Aging, a complex physiological process affecting all living things, is a major area of research, particularly focused on interventions to slow its progression. This study assessed the antiaging efficacy of dapagliflozin (DAPA) on various aging-related parameters in a mouse model artificially induced to age. Forty male Swiss albino mice were randomly divided into four groups of ten animals each. The control group (Group I) received normal saline. The aging model group (Group II) was administered D-galactose orally at 500mg/kg to induce aging. Following the aging induction, the positive control group received Vitamin C supplementation (Group III), while the DAPA group (Group IV) was treated with dapagliflozin. The inflammatory mediators (TNF-α and IL-1β) showed similar patterns of change. No statistically significant difference was observed between groups III and IV. Both groups had significantly lower values compared to GII, while it was significantly higher compared to GI. Glutathione peroxidase (GSH-Px) showed no statistically significant difference between groups GIII and GIV, but it was higher in GIII compared to GII and significantly lower in GIII compared to GI. The study demonstrated that dapagliflozin exerts a beneficial impact on many indicators of aging in mice. The intervention resulted in a reduction in hypertrophy in cardiomyocytes, an enhancement in skin vitality, a decrease in the presence of inflammatory mediators, and an improvement in the efficacy of antioxidants.

UNASSIGNED: The immunosuppressant tacrolimus is a major cause of new-onset diabetes after transplantation. The aim of this study was to evaluate whether a low dose of the histone-deacetylase inhibitor (vorinostat) might ameliorate tacrolimus-induced new-onset diabetes.
UNASSIGNED: Thirty 8-week-old male Wistar rats were randomly divided into five groups: a control group, tacrolimus group (1.5 mg/kg intraperitoneally for 28 days), vorinostat group (15 mg/kg orally for 28 days), a group receiving tacrolimus with vorinostat for 28 days; and a group receiving coadministration of tacrolimus for 28 days and vorinostat for 14 days. Diabetes development was assessed on the basis of serum glucose, insulin, HOMA-IR and C-peptide. To investigate the mechanism of vorinostat, we assessed inflammatory markers (tumor necrosis factor-α and interleukin-1β), an antioxidant marker (glutathione), an oxidant marker (nicotinamide adenine dinucleotide phosphate hydrogen oxidase) and an apoptosis marker (caspase-3). Kidney functions (creatinine and blood urea nitrogen) were also assessed.
UNASSIGNED: The administration of tacrolimus for 28 days resulted in significantly increased serum glucose and decreased C-peptide and insulin levels than those in the control group. However, coadministration of vorinostat significantly decreased hyperglycemia and increased C-peptide and insulin levels. Moreover, combined treatment with tacrolimus and vorinostat, compared with tacrolimus treatment alone, resulted in significantly reduced inflammatory and oxidant markers, and increased glutathione. Additionally, vorinostat improved the kidney parameters.
UNASSIGNED: Vorinostat at a low dose (15 mg/kg) induces anti-inflammatory and antioxidative effects that protect the pancreas and kidney against the development of new-onset diabetes due to tacrolimus in rats. This experimental study provides insights supporting further clinical trials to improve the post-kidney transplantation protocol through addition of vorinostat to the immunosuppressive regimen.
UNASSIGNED: يعتبر مثبط المناعة (التاكروليموس) أهم مسبب للإصابة بنوع السكري الجديد ما بعد زراعة الكلى. تهدف الدراسة لتقييم فعالية الفورينوستات (مثبط الهستون-دياسيتايلاز) في التحكم بالسكري الناتج عن التاكروليموس.
UNASSIGNED: تم تقسيم ثلاثين ذكر من جرذان ويستر البالغة 8-أسابيع عشوائيا إلى ٥ مجموعات: المجموعة الضابطة، مجموعة التاكروليموس (١.٥ مجم/كجم، داخل الصفاق لمدة ٢٨ يوم)، مجموعة الفورينوستات (١٥ مجم/كجم، عن طريق الفم لمدة ٢٨ يوم). ومجموعتان تم إعطاؤهما الدوائين معا: مجموعة التاكروليموس مع الفورينوستات لمدة ٢٨ يوم، ومجموعة التاكروليموس مع الفورينوستات لمدة ١٤ يوم قبل نهاية التجربة. تم تقييم تطور السكري بقياس نسبة الجلوكوز والأنسولين والببتيد الرابط. وللتحقق من آلية عمل الفورينوستات، تم قياس علامات الالتهاب (عامل نخر الورم-ألفا و انترلوكين١بيتا)، علامات مضادات الأكسدة (الجلوتاثيون) والأكسدة (أكسيد فوسفات ثنائي نيوكلوتيد الأدينين) ومؤشر موت الخلايا المبرمج (كاسباس-٣). أيضاً تم تقييم وظائف الكلى (اليوريا والكرياتينين).
UNASSIGNED: أدى العلاج بالتاكروليموس لمدة 28 يوم إلى زيادة ملحوظة في مستوى السكر وانخفاض في مستويات الببتيد الرابط والأنسولين مقارنة بالمجموعة الضابطة. ومع ذلك، فإن تزامن أخذ الدوائين معا قلل بشكل ملحوظ من ارتفاع السكر وزيادة مستويات الببتيد الرابط والأنسولين. كما قلل جمع الدوائين بشكل ملحوظ مستويات علامات الالتهاب والاكسدة وكاسباس-٣ مع زيادة مستوى الجلوتاثيون مقارنة بالمجموعة المعالجة بالتاكروليموس. أيضا، حافظ الفورينوستات على مستويات عوامل الكلى ضمن المعدل الطبيعي.
UNASSIGNED: استخدام الفورينوستات بجرعة صغيرة (15 مجم/كجم) يستحث التأثير المضاد للالتهاب والمضاد للأكسدة والتي تحمي بنكرياس وكلى الجرذان من الاصابة بالسكري الناتج عن التاكروليموس. تفتح هذه الدراسة الطريق لمزيد من التجارب السريرية لتحسين بروتوكول ما بعد زراعة الكلى عن طريق إضافة الفورينوستات في النظام العلاجي لمثبطات المناعة.

Osseointegration seems to be a foreign body reaction equilibrium due to the complicated interactions between the immune and skeletal systems. The heterogeneity of the osteoimmune microenvironment in the osseointegration of implant materials remains elusive. Here, a single-cell study involving 40043 cells is conducted, and a total of 10 distinct cell clusters are identified from five different groups. A preliminary description of the osteoimmune microenvironment revealed the diverse cellular heterogeneity and dynamic changes modulated by implant properties. The increased immature neutrophils, Ly6C + CCR2hi monocytes, and S100a8hi macrophages induce an aggressive inflammatory response and eventually lead to the formation of fibrous capsule around the stainless steel implant. The enrichment of mature neutrophils, FcgR1hi and differentiated immunomodulatory macrophages around the titanium implant indicates favorable osseointegration under moderate immune response. Neutrophil-depletion mice are conducted to explore the role of neutrophils in osseointegration. Neutrophils may improve bone formation by enhancing the recruitment of BMSCs via the CXCL12/CXCR3 signal axis. These findings contribute to a better knowledge of osteoimmunology and are valuable for the design and modification of \'osteoimmune-smart\' biomaterials in the bone regeneration field.

Ethylene glycol monomethyl ether (EGME) has been used in many products usually handled by humans including inks, paints, polishes, brake fluids and so on. This present study therefore, investigated its effect on lung, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of EGME for a period of 7, 14, and 21 days. Following 7 days of oral exposure to EGME, activities of GPx and SOD were significantly increased, as well as levels of K-Ras, c-Myc, p53, caspase-3, TNF-α and, IL-6, while NO level and GST activity were significantly reduced compared with control. At the end of 14 days exposure, GSH level was significantly decreased, while levels of K-Ras, c-Myc, p53, caspase-3, TNF-α, IL-6, NO and the activities of SOD and GPx were significantly elevated with respect to control. After 21 days of EGME administration, levels of Bcl-2, IL-10, GSH and NO as well as GST activity were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, IL-6, IL-1β, TNF-α, as well as GPx, CAT, and SOD activities were significantly elevated compared with control. Lung histopathology revealed chronic disseminated alveolar inflammation, bronchiolitis, severe alveolar and bronchi hyperplasia, severe disseminated inflammation, thrombosis, and thickened vessels as a result of EGME exposures. Exposures to EGME could trigger lung damage via the disorganization of the antioxidant system, eliciting the up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

BACKGROUND: Currently, spinal cord injury (SCI) is a pathological incident that triggers several neuropathological conditions, leading to the initiation of neuronal damage with several pro-inflammatory mediators\' release. However, pyroptosis is recognized as a new programmed cell death mechanism regulated by the stimulation of caspase-1 and/or caspase-11/-4/-5 signaling pathways with a series of inflammatory responses.
OBJECTIVE: Our current review concisely summarizes the potential role of pyroptosis-regulated programmed cell death in SCI, according to several molecular and pathophysiological mechanisms. This review also highlights the targeting of pyroptosis signaling pathways and inflammasome components and its therapeutic implications for the treatment of SCI.
UNASSIGNED: Multiple pieces of evidence have illustrated that pyroptosis plays significant roles in cell swelling, plasma membrane lysis, chromatin fragmentation and intracellular pro-inflammatory factors including IL-18 and IL-1β release. In addition, pyroptosis is directly mediated by the recently discovered family of pore-forming protein known as GSDMD. Current investigations have documented that pyroptosis-regulated cell death plays a critical role in the pathogenesis of multiple neurological disorders as well as SCI. Our narrative article suggests that inhibiting the pyroptosis-regulated cell death and inflammasome components could be a promising therapeutic approach for the treatment of SCI in the near future.

Ethylene glycol monomethyl ether (EGME) is a major component of paints, lacquers, inks, and automobile brake fluids. As a result, exposures to humans are inevitable. We therefore, investigated in this study, its effect on testicular cells in a time-course manner in male Wistar rats. Animals were orally administered 50 mg/kg body weight of EGME for duration of 7, 14, and 21 days. Following 7 days of the administration, levels of NO and GSH were significantly reduced, while levels of c-Myc, K-Ras, caspase-3, IL-6, TNF-α, and IL-1β were significantly increased compared with control. At the end of 14 days exposure, GPx, and SOD activities, as well as IL-10 level were significantly decreased, while levels of c-Myc, K-Ras, p53, Bax, caspase-3, IL-6, TNF-α, IL-1β, and GST activity were significantly elevated compared with control. After 21 days of EGME administration, Bcl-2, IL-10, and NO levels were significantly decreased, while levels of c-Myc, K-Ras, p53, Bax, caspase-3, IL-6, TNF-α, IL-1β, MDA and GST activity were significantly increased compared with control. After 7, 14, and 21 days of EGME administrations, testis histopathology showed severe loss of seminiferous tubules, the seminiferous epithelium revealed very few spermatocytes, spermatids, spermatogonia, spermatozoa, and Sertoli cells, while the interstitial tissue is eroded, with scanty abnormal Leydig cells, compared with the control that appeared normal. We therefore, concluded that EGME-induced testicular toxicity as a result of EGME administration could be via the disorganization of the endogenous antioxidant systems as well as up-regulation of pro-inflammatory, apoptotic and oncogenic mediators in rats.

2-methoxyethanol (2-ME) is an organic solvent widely used in the manufacture of brake fluids, paints, resins, varnish, nail polish, acetate cellulose, wood coloring, and as a plasticizer in plastics manufacturing. We therefore, investigated its effect on the liver, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of 2-ME for a period of 7, 14, and 21 days. Following 7 days of administration of 2-ME, there was a significant increase in the level of Bax, c-Myc, K-Ras, TNF-α, IL-1β, IL-6, MDA and GPx activity, while the levels of Bcl-2, NO and GSH were significantly reduced compared with control. At the end of 14 days exposure, Bcl-2, and GSH levels, as well as GST activity, were significantly decreased, while levels of Bax, c-Myc, K-Ras, caspase-3, TNF-α, IL-1β, IL-6, MDA and NO were significantly increased compared with control. After 21 days of 2-ME administration, Bcl-2, IL-10, and GSH levels, as well as SOD and GST activities, were significantly decreased, while levels of Bax, c-Myc, K-Ras, caspase-3, p53, TNF-α, IL-1β, IL-6, MDA and NO were significantly increased compared with control. Lastly, liver histopathology confirmed and corroborated the biochemical findings reported above. We therefore, advised that exposures to 2-ME should be strictly avoided as it could trigger hepatic damage through the disorganization of the antioxidant system, up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

Methyl cellosolve (MC) is used in production of textile, paints, stains, inks, surface coatings, and anti-icing additive in hydraulic fluids and jet fuel. Consequently, the present study investigated its effect on renal cells, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of MC for a period of 7, 14, and 21 days. Following 7 days of administration of MC, there was a significant increase in the levels of K-Ras, c-Myc, TNF-α, IL-6 and NO, while GSH level and SOD activity were significantly reduced compared with control. At the end of 14 days exposure, RKW, GSH, NO, and Bcl-2 levels were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, TNF-α, IL-1β, IL-6, MDA and GPx activity were significantly increased compared with control. After 21 days of MC administration, RKW, GSH, NO, IL-10 and Bcl-2 levels were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, TNF-α, IL-1β, IL-6, MDA and GST activity were significantly increased compared with control. Exposures to MC in any way should be strictly avoided as it could trigger renal damage through the disorganization of the antioxidant system, up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

OBJECTIVE: Lipid peroxides and their reactive aldehyde derivatives (LPPs) have been linked to obesity-related pathologies, but whether they have a causal role has remained unclear. Glutathione peroxidase 4 (GPx4) is a selenoenzyme that selectively neutralizes lipid hydroperoxides, and human gpx4 gene variants have been associated with obesity and cardiovascular disease in epidemiological studies. This study tested the hypothesis that LPPs underlie cardio-metabolic derangements in obesity using a high fat, high sucrose (HFHS) diet in gpx4 haploinsufficient mice (GPx4(+/-)) and in samples of human myocardium.
METHODS: Wild-type (WT) and GPx4(+/-) mice were fed either a standard chow (CNTL) or HFHS diet for 24 weeks, with metabolic and cardiovascular parameters measured throughout. Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart. Biochemical analysis was also performed on samples of human atrial myocardium from a cohort of 103 patients undergoing elective heart surgery.
RESULTS: Following HFHS diet, WT mice displayed moderate increases in 4-hydroxynonenal (HNE)-adducts and carbonyl stress, and a 1.5-fold increase in GPx4 enzyme in both liver and heart, while gpx4 haploinsufficient (GPx4(+/-)) mice had marked carbonyl stress in these organs accompanied by exacerbated glucose intolerance, dyslipidemia, and liver steatosis. Although normotensive, cardiac hypertrophy was evident with obesity, and cardiac fibrosis more pronounced in obese GPx4(+/-) mice. Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4(+/-) but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes. Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients.
CONCLUSIONS: These findings suggest LPPs are key factors underlying cardio-metabolic derangements that occur with obesity and that GPx4 serves a critical role as an adaptive countermeasure.

Acute liver failure (ALF) is a rare, potentially fatal complication of severe hepatic illness resulting from various causes. In a clinical setting, severe hepatic injury is usually recognised by the appearance of jaundice, encephalopathy and coagulopathy. The central and most important clinical event in ALF is occurrence of hepatic encephalopathy (HE) and cerebral edema which is responsible for most of the fatalities in this serious clinical syndrome. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a central role in the pathogenesis. The role of newer ammonia lowering agents is still evolving. Liver transplant is the only effective therapy that has been identified to be of promise in those with poor prognostic factors, whereas in the others, aggressive intensive medical management has been documented to salvage a substantial proportion of patients. A small fraction of patients undergo liver transplant and the remaining are usually treated with medical therapy. Therefore, identification of the complications and causes of death in such patients, and use of appropriate prognostic models to identify those who need liver transplant and those who can be managed with medical treatment is a vital component of therapeutic strategy. In this review, we discuss the various pathogenetic mechanisms and treatment options available.