Mesenchymal stem cell transplantation in burn wound healing: uncovering the mechanisms of local regeneration and tissue repair.

Burn injuries pose a significant healthcare burden worldwide, often leading to long-term disabilities and reduced quality of life. To explore the impacts of the transplantation of mesenchymal stem cells (MSCs) on the healing of burns and the levels of serum cytokines, 60 fully grown Sprague-Dawley rats were randomly divided into three groups (n = 20 each): group I (control), group II (burn induction), and group III (burn induction + bone marrow (BM)-MSC transplantation). Groups II and III were further divided into four subgroups (n = 5 each) based on euthanasia duration (7, 14, 21, and 28 days post transplant). The experiment concluded with an anesthesia overdose for rat death. After 7, 14, 21, and 28 days, the rats were assessed by clinical, laboratory, and histopathology investigations. The results revealed significant improvements in burn healing potentiality in the group treated with MSC. Furthermore, cytokine levels were measured, with significant increases in interleukin (IL)-6 and interferon alpha (IFN) observed, while IL-10 and transforming growth factor beta (TGF-ß) decreased at 7 days and increased until 28 days post burn. Also, the group that underwent the experiment exhibited increased levels of pro-inflammatory cytokines and the anti-inflammatory cytokine IL-10 when compared to the control group. Histological assessments showed better re-epithelialization, neovascularization, and collagen deposition in the experimental group, suggesting that MSC transplantation in burn wounds may promote burn healing by modulating the immune response and promoting tissue regeneration.

Exploring the cardioprotective effects of canagliflozin against cisplatin-induced cardiotoxicity: Role of iNOS/NF-κB, Nrf2, and Bax/cytochrome C/Bcl-2 signals.

Cardiotoxicity is a severe considerable side effect of cisplatin (CDDP) that requires much medical attention. The current study investigates the cardioprotective effects of canagliflozin (CA) against CDDP-induced heart toxicity. Rats were allocated to the control group; the CA group was administered CA 10 mg/kg/day orally for 10 days; the CDDP group was injected with 7 mg/kg, intraperitoneal as a single dose on the 5th day, and the CDDP + CA group. Compared to the CDDP-treated group, CA effectively attenuated CDDP-induced heart injury as evidenced by a decrease of serum aspartate aminotransferase, alkaline phosphatase, creatine kinase-MB, and lactate dehydrogenase enzymes and supported by the alleviation of histopathological changes in cardiac tissues. Biochemically, CA attenuated cardiac oxidative injury through upregulation of the nuclear factor-erythroid 2 related factor 2 (Nrf2) signal. CA suppressed inflammation by decreasing cardiac NO2 - , MPO, iNOS, nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha, and interleukin 1-beta levels. Besides, CA significantly upregulated cardiac levels of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and p-AKT proteins. Moreover, CA remarkably mitigated CDDP-induced apoptosis via modulation of Bax, cytochrome C, and Bcl-2 protein levels. Together, the present study revealed that CA could be a good candidate for preventing CDDP-induced cardiac injury by modulating iNOS/NF-κB, Nrf2, PI3K/AKT, and Bax/cytochrome C/Bcl-2 signals.

Nephroprotective effects of Acacia senegal against aflatoxicosis via targeting inflammatory and apoptotic signaling pathways.

Aflatoxin B1 (AFB1) is a common environmental pollutant that poses a major hazard to both humans and animals. Acacia senegal (Gum) is well-known for having antioxidant and anti-inflammatory bioactive compounds. Our study aimed to scout the nephroprotective effects of Acacia gum (Gum) against AFB1-induced renal damage. Four groups of rats were designed: Control, Gum (7.5 mg/kg), AFB1 (200 µg/kg b.w) and AFB1-Gum, rats were co-treated with both Gum and AFB1. Gas chromatography-mass spectrometry (GC/MS) analysis was done to determine the phytochemical constituents in Gum. AFB1 triggered profound alterations in kidney function parameters (urea, creatinine, uric acid, and alkaline phosphatase) and renal histological architecture. Additionally, AFB1 exposure evoked up-regulation of mRNA expression levels of inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor α (TNFα), inducible nitric oxide synthase (iNOS), and nuclear factor kB p65 (NF-κB/P65) in renal tissue. The oxidative distress and apoptotic cascade are also instigated by AFB1 intoxication as depicted in down-regulated protein expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide dismutase type 1 (SOD1) along with upregulation of cytochrome c (Cyto c), and cleaved Caspase3 (Casp3-17 and 19) in renal tissue. In conclusion, current study obviously confirms the alleviating effects of Gum supplementation against AFB1-induced renal dysfunction, oxidative harm, inflammation, and cell death. These mitigating effects are suggested to be attributed to Gum's antioxidant and anti-inflammatory activities. Our results recommend Gum supplementation as add-on agents to food that might aid in protection from AFB1-induced nephrotoxicity.

Neuroprotective effect of canagliflozin against cisplatin-induced cerebral cortex injury is mediated by regulation of HO-1/PPAR-γ, SIRT1/FOXO-3, JNK/AP-1, TLR4/iNOS, and Ang II/Ang 1-7 signals.

OBJECTIVES: Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor, is an anti-hyperglycemic drug that has been approved to treat diabetes. This study evaluated the beneficial effects of CAN on cerebral cortex intoxication induced by cisplatin (CIS). MATERIALS AND METHODS: Rats were allocated into four groups: normal control, CAN (10 mg/kg, P.O.) for 10 days, CIS (8 mg/kg, i.p.) as a single dose on the 5th day of the experiment, and CAN + CIS group. RESULTS: In comparison with CIS control rats, CAN significantly mitigated CIS-induced cortical changes in rats' behavior in the open field and forced swimming assessment as well as histological structure. Biochemically, CAN administration efficiently decreased lipid peroxidation biomarkers MDA and boosted the antioxidant status via a remarkable increase in the cortical reduced glutathione (GSH) content as well as enzymatic activities of antioxidant enzymes superoxide dismutase (SOD), glutathione-S-transferase (GST), catalase (CAT), and glutathione peroxidase (GPx) mediated by up-regulation of heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptors (PPARγ), and silent information regulator (SIRT1)/forkhead box-O3 (FOXO-3) signals. Additionally, pretreatment with CAN significantly decreased cortical myeloperoxidase (MPO), nitrite (NO2-), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels. At the same time, it elevated the IL-10 level associated with the downregulation of Jun N-terminal kinase (JNK)/activator protein 1 (AP-1), TLR4/inducible nitric oxide synthase (iNOS)/nitric oxide (NO), and Ang II/Ang 1-7 signals. CONCLUSIONS: Due to the potent antioxidant and anti-inflammatory properties of CAN, our findings showed that CAN could be a good candidate for the protection against CIS-induced cortical intoxication in the patient receiving CIS.

Innovative preconditioning strategies for improving the therapeutic efficacy of extracellular vesicles derived from mesenchymal stem cells in gastrointestinal diseases.

Gastrointestinal (GI) diseases have become a global health issue and an economic burden due to their wide distribution, late prognosis, and the inefficacy of recent available medications. Therefore, it is crucial to search for new strategies for their management. In the recent decades, mesenchymal stem cells (MSCs) therapy has attracted attention as a viable option for treating a myriad of GI disorders such as hepatic fibrosis (HF), ulcerative colitis (UC), acute liver injury (ALI), and non-alcoholic fatty liver disease (NAFLD) due to their regenerative and paracrine properties. Importantly, recent studies have shown that MSC-derived extracellular vesicles (MSC-EVs) are responsible for most of the therapeutic effects of MSCs. In addition, EVs have revealed several benefits over their parent MSCs, such as being less immunogenic, having a lower risk of tumour formation, being able to cross biological barriers, and being easier to store. MSC-EVs exhibited regenerative, anti-oxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in different experimental models of GI diseases. However, a key issue with their clinical application is the maintenance of their stability and efficacy following in vivo transplantation. Preconditioning of MSC-EVs or their parent cells is one of the novel methods used to improve their effectiveness and stability. Herein, we discuss the application of MSC-EVs in several GI disorders taking into account their mechanism of action. We also summarise the challenges and restrictions that need to be overcome to promote their clinical application in the treatment of various GI diseases as well as the recent developments to improve their effectiveness. A representation of the innovative preconditioning techniques that have been suggested for improving the therapeutic efficacy of MSC-EVs in GI diseases. The pathological conditions in various GI disorders (ALI, UC, HF and NAFLD) create a harsh environment for EVs and their parents, increasing the risk of apoptosis and senescence of MSCs and thereby diminishing MSC-EVs yield and restricting their large-scale applications. Preconditioning with pharmacological agents or biological mediators can improve the therapeutic efficacy of MSC-EVs through their adaption to the lethal environment to which they are subjected. This can result in establishment of a more conducive environment and activation of numerous vital trajectories that act to improve the immunomodulatory, reparative and regenerative activities of the derived EVs, as a part of MSCs paracrine system. ALI, acute liver injury; GI diseases, gastrointestinal diseases; HF, hepatic fibrosis; HSP, heat shock protein; miRNA, microRNA; mRNA, messenger RNA; MSC-EVs, mesenchymal stem cell-derived extracellular vesicles; NAFLD, non-alcoholic fatty liver disease; UC, ulcerative colitis.

A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF/NF-ĸB p65/TGF-ß1 and hedgehog/HIF-1α/VEGF trajectories.

Hepatic fibrosis is one of the major worldwide health concerns which requires tremendous research due to the limited outcomes of the current therapies. The present study was designed to assess, for the first time, the potential therapeutic effect of rupatadine (RUP) in diethylnitrosamine (DEN)-induced liver fibrosis and to explore its possible mechanistic actions. For the induction of hepatic fibrosis, rats were treated with DEN (100 mg/kg, i.p.) once weekly for 6 consecutive weeks, and on the 6th week, RUP (4 mg/kg/day, p.o.) was administered for 4 weeks. Treatment with RUP ameliorated changes in body weights, liver indices, liver function enzymes, and histopathological alterations induced by DEN. Besides, RUP amended oxidative stress, which led to the inhibition of PAF/NF-κB p65-induced inflammation, and, subsequently, prevention of TGF-ß1 elevation and HSCs activation as indicated by reduced α-SMA expression and collagen deposition. Moreover, RUP exerted significant anti-fibrotic and anti-angiogenic effects by suppressing Hh and HIF-1α/VEGF signaling pathways. Our results highlight, for the first time, a promising anti-fibrotic potential of RUP in rat liver. The molecular mechanisms underlying this effect involve the attenuation of PAF/NF-κB p65/TGF-ß1 and Hh pathways and, subsequently, the pathological angiogenesis (HIF-1α/VEGF).

The involvement of Nrf2/HO-1/cytoglobin and Ang-II/NF-κB signals in the cardioprotective mechanism of lansoprazole against cisplatin-induced heart injury.

Cardiac toxicity is a serious adverse effect of cisplatin (CIS). Lansoprazole (LPZ) is a proton pump inhibitor with promising cardioprotective effects. Our study planned to examine the cardioprotective effect of LPZ against CIS-induced cardiac injury. To achieve this goal, 32 male rats were randomly allocated into four groups. CIS, 7 mg/kg, was injected i.p. on the fifth day of the experiment. LPZ was administered via oral gavage at a dose of 50 mg/kg. The present study revealed that CIS injection induced a remarkable cardiac injury evidenced by an increase in serum ALP, AST, CK-MB, LDH, and troponin-I levels. The cardiac oxidative damage was also observed after CIS injection and mediated by downregulation of GSH, SOD, GST, Nrf2, HO-1, PPAR-γ, and cytoglobin levels associated with the upregulation of MDA content. Besides, CIS injection caused a significant inflammatory reaction mediated by alteration of cardiac NF-κB, STAT-3, p-STAT-3, and IκB expressions. Additionally, cardiac Ang-II expression was significantly increased in CIS control rats, while Ang 1-7 expression was significantly reduced relative to normal rats. In contrast, LPZ administration remarkably ameliorated these changes in the heart of CIS-intoxicated rats. Collectively, LPZ potently attenuated cardiac toxicity induced by CIS via regulation of Nrf2/HO-1, PPAR-γ, cytoglobin, IκB/NF-κB/STAT-3, and Ang-II/Ang 1-7 signals.

Can Concomitant Bladder Neck Incision and Primary Valve Ablation Reduce Early Re-admission Rate and Secondary Intervention?

OBJECTIVE: To assess the effect of bladder neck morphology and its incision (BNI) in patients with posterior urethral valve (PUV) on early reintervention rate. PATIENTS AND METHODS: Infants undergoing PUV ablation (PVA) before 24 months of age and had at least 18 months of follow-up, were categorized into three groups according to the bladder neck appearance on baseline radiological and endoscopic examination: group 1; normal bladder neck underwent PVA, group 2; high bladder neck underwent PVA plus BNI, group 3; high bladder neck underwent PVA only. Early reintervention was defined as the need for check cystoscopy because of persistent renal function deterioration, worsening hydronephrosis and/or unsatisfactory VCUG improvement during the 1st six months post primary PVA. RESULTS: Between 2000 and 2017, a total of 114 patients underwent PVA and met the study criteria with a median follow-up of 58 (18-230) months. For group 1, 16 (22.9%) patients needed readmission. Check cystoscopy was free and no further intervention was performed in 5(7.5%) and re-ablation was performed in 11(15.7%) patients. For group 2, 3(14.3%) patients needed reintervention. Re-ablation and re-ablation plus BNI were performed in 1(4.8%) and 2(9.5%), respectively. For group 3, cystoscopy was free in 1(4.3%), re-ablation and re-ablation plus BNI were performed 2(8.7%) and 1(4.3%), respectively. There were no significant differences in the re-admission and re-intervention rates among the three study groups (p=0.65 and p=0.50, respectively). CONCLUSION: In morphologically high bladder neck associated PUV, concomitant BNI with PVA doesn't reduce early re-intervention rate.

Chemoprophylaxis during transrectal prostate needle biopsy: critical analysis through randomized clinical trial.

PURPOSE: To compare the efficacy of three chemoprophylaxis approaches in prevention of post-transrectal biopsy infectious complications (TBICs). METHODS: Patients were randomly assigned to receive ciprofloxacin 3 days 500 mg B.I.D 3 days starting the night prior to biopsy (standard prophylaxis), augmented prophylaxis using ciprofloxacin and single preprocedure shot of 160 mg gentamicin IM (augmented prophylaxis) and rectal swab culture-based prophylaxis (targeted prophylaxis). Patients were assessed 2 weeks prior to biopsy, at biopsy and 2 weeks after. Primary end point was occurrence of post-TBICs that included simple UTI, febrile UTI or sepsis. Secondary end points were post-biopsy change in the inflammatory markers (TLC, ESR and CRP), unplanned visits, hospitalization and occurrence of fluoroquinolones resistance (FQ-R; bacterial growth on MacConkey agar plate with 10 µg/ml ciprofloxacin) in the fecal carriage of screened men. RESULTS: Between April/2015 and January/2017, standard, augmented and targeted prophylaxes were given to 163, 166 and 167 patients, respectively. Post-TBICs were reported in 43 (26%), 13 (7.8%) and 34 (20.3%) patients following standard, augmented and targeted prophylaxes protocols, respectively (P = 0.000). Post-TBICs included UTI in 23 (4.6%), febrile UTI in 41 (8.2%) and sepsis in 26 (5.2%) patients. Significantly lower number of post-biopsy positive urine culture was depicted in the augmented group (P = 0.000). The number of biopsy cores was statistically different in the three groups (P = 0.004). On multivariate analysis, augmented prophylaxis had independently lower post-TBICs (OR 0.2, 95% CI 0.1-0.4, P = 0.000) when compared with the other two groups regardless of the number of biopsy cores taken (OR 1.07, 95% CI 0.95-1.17, P = 0.229). Post-biopsy hospitalization was needed in four (2%), one (0.6%) and ten (6%) patients following standard, augmented and targeted prophylaxes, respectively (P = 0.014). However, sepsis-related hospitalization was not statistically different. Post-biopsy changes in the inflammatory markers were significantly less in augmented prophylaxis (P < 0.05). FQ-R was depicted in 139 (83.2%) of the screened men. CONCLUSION: Augmented prophylaxis with single-dose gentamicin is an effective and practical approach. Targeted prophylaxis might be reserved for cases with contraindication to gentamicin.

Vitamin B1 and calcitriol enhance glibenclamide suppression of diabetic nephropathy: Role of HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories.

Glibenclamide is one of the most prescribed insulin secretagogues in diabetes due to its low cost, but its efficacy on suppressing diabetic complications is limited. Here, we examine whether addition of either vitamin B1 or calcitriol to glibenclamide could produce more suppression of diabetic nephropathy. Type 2 diabetes was induced by high fructose (10 % in drinking water), high salt (3 % in diet), and high fat diet (25 % in diet) for 3 weeks, followed by single dose of STZ (40 mg/kg, i.p.). Diabetic rats were treated with either glibenclamide (0.6 mg/kg), vitamin B1 (70 mg/kg), glibenclamide/vitamin B1, calcitriol (0.1 µg/kg), or glibenclamide/calcitriol. Addition of either vitamin B1 or calcitriol to glibenclamide therapy enabled more suppression of diabetic nephropathy development as evidenced by more preserved creatinine clearance and less renal damage scores. Combination therapy resulted in mild enhancement in the effect of glibenclamide on glucose tolerance without affecting the area under the curve. Combination therapy was associated with more suppression of inflammatory cascades as evidenced by reducing the expression of high mobility group box-1 (HMGB1), toll-like receptor-4 (TLR4), nuclear factor-kappa B (NF-κB), and tumor necrosis factor-α (TNF-α). In addition, combination therapy enhanced the antioxidant mechanisms as evidenced by increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione content and reducing malondialdehyde and nitric oxide levels. Furthermore, combination therapy provided more suppression of fibrotic pathways as appear from reducing collagen deposition and the expression of α- smooth muscle actin (α-SMA). In conclusion, addition of vitamin B1 or calcitriol to glibenclamide therapy can enhance the therapeutic efficiency of glibenclamide in suppressing diabetic nephropathy progression to the same extend, the protective effect is mediated through modulating HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories.

Expression of recombinant Florida clade 2 hemagglutinin in baculovirus expression system: A step for subunit vaccine development against H3N8 equine influenza virus.

Background: Equine influenza (EI) is a transmissible viral respiratory sickness of the Equidae family. Two viruses, H7N7 and H3N8 caused EI; however, H7N7 has not been detected for decades. H3N8 has circulated and bifurcated into Eurasian and American lineages. The latter subsequently diversified into Kentucky, South America, and Florida sub-lineages. Florida clade 1 (FC1) and Florida clade 2 (FC2) strains are the only circulating EI viruses (EIVs) in the meantime. Immunization is considered the major means for the prevention and control of EI infection. Using disparate technologies and platforms, several vaccines have been developed and commercialized. According to the recommendations of the World Organization for Animal Health (WOAH), all commercial vaccines shall comprise representatives of both FC1 and FC2 strains. Unfortunately, most of the commercially available vaccines were not updated to incorporate a representative of FC2 strains. Aim: The purpose of this research was to develop a new EI vaccine candidate that incorporates the hemagglutinin (HA) antigen from the currently circulating FC2. Methods: In this study, we report the expression of the full-length recombinant HA gene of FC2 in the baculovirus expression system. Results: The HA recombinant protein has been proven to maintain its biological characteristics by hemadsorption (HAD) and hemagglutination tests. Moreover, using a reference-specific serum, the specificity of the HA has been confirmed through the implementation of immunoperoxidase and western immunoblotting assays. Conclusion: In conclusion, we report the expression of specific biologically active recombinant HA of FC2, which would act as a foundation for the generation of an updated EI subunit or virus vector vaccine candidates.

Unlocking the miRNA-34a-5p/TGF-ß and HMGB1/PI3K/Akt/mTOR crosstalk participate in the enhanced cardiac protection of liraglutide against isoproterenol-induced acute myocardial injury rat model.

Liraglutide (LIRA), a drug used to treat type 2 diabetes mellitus that belongs to the glucagon-like peptide-1 class, has recently drawn attention for its potential cardioprotective properties because of its anti-oxidative and anti-inflammatory properties. This current investigation was designed to assess the impact of LIRA on myocardial injury induced by isoproterenol (ISO). The experiment included 24 male Wistar rats in total, and they were divided into four groups: Control, LIRA (200 µg/kg/12 hrs., S.C.), ISO (85 mg/kg, S.C.), and ISO + LIRA. To assess the results, various biochemical and histopathological analyses were carried out. The findings showed elevated serum enzyme levels, a sign of cardiac injury. ISO-treated rats showed an upregulation of oxidative stress and inflammatory biomarkers like MDA, MPO, nitrites, NADPH oxidase, TNF-α, IL-1ß, IL-6, 8-Hydroxyguanosine (8-OHdG), and TGF-ß, as well as altered gene expressions like TLR-1 and miRNA-34a-5p. According to western blotting analysis, protein levels of AKT, PI3K, and mTOR were obviously enhanced. Additionally, ISO-treated samples showed altered tissue morphology, elevated caspase 3, and decreased Bcl2 concentrations. The levels of these dysregulated parameters were significantly normalized by LIRA therapy, demonstrating its cardioprotective function against ISO-induced myocardial injury in rats. This protective mechanism was linked to anti-inflammatory properties, redox balance restoration, and modulation of the miRNA-34a-5p/TGF-ß pathway.

Mitigation of biochemical alterations in streptozotocin-induced gestational diabetes in rats through mesenchymal stem cells and olive leaf extract.

Treatment with mesenchymal stem cells (MSCs) is a new promising therapeutic approach with substantial very auspicious potential. They have been shown to protect various played a role in protecting organs from damage. This current study aims to evaluate the impact of the treatment of olive leaf extract (OLE), bone marrow-derived (BM-MSCs), and their combination on hepatotoxicity in pregnant rats with diabetes. METHODS: Animals were divided into five groups (10 pregnant rats each) as follows: control, GDM group, and OLE group (rats received streptozotocin (STZ) at a dose of 35 mg/kg body weight). GD + OLE set (pregnant rats were administered OLE at a dose of 200 mg extract/kg of body weight). GD + MSCs group (pregnant rats treated with MSCs). GD + OLE + MSCs group (pregnant rats were treated with both MSCs and OLE). RESULTS: STZ induced significant changes in liver parameters, lipid profile, and oxidative stress. Treatment with OLE, BM-MSCs, and their combination significantly ameliorated STZ-induced liver damage and oxidative stress. STZ resulted in a significant change in liver parameters, lipid profile, and oxidative stress. OLE, BM-MSC, and combination have significantly improved STZ-induced deterioration in liver and improved oxidative stress. CONCLUSIONS: The findings demonstrate that OLE and BM-MSCs have beneficial effects in mitigating diabetes-related liver alterations. These outcomes showed that OLE and BM-MSC have beneficial effects in alleviating diabetes-related alterations in the liver.

Mobility and Sporting Activity After Renal Trauma: A Survey Regarding Best Clinical Practice During the Recovery Stage.

OBJECTIVE: To evaluate strategies that are followed after pediatric renal trauma during the recovery stage, with an emphasis on mobility and involvement in subsequent sporting activities. Renal trauma is the most common urogenital trauma in children. The American Association for the Surgery of Trauma (AAST) scale is most commonly used to stratify the severity of injury. There is no consensus in the existing literature with respect to the recovery stage following renal trauma. METHODS: A survey was constructed by the European Association of Urology (EAU) - Young Academic Urologists (YAU) Pediatric Urology Working Group and then made digitally available on SurveyMonkey. The survey consists of 15 questions exploring relevant factors and timing to start again with mobility and activity. RESULTS: In total 153 people responded, of whom 107 completed the entire survey. The presence of pain and severity of trauma were acknowledged as most important factors to commence mobilization, whereas presence of hematuria was identified as an additional factor for sporting activity. Regardless of severity of trauma a minimum of 90% of respondents recommend return to noncontact sports within 12weeks. For contact sports, a minimum of 33% of respondents advised >12weeks minimum before starting again. A small number of respondents would never allow sporting activities again. CONCLUSION: The time to allow sporting activity shows high variation among the respondents, some even restricting sporting activities completely. This survey highlights the need for a standardized protocol based on multicenter follow-up data.

Combined diosmin and bisoprolol attenuate cobalt chloride-induced cardiotoxicity and endothelial dysfunction through modulating miR-143-3P/MAPK/MCP-1, ERK5/CXCR4, Orai-1/STIM-1 signaling pathways.

Even while accelerated cardiomyocyte apoptosis is one of the primary causes of cardiac damage, the underlying mechanism is still mostly unknown. In addition to examining potential protective effects of bisoprolol and diosmin against CoCl2-induced cardiac injury, the goal of this study was to identify potential mechanisms regulating the hypoxic cardiac damage caused by cobalt chloride (CoCl2). For a period of 21 days except Cocl2 14 days from the first day of the experiment, rats were split into the following groups: Normal control group, rats received vehicle only (2 ml/kg/day, p.o.), (Cocl2, 150 mg/kg/day, p.o.), bisoprolol (25 mg/kg/day, p.o.); diosmin (100 mg/kg/day, p.o.) and bisoprolol + diosmin + Cocl2 groups. At the end of the experimental period, serum was taken for estimation of cardiac function, lipid profile, and pro/anti-inflammatory cytokines. Moreover, tissue samples were collected for evaluation of oxidative stress, endothelial dysfunction, α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Diosmin and bisoprolol, either alone or in combination, enhance heart function by reducing abnormalities in the electrocardiogram and the hypotension brought on by CoCl2. Additionally, they significantly ameliorate endothelial dysfunction by downregulating the cardiac expressions of α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Bisoprolol and diosmin produced modulatory activity against inflammatory state, redox balance, and atherogenic index concurrently. Together, diosmin and bisoprolol, either alone or in combination, significantly reduced all the cardiac alterations brought on by CoCl2. The capacity to obstruct hypoxia-induced α-SMA, PKC-α, MiR-143-3P/MAPK/MCP-1, MiR-143-3P/ERK5/CXCR4, Orai-1/STIM-1 signaling activation, as well as their anti-inflammatory, antioxidant, and anti-apoptotic properties, may be responsible for these cardio-protective results.

Combined sulforaphane and ß-sitosterol mitigate olanzapine-induced metabolic disorders in rats: Insights on FOXO, PI3K/AKT, JAK/STAT3, and MAPK signaling pathways.

One of the best antipsychotics for treating schizophrenia and bipolar disorders is olanzapine (OLA). However, its use is restricted owing to unfavorable adverse effects as liver damage, dyslipidemia, and weight gain. The primary objective of the present investigation was to examine the signaling mechanisms that underlie the metabolic disruption generated by OLA. Besides, the potential protective effect of sulforaphane (SFN) and ß-sitosterol (ßSS) against obesity and metabolic toxicity induced by OLA were inspected as well. A total of five groups of male Wistar rats were established, including the control, OLA, SFN+OLA, ßSS+OLA, and the combination + OLA groups. Hepatic histopathology, biochemical analyses, ultimate body weights, liver function, oxidative stress, and pro-inflammatory cytokines were evaluated. In addition to the relative expression of FOXO, the signaling pathways for PI3K/AKT, JAK/STAT3, and MAPK were assessed as well. All biochemical and hepatic histopathological abnormalities caused by OLA were alleviated by SFN and/or ßSS. A substantial decrease in systolic blood pressure (SBP), proinflammatory cytokines, serum lipid profile parameters, hepatic MDA, TBIL, AST, and ALT were reduced through SFN or/and ßSS. To sum up, the detrimental effects of OLA are mediated by alterations in the Akt/FOXO3a/ATG12, Ras/SOS2/Raf-1/MEK/ERK1/2, and Smad3,4/TGF-ß signaling pathways. The administration of SFN and/or ßSS has the potential to mitigate the metabolic deficit, biochemical imbalances, hepatic histological abnormalities, and the overall unfavorable consequences induced by OLA by modulating the abovementioned signaling pathways.

Has robot-assisted pyeloplasty reached outcome parity with laparoscopic pyeloplasty in children <15 kg? A Paediatric YAU international multi-center study.

INTRODUCTION: Ureteropelvic Junction Obstruction (UPJO), is a major cause of pathological hydronephrosis in children. Minimally invasive surgery (MIS), including laparoscopic pyeloplasty (LP) and robot-assisted laparoscopic pyeloplasty (RALP), has gained popularity due to its known advantages. LP faces technical difficulties and a steep learning curve. RALP has overcome these limitations, making it safer and more effective for children. The study aims to assess the safety and effectiveness of LP and RALP in infants weighing ≤15 kg. MATERIALS AND METHODS: This is a retrospective analysis (2010-2022). The study included pediatric patients who had a confirmed diagnosis of UPJO and weighed ≤15 kg. The patients were divided into two groups: LP and RALP. The study evaluated preoperative, intraoperative, perioperative, and follow-up data, including complications. Success was defined as no worsening of hydronephrosis on postoperative ultrasound in the first year of follow-up. RESULTS: The total patients were 94: 42 in the LP group, and 52 in the RALP group. The median age at the intervention was 17.5 months (LAP group) versus 29 months (RALP group) (p = 0.01). The median weight at the time of intervention was 9.5 Kg (LP group), and 11.6 Kg (RALP group) (p = 0.44). The median operative time was significantly longer in the LP group: 245 min versus 125.5 min in the RALP group (p = 0.001). The median length of hospitalization was comparable: 4.3 days (LP group) and 3.5 days (RALP group) (p = 0.42). No intraoperative complications were reported in either group. There were no statistically significant differences regarding postoperative complications. During follow-up, all patients remained asymptomatic, with no episodes of urinary tract infection or abdominal pain, and none of them had a recurrence of UPJ obstruction. Consequently, the two techniques are equally effective and safe in the short term. DISCUSSION: Both procedures offer excellent outcomes with comparable postoperative complications. LOS was similar for both groups, with no intraoperative complications or conversions, and a non-significant increase in postoperative complications. A notable finding was the significant difference in operation times between the procedures, emphasizing the importance of reduced surgical time in pediatric patients for minimizing anesthetic and intubation durations. CONCLUSION: For the absence of intra- and postoperative complications and recurrences, RALP is as effective as LP in pyeloplasty in children weighing 15 kg or less. This finding reinforces the idea that RALP can be safely executed, benefiting from its advanced technology and the learning curve, for patients of any age regarding pyeloplasty for UPJO.

A First Metabolite Analysis of Norfolk Island Pine Resin and Its Hepatoprotective Potential to Alleviate Methotrexate (MTX)-Induced Hepatic Injury.

Drug-induced liver injury (DILI) represents a significant clinical challenge characterized by hepatic dysfunction following exposure to diverse medications. Methotrexate (MTX) is a cornerstone in treating various cancers and autoimmune disorders. However, the clinical utility of MTX is overshadowed by its ability to induce hepatotoxicity. The current study aims to elucidate the hepatoprotective effect of the alcoholic extract of Egyptian Araucaria heterophylla resin (AHR) on MTX-induced liver injury in rats. AHR (100 and 200 mg/kg) significantly decreased hepatic markers (AST, ALT, and ALP), accompanied by an elevation in the antioxidant's markers (SOD, HO-1, and NQO1). AHR extract also significantly inhibited the TGF-ß/NF-κB signaling pathway as well as the downstream cascade (IL-6, JAK, STAT-3, and cyclin D). The extract significantly reduced the expression of VEGF and p38 with an elevation in the BCL2 levels, in addition to a significant decrease in the IL-1ß and TNF-α levels, with a prominent effect at a high dose (200 mg/kg). Using LC-HRMS/MS analysis, a total of 43 metabolites were tentatively identified, and diterpenes were the major class. This study presents AHR as a promising hepatoprotective agent through inhibition of the TGF-ß/NF-κB and JAK/STAT3 pathways, besides its antioxidant and anti-inflammatory effects.

Farnesol attenuates cadmium-induced kidney injury by mitigating oxidative stress, inflammation and necroptosis and upregulating cytoglobin and PPARγ in rats.

Heavy metals are environmental pollutants that can harm animals and humans even at low concentrations. Cadmium (Cd) is known for its serious health effects on different organs and its toxicity is associated with oxidative stress (OS) and inflammation. Farnesol (FAR), a sesquiterpene alcohol found in many vegetables and fruits, possesses promising anti-inflammatory and antioxidant activities. This study evaluated the effect of FAR on Cd-induced kidney injury, pinpointing its effect of the redox status, inflammation, fibrosis and necroptosis. Rats in this study received FAR for 14 days and Cd on day 7. Elevated serum creatinine, urea and uric acid, and several kidney histopathological alterations were observed in Cd-administered rats. Cd increased MDA, decreased antioxidants, downregulated PPARγ and upregulated NF-κB p65, IL-6, TNF-α, and IL-1ß. Necroptosis mediators (RIP1, RIP3, MLKL, and caspase-8) and α-SMA were upregulated, and collagen deposition was increased in Cd-administered rats. FAR ameliorated kidney injury markers and tissue damage, attenuated OS, suppressed NF-κB and inflammatory mediators, and enhanced antioxidants. In addition, FAR suppressed RIP1, RIP3, MLKL, caspase-8, and α-SMA, and enhanced kidney cytoglobin and PPARγ. In conclusion, FAR protects against Cd nephrotoxicity by suppressing OS, inflammatory response and necroptosis, effects associated with enhanced antioxidants, cytoglobin, and PPARγ.

The potential anti-Alzheimer's activity of Oxalis corniculata Linn. Methanolic extract in experimental rats: Role of APOE4/LRP1, TLR4/NF-κß/NLRP3, Wnt 3/ß-catenin/GSK-3ß, autophagy and apoptotic cues.

ETHNOPHARMACOLOGICAL RELEVANCE: Oxalis corniculata (O. corniculata) is a member of Oxalidaceae family, widely distributed in Asia, Europe, America, and Africa, used extensively as food and its traditional folkloric uses include management of epilepsy, gastric disorders, and neurodegenerative diseases, together with its use in enhancing health. Numerous pharmacological benefits of O. corniculata are linked to its anti-inflammatory and antioxidant abilities. One of the most prevalent neurodegenerative disorders is Alzheimer's disease (AD) in which neuroinflammation and oxidative stress are its main pathogenic processes. AIM OF THE STUDY: Our research aimed to study the neuroprotective effect of the methanolic extract of Oxalis corniculata Linn. (O. corniculata ME), compared to selenium (Se) against AlCl3-induced AD. MATERIALS AND METHODS: Forty male albino rats were allocated into four groups (Gps). Gp I a control group, the rest of the animals received AlCl3 (Gp II-Gp IV). Rats in Gp III and IV were treated with Se and O. corniculata ME, respectively. RESULTS: The chemical profile of O. corniculata ME was studied using ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry, allowing the tentative identification of sixty-six compounds, including organic acids, phenolics and others, cinnamic acid and its derivatives, fatty acids, and flavonoids. AlCl3 showed deterioration in short-term memory and brain histological pictures. Our findings showed that O. corniculata ME and selenium helped to combat oxidative stress produced by accumulation of AlCl3 in the brain and in prophylaxis against AD. Thus, Selenium (Se) and O. corniculata ME restored antioxidant defense, via enhancing Nrf2/HO-1 hub, hampered neuroinflammation, via TLR4/NF-κß/NLRP3, along with dampening apoptosis, Aß generation, tau hyperphosphorylation, BACE1, ApoE4 and LRP1 levels. Treatments also promoted autophagy and modulated Wnt 3/ß-catenin/GSK3ß cue. CONCLUSIONS: It was noted that O. corniculata ME showed a notable ameliorative effect compared to Se on Nrf2/HO-1, TLR4/NF-κß/NLRP3, APOE4/LRP1, Wnt 3/ß-catenin/GSK-3ß and PERK axes.