here, we investigated the impact of resveratrol on liver and kidney toxicity and Al-induced levels of catalase and malondialdehyde. The mice group was the control group, Al-group, Al+REST5-group, and Al+REST10-group. Aluminum and resveratrol were administered intraperitoneally to mice for four weeks, but resveratrol was administered one hour after exposure to aluminum. Mice were killed by cervical dislocation; the liver and kidney were isolated for slide, and the level of an antioxidant enzyme of catalase and oxidant of malondialdehyde was measured. The results showed that administration of aluminum at a dose of 200 mg/kg body weight caused glomerular shrinkage and proximal tubule degeneration in the kidneys. In addition, it also caused liver tissue damage, with hepatocytes undergoing degeneration, sinusoids dilating, and decreased body weight in the mice. Administration of resveratrol-tempeh tended to decrease malondialdehyde levels and increase catalase activity, although the changes were not significant. It seems that resveratrol-tempeh can repair liver and kidney damage and restore them to normal conditions. Conclusion: Aluminum at 200 mg/kg is toxic to mice. Resveratrol-tempeh can be considered a potential candidate to protect kidney and liver damage caused by aluminum chloride toxicity.

Effects of Local Hypothermia on Limb Viability in a Swine Model of Acute Limb Ischemia During Prolonged Damage-Control Resuscitation.

New strategies are needed to mitigate further tissue injury during traumatic limb ischemia in cases requiring damage control resuscitation (DCR). Little is known about the pathophysiology and injury course in acute limb ischemia (ALI) with DCR in polytraumatized casualties. We therefore investigated the effects of therapeutic limb hypothermia in a swine model of ALI and DCR. Fifteen swine underwent a published 6-hour DCR protocol of hemorrhage and then resuscitation. After hemorrhage, animals were randomized to 5oC or 15oC cooling of one hindlimb; the contralateral limb serving as an uncooled control. Physiologic variables, limb temperature, and limb tissue metabolites (glucose, lactate, and pyruvate) were measured throughout the DCR protocol. Muscle and nerve biopsies were obtained after the 6-hour protocol. Lactate and pyruvate levels were significantly lower in the cooled limbs than in the uncooled control limbs but did not differ between the 5oC and 15oC groups. Tissue glucose levels did not differ between the 5oC group, the 15oC group, and controls. Mean histologic muscle score was significantly higher in the 5oC group than in controls (p = 0.03). Mean nerve histology scores did not differ between the 5oC and paired control limbs, or between the mean muscle and nerve histology scores of the 15oC and paired control limbs. Cooling to 15oC significantly reduced local tissue metabolites compared to paired controls, while producing no significant increase in histologic damage, whereas cooling to 5oC increased histologic muscle damage. These results suggest an approach to prevention of ischemic injury through local hypothermia but warrant further functional testing.

Dichloroacetate reduces cisplatin-induced apoptosis by inhibiting the JNK/14-3-3/Bax/caspase-9 pathway and suppressing caspase-8 activation via cFLIP in murine tubular cells

Cisplatin-induced injury to renal proximal tubular cells stems from mitochondrial damage-induced apoptosis and inflammation. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, a potential generator of ROS and ATP, protects against cisplatin-induced nephrotoxicity by promoting the TCA cycle. However, its effects on apoptotic pathways and ROS production in renal tubular cells remain unclear. Here, we investigated the detailed molecular mechanisms of the DCA’s effects by immunoblot, RT-PCR, RNA-sequencing, and RNA-silencing in a murine renal proximal tubular (mProx) cell line and mouse kidneys. In mProx cells, DCA suppressed cisplatin-induced apoptosis by attenuating the JNK/14-3-3/Bax/caspase-9 and death receptor/ligand/caspase-8 pathways without impeding inflammatory signaling. RNA-sequencing demonstrated that DCA increased the cisplatin-reduced expression of cFLIP, a caspase-8 inactivator, and decreased the expression of almost all oxidative phosphorylation (OXPHOS) genes. DCA also increased NF-kB activation and ROS production, probably enhancing the cFLIP induction and OXPHOS gene reduction, respectively. Furthermore, cFLIP silencing weakened the DCA’s anti-apoptotic effects. Finally, in mouse kidneys, DCA attenuated cisplatin-caused injuries such as functional and histological damages, caspase activation, JNK/14-3-3 activation, and cFLIP reduction. Conclusively, DCA mitigates cisplatin-induced nephrotoxicity by attenuating the JNK/14-3-3/Bax/caspase-9 pathway and inhibiting the caspase-8 pathways via cFLIP induction, probably outweighing the cisplatin plus DCA-derived cytotoxic effects including ROS.

Nano Spirulina platensis countered cisplatin-induced repro-toxicity by reversing the expression of altered steroid hormones and downregulation of the StAR gene.

Cisplatin is a commonly utilized chemotherapy medication for treating different sarcomas and carcinomas. Its ability interferes with cancer cells' DNA repair pathways and postpones unfavorable outcomes in cancer patients. The current investigation's goal was to ascertain if nano Spirulina platensis (NSP) might shield rat testicles from cisplatin damage by assessing the expression of the StAR and SOD genes, sex hormones, 17ß-hydroxysteroid dehydrogenase(17ß-HSD), sperm profile picture, oxidative condition of testes, testicular histology, and DNA damage. Four equal and random groups of 28 adult male Wistar rats were created; the control group was given saline for 8weeks. An extraction of NSP at a concentration of 2500mg/kg body weight was administered orally for 8weeks to the NSP group. For the first 4weeks, the cisplatin group was intraperitoneally injected with 2mg/kg/body weight of cisplatin, and for the next 4weeks, they were given a dosage of 4mg/kg/body weight. The cisplatin + NSP group was given both NSP and cisplatin. The results of the experiment showed that intake of NSP and cisplatin improved sperm profile; re-established the balance of oxidizing agents and antioxidant state; enhanced testicular histology; promoted the histometric parameters of seminiferous tubules including epithelial height, their diameter, and Johnsen's score, decreasing DNA breakage in testicular tissue; increased testosterone level; decreased 17ß-HSD concentration; and upregulated both the StAR and SOD gene expression in testicles compared to rats exposed to cisplatin alone. These results demonstrate that NSP is a promising agent for improving cisplatin-induced testicular injury and infertility.

Large Animal Models Enhance the Study of Crypt-Mediated Epithelial Recovery from Prolonged Intestinal Ischemia Reperfusion Injury.

Intestinal ischemia and reperfusion injury (IRI) is a deadly and common condition. Death is associated with sepsis due to insufficient epithelial repair, requiring stem cell-driven regeneration, typically beginning 48 hours after injury. Animal models are critical to advancing this field. To effectively study epithelial healing, models must survive clinically relevant intestinal ischemic injury extending to the crypt. Though mouse models are indispensable to intestinal research, their application for studying epithelial repair following severe IRI may be limited. Ischemic injury was induced in mouse and porcine jejunum for up to 3 hours, with up to 72 hours of reperfusion. Histologic damage was scored by Chiu-Park grade and animal survival was assessed. Findings were compared between species. A mouse IRI literature review was performed to evaluate the purported degree of injury, duration of recovery, and reported survival rates. In mice and pigs, 3 hours of ischemia induced severe, reliable injury extending into the crypt. However, at 48 hours, mouse survival was only 23.5% compared to 100% survival in pigs. In literature, ischemia was induced for >1 hour in only 4 of 102 mouse studies and none to 3 hours. Recovery was attempted for 48 hours in only 6 reports. 47 studies reported intestinal crypt injury. Of those that featured histologic intestinal crypt damage, survival rates at 48 hours ranged from 10-50% (median 30%). Mouse models are not ideal to study intestinal stem cell mediated recovery from severe IRI. Alternative large animal models, like pigs, are recommended.

Nanopolystyrene and phoxim pollution: A threat to hepatopancreas toxicity in Chinese mitten crab (Eriocheir sinensis)

Significant concerns have been raised by the widespread pollutants phoxim (PHO) and nanopolystyrene (NP) in the natural environment. This study evaluated the toxicity effects on the hepatopancreas of Eriocheir sinensis caused by NP and/or PHO at concentrations found in the environment. Subchronic exposure to NP and/or PHO triggered hepatopancreas histological damage within a 21-day exposure period. The NP, PHO, and co-exposure (NPO) groups exhibited fewer blister-like (B) cells, along with the appearance of vacuolation. Furthermore, these exposures induced impairment in the hepatic tubule mucus barrier and mechanical barrier, as evidenced by altered expression of oxidative stress-related genes, mucin-related genes, and TJ-related genes. Additionally, alterations in immunity-related genes and inflammatory cytokine genes expression were observed. The findings showed that hepatopancreas inflammation was caused by both individual and combined exposure to NP and PHO and that the inflammatory response was exacerbated by the co-exposure. The possible pathways of hepatopancreas toxicity were further investigated by transcriptomic analysis. Hepatopancreas inflammation was brought on by subchronic exposure to PHO and co-exposure; this inflammation was exacerbated by co-exposure and was backed by the activation of NF-κB signaling pathway via targeting-related genes. In summary, this research represents the initial documentation, to the best of our understanding of the detrimental effects of exposured to NP and/or PHO at levels found in the environment disrupt the hepatopancreas mucus and mechanical barrier in crustaceans, triggering inflammatory responses. These findings highlight the significance of NP and/or PHO pollution for hepatopancreas health.

Anti-tissue transglutaminase antibody correlation with severity of villous abnormalities in celiac disease: A Systematic Review and Meta-analysis

Abstract Introduction/Objective Celiac disease (CD) is a long-term autoimmune disorder that affects individuals genetically predisposed to gluten intolerance. Biomarkers, particularly anti-tissue transglutaminase antibody (anti-tTG ab), are crucial in indicating disease states and have potential as non-invasive substitutes for mucosal biopsies in assessing the severity of intestinal damage. This study aims to systematically review and analyze the correlation between anti- tTG antibody levels and the severity of villous abnormalities in patients with celiac disease to evaluate the potential of anti-tTG as a non-invasive diagnostic tool. Methods/Case Report Following PRISMA guidelines, a comprehensive literature search selected 15 studies focusing on the correlation between anti-tTG antibodies and villous atrophy. Systematic data extraction and quality assessments were performed, followed by statistical analyses to determine the strength and consistency of associations. Results (if a Case Study enter NA) Analysis of data from four studies on anti-tTG antibody positivity revealed a nearly significant pooled effect size (p = 0.06) with considerable heterogeneity (I^2 = 97%, p < 0.00001). Additionally, data from five studies using the MARSH classification of histological damage, aggregated using a random-effects model, showed overall statistical significance (Z = 3.36, p = 0.0008). Conclusion Anti-tTG antibodies serve as a reliable indicator of villous damage in CD, supporting their dual utility in diagnosis and monitoring. High anti-tTG antibody titers could potentially eliminate the need for invasive biopsy procedures in certain patient subsets, underscoring the promise of more refined and non-invasive diagnostic approaches, although further research is needed to address the implications of high heterogeneity observed in the studies.

Nose-to-brain delivery of stem cells in stroke: the role of extracellular vesicles.

Stem cell transplantation offers a promising therapy that can be administered days, weeks, or months after a stroke. We recognize 2 major mitigating factors that remain unresolved in cell therapy for stroke, notably: (1) well-defined donor stem cells and (2) mechanism of action. To this end, we advance the use of ProtheraCytes, a population of non-adherent CD34+ cells derived from human peripheral blood and umbilical cord blood, which have been processed under good manufacturing practice, with testing completed in a phase 2 clinical trial in post-acute myocardial infarction (NCT02669810). We also reveal a novel mechanism whereby ProtheraCytes secrete growth factors and extracellular vesicles (EVs) that are associated with angiogenesis and vasculogenesis. Our recent data revealed that intranasal transplantation of ProtheraCytes at 3 days after experimentally induced stroke in adult rats reduced stroke-induced behavioral deficits and histological damage up to 28 days post-stroke. Moreover, we detected upregulation of human CD63+ EVs in the ischemic brains of stroke animals that were transplanted with ProtheraCytes, which correlated with increased levels of DCX-labeled neurogenesis and VEGFR1-associated angiogenesis and vasculogenesis, as well as reduced Iba1-marked inflammation. Altogether, these findings overcome key laboratory-to-clinic translational hurdles, namely the identification of well-characterized, clinical grade ProtheraCytes and the elucidation of a potential CD63+ EV-mediated regenerative mechanism of action. We envision that additional translational studies will guide the development of clinical trials for intranasal ProtheraCytes allografts in stroke patients, with CD63 serving as a critical biomarker.

Cimicifuga heracleifolia kom. Attenuates ulcerative colitis through the PI3K/AKT/NF-κB signaling pathway

Ethnopharmacological relevanceCimicifuga heracleifolia Kom. (C. heracleifolia) has demonstrated efficacy in treating gastrointestinal disorders, including splenasthenic diarrhea. Ulcerative colitis (UC), a chronic inflammatory bowel disease, shares similarities with splenasthenic diarrhea. However, the pharmacological effects of C. heracleifolia on UC and the underlying mechanisms remain unexplored. Aim of the studyThe present study investigates the therapeutic potential and mechanisms of C. heracleifolia in UC. MethodsInitially, network pharmacology analysis, encompassing ingredient screening, target prediction, protein-protein interaction (PPI) network analysis, and enrichment analysis, was employed to predict the mechanisms of C. heracleifolia. The findings were further validated using transcriptomics and functional assays in a dextran sulfate sodium (DSS)-induced UC model. Additionally, bioactive compounds were identified through surface plasmon resonance (SPR) analysis, molecular docking, and cell-based assays. ResultsA total of 52 ingredients of C. heracleifolia were screened, and 32 key targets were identified within a PPI network comprising 285 potential therapeutic targets. Enrichment analysis indicated that the anti-UC effects of C. heracleifolia are mediated through immune response modulation and the inhibition of inflammatory signaling pathways. In vivo experiments showed that C. heracleifolia mitigated histological damage in the colon, reduced the expression of phosphorylated Akt1, nuclear factor-kappa B (NF-κB) p65, and inhibitor of Kappa B kinase α/β (IKKα/β), suppressed the content of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and enhanced the expression of tight junction proteins. Moreover, cimigenoside, caffeic acid, and methyl caffeate were identified as the bioactive constituents responsible for the UC treatment effects of C. heracleifolia. ConclusionsIn summary, this study is the first to demonstrate that C. heracleifolia exerts therapeutic effects on UC by enhancing the intestinal mucosal barrier and inhibiting the phosphatidylinositol 3-kinase (PI3K)/AKT/NF-κB signaling pathway. These findings offer valuable insights into the clinical application of C. heracleifolia for UC management.

Apoptosis-stimulating protein of p53 (ASPP) participates in the regulation of apoptosis in Litopenaeus vannamei under ammonia-N and nitrite-N stress

Apoptosis-stimulating protein of p53 (ASPP) is a key regulatory factor closely related to p53 in apoptosis pathway. To further investigate the molecular mechanisms of ASPP in Litopenaeus vannamei, the expression of LvASPP mRNA under ammonia-N and nitrite-N stress was explored, and the effects of knocking out LvASPP on mortality, histological damage, and the apoptosis pathway in L. vannamei under ammonia-N and nitrite-N stress were investigated. Healthy L. vannamei (7.78 ± 0.70 g) were used in this study. After shrimp were stressed with an ammonia-N concentration of 30.00 mg/L for 48 h, qRT-PCR was used to detect a significant increase in LvASPP mRNA expression in the hepatopancreas, gills, and muscle. Following 48 h of nitrite-N stress at a concentration of 60.00 mg/L, LvASPP mRNA expression was significantly increased in the hepatopancreas. The survival rate notably increased under 80 h of ammonia-N stress (25.00 mg/L) after LvASPP RNA interference (30 % more than the control group), and the number of shrimp deaths decreased after 48 h of nitrite-N stress. Moreover, under the stress of ammonia-N and nitrite-N respectively, LvASPP silencing reduced the expression of p53, and led to a decrease in the expression of apoptosis-related genes (Bax, Apaf-1, Caspase 9, MDM2). Caspase 3 activity, TUNEL-positive cells and the apoptotic index in the hepatopancreas markedly reduced under ammonia-N and nitrite-N stress. The potential pathway suggests that inhibiting LvASPP reduces the mRNA expression of p53, which leads to a decrease in Caspase 3 activity, inhibiting apoptosis in the hepatopancreatic cells of L. vannamei under ammonia-N and nitrite-N stress. These data indicate that the knockdown of LvASPP positively impacted the tolerance of L. vannamei to ammonia-N and nitrite-N stress by regulating the apoptosis pathway. This suggests that employing gene-targeted dsRNA could be an effective strategy for alleviating the environmental pressures faced by shrimp in aquaculture management.

Reserpine alleviates cisplatin-induced acute kidney injury via anti-ferroptosis and cGAS/STING pathway

Cisplatin plays a pivotal role in the chemotherapy treatment of various cancers, but its use is often limited due to its nephrotoxic side effects. Identifying compounds that can mitigate cisplatin-induced nephrotoxicity is therefore of great importance. This study focused on evaluating the protective effects of reserpine against cisplatin-induced acute kidney injury. Reserpine was found to significantly safeguard against kidney damage caused by cisplatin, as indicated by the decreased levels of serum creatinine, blood urea nitrogen, and lactate dehydrogenase induced by cisplatin. Moreover, reserpine improved kidney histology damage caused by cisplatin treatment, with hematoxylin-eosin and periodic acid-Schiff staining revealing notable recovery from renal injury. Mechanistically, reserpine mitigated oxidative stress triggered by cisplatin and exhibits the ability to inhibit ferroptosis both in vivo and in vitro. Additionally, reserpine blocked the activation of the cGAS/STING signaling pathway and the subsequent expression of inflammatory genes, thus reducing inflammation-driven kidney damage. In summary, the findings suggest that reserpine offers a promising new strategy for preventing nephrotoxicity induced by cisplatin.

Development of a Preclinical Double Model of MandibularIrradiated Bone and Osteoradionecrosis in NewZealand Rabbits.

Radiotherapy (RT) plays a crucial role in head and neck (HN) cancer treatment. Nevertheless, it can lead to serious and challenging adverse events such as osteoradionecrosis (ORN). A preclinical rabbit model of irradiated bone and ORN is herein proposed, with the aim to develop a viable model to be exploited for investigating new therapeutic approaches. Nine New Zealand white rabbits were irradiated using a single beam positioned to the left of the mandible and directed perpendicular to the left mandible. A 10 × 10 mm2 region of interest (ROI) located below the first molar tooth on the left side was identified and irradiated with 7 Gy each fraction, once every 2 days, for five fractions. Dose distributions demonstrated that the corresponding ROI on the contralateral (right) mandibular side received approximately 5 Gy each fraction, thus bilateral irradiation of the mandible was achieved. ROIs were categorized as ROIH on the left side receiving the high dose and ROIL on the right side receiving the low dose. Rabbits were followed up clinically and imaged monthly. After 4 months, the irradiated bone was excised, and histological examination of ROIs was performed. Radiological signs suggestive for ORN were detected in the entire population (100%) 16 weeks after irradiation on ROIH, which consisted of cortical erosion and loss of trabeculae. ROIL did not show any radiological evidence of bone damage. Histologically, both sides showed comparable signs of injury, with marked reduction in osteocyte count and increase in empty lacunae count. A preclinical double model was successfully developed. The side receiving the higher dose showed radiological and histological signs of bone damage, resulting in an ORN model. Whereas the contralateral side, receiving the lower dose, presented with histological damage only and a normal radiological appearance. This work describes the creation of a double model, an ORN and irradiated bone model, for further study using this animal species.