Traumatic brain injury (TBI) is a prevalent neurological disorder with significant morbidity and mortality rates, often leading to systemic inflammatory responses and secondary organ damage. Among the organs affected, the liver is particularly vulnerable, with the inflammatory process following TBI impairing liver function and worsening disease progression. Despite existing treatments, there remains a need for effective therapies to mitigate organ damage in the aftermath of TBI. Melatonin, a neurohormone known for its anti-inflammatory and antioxidant properties, has shown potential as a therapeutic agent for reducing such damage. Tasimelteon (TASI), a melatonin agonist, binds to melatonin receptors and exhibits similar biological effects. However, limited research exists on the protective effects of TASI against TBI-induced liver damage, and its potential dose-dependency remains unclear.This study aimed to investigate the impact of TASI on the inflammatory response in traumatic secondary liver injury (TSLI) induced by TBI, specifically evaluating the role of anti-inflammatory cytokine interleukin (IL)-10 levels. Forty Wistar Albino male rats were divided into four groups: sham, TSLI (trauma induced by dropping a 50 g weight from a height of 80 cm to create 0.2 N severity according to Newton's law), TASI-1 (TSLI+TASI 1 mg/kg, ip) and TASI-10 (TSLI+TASI 10 mg/kg, IP). After 48 hours, rats were sacrificed under anesthesia and the liver tissues were collected for histopathological and immunohistochemical examination. The TSLI group exhibited moderate hyperemia, mild hemorrhages, inflammatory cell infiltrations, and necrosis, along with increased IL-1(3, TNF-alpha, and decreased IL-10 expression levels compared to the sham group. Treatment with TASI significantly reversed these findings in both TASI-treated groups. Our results suggest that TASI, a melatonin agonist, effectively attenuates inflammatory liver damage induced by TBI in a dose-dependent manner by increasing IL-10 levels. However, these positive effects should be further explored in future studies.

Sepsis-associated liver injury is a major cause of morbidity and mortality, with oxidative stress, inflammation, and apoptotic signaling playing central roles in pathogenesis. Non-invasive physical modalities such as pulsed magnetic fields (PMF) and radiofrequency electromagnetic fields (RF-EMF) have shown organ-protective effects in various experimental settings; however, their combined application in hepatic inflammation has not been previously investigated. Forty female Wistar rats were randomized into five groups: Control, LPS, LPS + PMF, LPS + RF, and LPS + PMF+RF. Acute liver injury was induced with intraperitoneal LPS. PMF and RF-EMF were applied individually or in combination. Liver tissues were analyzed by histopathology, immunohistochemistry, and RT-qPCR for oxidative (NRF2, SOD), inflammatory (TNF-α), mitochondrial apoptotic (BCL2, BAX, Cyt-C, Caspase-9), and ER stress (PERK, Caspase-12, Caspase-3) markers. Serum ALT, AST, and albumin levels were also measured. LPS significantly increased TNF-α, BAX, Cyt-C, Caspase-9, PERK, Caspase-12, and Caspase-3 expression, while decreasing NRF2, SOD, and BCL2 (all ***p < 0.001). Both PMF and RF monotherapies partially restored these parameters; however, the combined PMF + RF application achieved the most pronounced effects at the molecular and histopathological levels, normalizing oxidative stress markers, reducing pro-inflammatory and apoptotic signaling, and improving histopathological scores (all **p < 0.05 to ***p < 0.001 vs. LPS). Serum AST and ALT levels were significantly reduced by PMF monotherapy, while RF and combined PMF + RF treatments also produced significant decreases compared to the LPS group, albeit to a lesser extent. Serum albumin levels remained unchanged across all groups. Concurrent low-frequency PMF and RF-EMF exposure confers synergistic hepatoprotection in endotoxin-induced liver injury by modulating oxidative, inflammatory, and apoptotic pathways. These findings suggest that dual-modality PMF and RF-EMF exposure may represent a promising non-invasive experimental strategy for mitigating endotoxin-driven hepatic injury. Further studies in clinically relevant sepsis and ischemia-reperfusion models, with extended follow-up and mechanistic validation, are warranted before translational inference.

Background and Objectives: Traumatic brain injury (TBI) triggers oxidative stress, mitochondrial dysfunction, and sterile inflammation. Amantadine (ATD), a weak NMDA receptor antagonist, has shown neuroprotective potential, but its mechanistic basis remains unclear. This study examined whether ATD treatment is associated with changes in molecular and histological markers related to the HIF-1α/BNIP3L/HMGB1-mediated hypoxia–mitophagy–inflammation response in a rat TBI model. Materials and Methods: Thirty-two Wistar rats were assigned to four groups: sham, trauma, trauma + ATD (1 day), and trauma + ATD (7 days). TBI was induced using the impact-acceleration model, and ATD (45 mg/kg, i.p.) was administered post-injury. Oxidative stress indices (TOS, TAS, OSI), histopathology, inflammatory/apoptotic markers (CRP, TNF-α, Caspase-3), and gene expression (HIF-1α, BNIP3L, HMGB1) were evaluated. Results: ATD improved oxidative balance and histopathological integrity while reducing TNF-α, CRP, and Caspase-3 immunoreactivity. qPCR analysis showed lower HIF-1α, BNIP3L, and HMGB1 expression in ATD-treated groups, which is consistent with attenuation of hypoxia-related, mitochondrial stress-associated, and damage-associated molecular pattern-associated signaling after injury. Conclusions: In this experimental model, amantadine ameliorated oxidative, inflammatory, and apoptotic markers and was associated with reduced expression of HIF-1α, BNIP3L, and HMGB1. These findings support a mechanistic correlation between ATD treatment and suppression of secondary injury signatures; however, causal pathway relationships and functional neurological outcomes were not assessed.

Methotrexate (MTX) is a cornerstone chemotherapeutic and immunosuppressive agent widely used in the treatment of hematological malignancies, including acute lymphoblastic leukemia, Burkitt lymphoma, and primary central nervous system lymphoma. Despite its clinical efficacy, MTX use may be limited by pulmonary toxicity, a rare but potentially life-threatening adverse effect. Previous studies suggest that MTX-induced lung injury is associated with inflammatory responses, endothelial activation, and oxidative stress–related mechanisms reported in the literature. These processes may contribute to structural lung damage and impaired pulmonary integrity. Pregabalin (PREG), a structural analog of γ-aminobutyric acid, has been reported to exhibit anti-inflammatory, and cytoprotective properties in several experimental models. In addition, previous experimental studies suggest that PREG may attenuate endothelial activation and inflammatory mediator release. Therefore, the present study aimed to investigate the potential protective effects of PREG against MTX-induced pulmonary injury, focusing on histopathological and immunohistochemical alterations. Adult male Wistar rats were randomly allocated into four experimental groups: Control, MTX, MTX + PREG, and PREG. Pulmonary injury was induced by a single intraperitoneal administration of MTX (20 mg/kg). PREG (30 mg/kg/day) was administered orally for seven consecutive days. At the end of the experimental period, lung tissues were collected for histopathological examination using hematoxylin and eosin staining. Immunohistochemical analyses were performed to evaluate the expression of cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Immunoreactivity was assessed semi-quantitatively across the experimental groups. MTX exposure resulted in marked pulmonary injury characterized by pronounced alveolar septal thickening, interstitial and alveolar edema, hemorrhage, and extensive inflammatory infiltration. These histopathological changes were accompanied by a significant increase in COX-2, IL-6, and VCAM-1 immunoreactivity, indicating enhanced inflammatory and endothelial activation within lung tissue. In contrast, PREG co-treatment significantly attenuated MTX-induced lung injury, as evidenced by lower histopathological injury scores and reduced numbers of immunopositive cells for all markers. The PREG-only group exhibited preserved pulmonary architecture without detectable pathological alterations. PREG significantly attenuated MTX-induced pulmonary injury in this experimental model, as demonstrated by improved histopathological findings and reduced expression of inflammatory and endothelial activation markers, including COX-2, IL-6, and VCAM-1. These results provide tissue-level evidence supporting the potential protective effects of PREG against MTX-associated lung injury. However, oxidative stress parameters, functional pulmonary assessments, and intracellular signaling pathways were not directly evaluated in the present study. Therefore, the findings should be interpreted as morphological and hypothesis-generating evidence. Further investigations incorporating molecular, biochemical, and functional analyses are required to clarify the underlying mechanisms and to determine the translational relevance of these observations.

Kisspeptin is a peptide that plays a pivotal role in the central regulation of gonadotropins. It is regarded as a key regulator of reproductive processes, including follicular and luteal development and endometrial remodelling. The objective of this study was to investigate the expression of KISS1, its receptor KISS1R and the proliferation marker Ki-67 in the uterus, oviduct and ovary of bitches at different stages of the oestrous cycle using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. Thirty-five healthy female dogs were divided into five groups based on reproductive stage as follows: anestrus, proestrus, estrus, diestrus and prepubertal. Each group consisted of an equal number of animals (n = 7). KISS1 mRNA expression was significantly elevated in estrus, while KISS1R mRNA expression remained consistently low across all tissues. Ki-67 mRNA expression increased significantly in the uterus during estrus, whereas the highest levels in the oviduct and ovary were observed in anestrus. Immunohistochemical analysis revealed a marked increase in KISS1 expression in the endometrium during estrus, accompanied by elevated Ki-67 positivity in the uterus, oviduct and ovary, particularly in glandular epithelial and luteal cells. Conversely, KISS1R protein showed strong localisation during estrus despite low transcript levels, suggesting possible post-transcriptional regulation. The synchronised upregulation of KISS1 and Ki-67 in the endometrium during estrus supports their coordinated roles in endometrial proliferation and remodelling. These findings emphasise the significance of local kisspeptin signalling in canine reproductive tissues and suggest its contribution to tissue adaptations during the estrous cycle. The results provide new insights into the peripheral functions of the kisspeptin system and highlight its potential as a target for improving reproductive management in bitches.

Circadian rhythms are biological processes that occur in approximately 24-hour cycles in organisms. Disruption of circadian rhythms (CD) is thought to have adverse effects on many organs, including the eyes. The aim of this study was to evaluate the effects of circadian disruption on the cornea and conjunctiva, as well as the impact of two forms of omega-3 supplementation on the ocular surface, using a rat model of circadian disruption. This experimental study included 32 female Wistar albino rats, which were divided into four groups. The control group (Group 1) was maintained under normal feeding and sleeping conditions without any disruption. Circadian disruption was induced in the other three groups, which were administered saline (Group 2), fish oil (Group 3), or flaxseed oil (Group 4) via oral gavage. On the 31st day, all rats were euthanized, and corneal, conjunctival, and palpebral tissues were collected from both eyes through enucleation. Histological examination and immunohistochemical analysis of Caspase-3 (Cas-3), tumor necrosis factor-alpha (TNF-α), and PERIOD-2 (PER-2) were performed on the corneal and conjunctival tissues. Group 2 exhibited significantly thicker corneas compared to Group 1 (P < 0.001). Additionally, hyperemia, inflammatory cell infiltration in the conjunctiva, higher expression levels of Cas-3 and TNF-α, and decreased PER-2 expression were observed in the corneal and conjunctival tissues of Group 2. These pathological changes were minimal or absent in Groups 3 and 4. Notably, Group 3 showed better amelioration of these alterations compared to Group 4. Disruption of circadian rhythms can have a negative impact on the cornea and conjunctiva. Omega-3 supplementation demonstrated a significant protective effect against ocular tissue damage induced by circadian disruption. Fish oil was more effective than flaxseed oil in reducing corneal thickening, inflammation, and apoptotic marker expression, highlighting its potential as a therapeutic intervention for circadian rhythm-related ocular pathologies.

Abstract:Diabetes mellitus (DM) and hypercortisolemia are closely associated endocrine disorders that significantly affect glucose metabolism; however, their direct organ-specific interactions remain incompletely understood. This study aimed to comparatively evaluate the effects of experimental DM on the adrenal gland and glucocorticoid-induced hypercortisolemia on the pancreas. Thirty male Wistar albino rats were allocated into three groups: control, DM (streptozotocin, 20 mg/kg), and hypercortisolemia (prednisolone, 10 mg/kg/day) for 30 days. Postprandial glucose levels were measured. Pancreatic and adrenal tissues were examined using histopathological and immunohistochemical methods to assess insulin, glucagon, and insulin receptor expression. Both experimental conditions were associated with histopathological alterations in endocrine tissues. The DM group exhibited degenerative changes in pancreatic islets, while the hypercortisolemia group showed structural alterations in both pancreatic islets and adrenal cortex. Immunohistochemical analysis revealed reduced insulin and insulin receptor expression in both groups. Postprandial glucose levels were significantly elevated (p<0.001), including in the hypercortisolemia group, supporting the hyperglycemic effect of glucocorticoid exposure. These findings suggest that both DM and glucocorticoid excess are associated with structural and functional alterations in endocrine tissues. These findings suggest that both DM and glucocorticoid excess are associated with parallel structural and functional alterations in endocrine tissues, rather than indicating a direct bidirectional interaction. Further molecular studies are required to clarify the underlying mechanisms and causal relationships. These findings highlight that each condition induces structural alterations in the reciprocal endocrine organ, suggesting cross-organ vulnerability under metabolic stress.

Sepsis triggers acute kidney injury (AKI) through inflammatory, oxidative, apoptotic, and microvascular mechanisms. This study investigated the renoprotective effects of ranolazine (RAN) in a lipopolysaccharide (LPS)-induced AKI model. Thirty-two male Wistar albino rats were allocated to four groups: Control, LPS (5 mg/kg, intraperitoneal), LPS + RAN (100 mg/kg orally, twice daily for three days), and RAN. Six hours after LPS administration, kidney tissues were collected for histopathological and immunohistochemical analysis of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor alpha (TNF-α), and caspase 3 (Cas-3). Biochemical assessments included total antioxidant status (TAS), total oxidative status (TOS), oxidative stress index (OSI), and serum blood urea nitrogen (BUN) and creatinine levels. Gene expression of interleukin-1 beta (IL-1β), sirtuin 1 (SIRT-1), heme oxygenase-1 (HO-1), hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), fms-related tyrosine kinase-1 (FLT-1), and aquaporin 2 (AQP-2), sodium channel epithelial 1 alpha subunit (SCNN1A), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM1) was analyzed. LPS induced renal injury, evidenced by increased NF-κB, TNF-α, Cas-3, TOS, OSI, BUN, creatinine, and FLT-1, SCNN1A, NGAL, and KIM1 expression, together with decreased TAS, SIRT-1, HO-1, HIF-1α, VEGF, and AQP-2. RAN treatment significantly attenuated these alterations, reducing inflammation, oxidative stress, and apoptosis, tubular injury and tubular transport-related signaling while partially restoring vascular and hypoxia-related signaling. Prophylactic RAN attenuated inflammation, oxidative stress, and tubular injury while preserving renal function and modulating vascular and tubular pathways in sepsis-associated AKI, supporting its potential as an adjunctive therapeutic strategy.

Objective(s): Lung ischemia-reperfusion (IR) injury is a critical clinical condition characterized by oxidative stress, inflammation, and necroptosis, often leading to severe complications. Cannabidiol (CBD), a non-psychoactive cannabinoid, has demonstrated anti-oxidant and anti-inflammatory properties, but its role in modulating lung IR injury remains incompletely understood. This study investigated the protective effects of CBD on lung IR injury in rats, focusing on the RIPK1/RIPK3 necroptosis pathway and the HIF-1α/VEGF/eNOS signaling axis.Materials and Methods: Forty male Wistar albino rats were randomized into four groups: control, IR, IR+CBD (5 mg/kg), and CBD-only. Histopathological, immunohistochemical (TNF-α, Caspase-3), biochemical (TOS, TAS, OSI), and gene expression (RIPK1, RIPK3, HIF-1α, VEGF, eNOS) analyses were performed. The IR group exhibited significant oxidative stress, inflammation, and tissue damage, with elevated TNF-α, Caspase-3, TOS, OSI, and necroptosis/apoptosis markers.Results: CBD treatment markedly attenuated these effects, reducing oxidative stress (↑TAS, ↓TOS/OSI), suppressing inflammation (↓TNF-α), and inhibiting both apoptotic (↓Caspase-3) and necroptotic (↓RIPK1/RIPK3) pathways. Additionally, CBD down-regulated HIF-1α/VEGF/eNOS expression, suggesting modulation of hypoxia-responsive signaling. Conclusion: These findings demonstrate that CBD mitigates lung IR injury by targeting oxidative stress, inflammation, and cell death mechanisms, highlighting its potential as a therapeutic agent. Further preclinical and clinical studies are warranted to validate these results.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect of long-term bisphosphonate therapy characterized by impaired bone remodeling, inflammation, and fibrosis. Gallic acid (GA), a natural phenolic compound with potent antioxidant and anti-inflammatory properties, has been proposed as a protective agent against drug-induced tissue injury. This study investigated the prophylactic and therapeutic effects of GA on zoledronic acid (ZOA)–induced MRONJ in rats. Thirty-two adult female Wistar albino rats were randomly divided into four groups (n = 8): Control, MRONJ (ZOA + tooth extraction), MRONJ + Pre-GA (prophylactic GA), and MRONJ + Post-GA (therapeutic GA). MRONJ was induced by intraperitoneal ZOA (0.06 mg/kg/week, 5 weeks) followed by mandibular molar extraction. GA (100 mg/kg, i.p.) was administered either before or after ZOA exposure for 7 days. Mandibular tissues were analyzed histopathologically, immunohistochemically (Fibroblast growth factor [FGF], transforming growth factor beta 1 [TGF-1β], tumor necrosis factor alpha [TNF-α]), and molecularly (TNF-α, TGF-1β, endothelial nitric oxide synthase [eNOS], cytochrome c [Cyt-C], caspase-3 [Cas-3], protein kinase RNA-like ER kinase [PERK], C/EBP homologous protein [CHOP]). MRONJ rats exhibited severe osteonecrosis, increased inflammation and fibrosis, disrupted collagen organization, elevated osteoclast activity, and suppressed osteoblast function. Immunohistochemistry revealed significant downregulation of FGF and TGF-1β with a concomitant rise in TNF-α. Gene expression analyses showed upregulation of TNF-α, TGF-1β, CHOP, PERK, Cyt-C, and Cas-3, along with downregulation of eNOS. GA administration markedly ameliorated these alterations, restoring bone architecture, normalizing growth factor expression, suppressing pro-inflammatory and apoptotic signaling, and reducing ER stress. The prophylactic regimen showed the most pronounced protective efficacy. GA confers both preventive and therapeutic benefits against MRONJ by mitigating oxidative stress, inflammation, fibrosis, ER stress and mitochondrial apoptosis. These findings suggest that GA may represent a promising adjuvant strategy for managing or preventing MRONJ in patients receiving long-term antiresorptive therapy.

This study investigated the molecular and histological responses of male rat reproductive tissues to combined radiofrequency electromagnetic field (RF-EMF) and pulsed magnetic field (PMF) exposure. Sixty adult male Wistar rats were assigned to ten groups and exposed once, twice, or three times daily for 1 day, 1 week, and 1 month. Penile, testicular, prostatic, and renal tissues were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR), histopathology, and immunohistochemistry. Dual-mode electromagnetic exposure produced a marked increase in endothelial nitric oxide synthase (eNOS) mRNA expression, particularly in long-term and higher-frequency groups, whereas vascular endothelial growth factor (VEGF) levels displayed only minimal changes. Tumor necrosis factor-alpha (TNF-α) expression decreased in penile tissue following short-term exposure but showed a mild elevation in the long-term, high-frequency testicular group, indicating localized sensitivity. Histopathological examination revealed preserved tissue architecture in the penis, prostate, and kidneys, with hyperemia being the primary finding in penile sections. Caspase-3 (Cas-3) immunoreactivity remained low across all groups, demonstrating an absence of apoptotic activation. Testicular tissues maintained overall tubular integrity, although a moderate reduction in intratubular spermatozoa was noted in the one-month high-frequency group without accompanying necrosis or apoptosis. These findings indicate that RF-EMF and PMF exposure enhances endothelial activation mainly through eNOS upregulation while maintaining general tissue integrity in male reproductive organs. The mild testicular inflammatory response observed under prolonged exposure underscores the importance of dose-dependent application. Overall, the results support the biological safety and physiological relevance of dual electromagnetic stimulation under controlled experimental conditions.

Pulmonary hypertension (PH) is a progressive and fatal disease characterised by pulmonary vascular remodelling, right ventricular hypertrophy, and increased pulmonary arterial pressure. Apelin, an endogenous ligand of the APJ receptor, exerts cardioprotective and vasoprotective effects and has been proposed as a potential therapeutic agent in PH. This study aimed to investigate the therapeutic effects of Apelin-13 on hemodynamic, histomorphological, and molecular alterations in a monocrotaline (MCT)-induced PH rat model. Male Wistar rats were divided into four groups: control, MCT, MCT + Apelin-13, and sham-Apelin. A single intraperitoneal injection of MCT (60 mg/kg) was used to induce PH. Apelin-13 was administered intraperitoneally for 21 days. Hemodynamic parameters (Pmax, Pmin, mPAP, EDP, dP/dtmax, dP/dtmin, MAP), morphometric indices (RVHI, PAWTR, PAVR), histological and immunohistochemical analyses (Apelin-13, ACE, Caspase-3, IL-1β) were evaluated. MCT administration significantly increased pulmonary arterial pressure, right ventricular hypertrophy, and vascular wall thickness, while reducing Apelin-13 and ACE expression and elevating Caspase-3 and IL-1β levels. Apelin-13 treatment markedly attenuated these pathological alterations by lowering right ventricular overload, improving vascular remodelling, restoring Apelin-13 and ACE expression, and reducing apoptotic and inflammatory markers. Apelin-13 exerts multifaceted protective effects in MCT-induced PH by modulating hemodynamic load, vascular structure, and inflammatory-apoptotic pathways. These findings provide novel evidence supporting Apelin-13 as a promising therapeutic candidate for PH and warrant further studies to explore its long-term efficacy and translational potential.

This study investigated the protective effects of Gallic acid (GA) on Lipopolysaccharide (LPS)-induced acute lung injury (ALI), focusing on inflammatory cytokines and barrier integrity markers through histopathological, immunohistochemical, and genetic evaluations. Thirty-two adult male Wistar Albino rats were divided into Control, LPS, LPS + GA, and GA groups. LPS (5 mg/kg, intraperitoneal) induced ALI and GA (100 mg/kg, intraperitoneal) was administered to the treatment group. LPS caused hemorrhage, interalveolar septa thickening, inflammatory cell infiltration, and hyperemia. Interleukin (IL)-1β, IL-6, IL-17A, and glycogen synthase kinase-3 beta (GSK3β) increased, while IL-10, aquaporin 2 (AQP2), zonula occludens 1 (ZO-1), claudin 5 (Clau-5), serine/threonine kinase 1 (AKT1), and nuclear factor erythroid 2-related factor 2 (NRF2) decreased. GA reduced tissue damage and pro-inflammatory cytokines while restoring AKT1, NRF2, AQP2, ZO-1, and Clau-5. These findings suggest that GA attenuates LPS-induced lung injury and is associated with modulation of inflammatory and antioxidant-related signaling, including components of the IL-10-AKT1/GSK3β/NRF2 axis.

Methotrexate (MTX)-induced nephrotoxicity remains a clinically relevant limitation associated with oxidative stress, inflammation, and apoptosis. Dexpanthenol (DEX), a pantothenic acid derivative, has demonstrated cytoprotective properties; however, its effects on MTX-induced renal injury and related molecular pathways are not fully elucidated. This study investigated the potential renoprotective effects of DEX with a focus on inflammation- and redox-associated signaling. Thirty-two male Wistar rats were allocated into four groups: Control, MTX, MTX + DEX, and DEX. Renal injury was assessed by histopathology, immunohistochemical analysis of caspase-3, NF-κB, and TNF-α, biochemical parameters (urea and creatinine), and RT-qPCR analysis of SIRT1, PGC-1α, NRF2, and HO-1 gene expression. MTX administration resulted in marked renal damage characterized by tubular degeneration, hyperemia, and inflammatory infiltration, accompanied by increased caspase-3, NF-κB, and TNF-α expression (p < 0.001). MTX also significantly suppressed SIRT1, PGC-1α, NRF2, and HO-1 gene expression (p < 0.001). DEX co-treatment attenuated histopathological injury and significantly reduced pro-inflammatory and apoptotic markers while restoring SIRT1, PGC-1α, and HO-1 expression (p < 0.01-0.001), with a non-significant upward trend in NRF2 levels. Biochemically, DEX reduced MTX-induced urea and creatinine elevation. DEX confers significant protection against MTX-induced renal injury, likely through modulation of inflammatory and oxidative stress-related regulatory pathways and attenuation of apoptosis. These findings support the potential of DEX as a pharmacological candidate for mitigating drug-induced nephrotoxicity; however, further studies at the protein and functional levels are warranted.

PURPOSE:The purpose of this study was to evaluate the effects of a bovine colostrum-based gel (CG) and a carnosine-based gel (BepanGel, BG) on wound healing in a full-thickness excisional wound model in rats. MATERIALS AND METHODS:Male Sprague-Dawley rats (n = 27) were randomly assigned to three groups (n = 9 for each): Control (0.9% NaCl), CG, and BG. Four standardized full-thickness excisional wounds were created on the dorsal surface of each rat. Treatments were applied topically once daily for 14 days. Wound surface area measurements were performed on days 3, 7, and 14. Histopathological assessments and immunohistochemical analyses (Caspase-3, TGF-α, TNF-α, and VEGF expression) were conducted at each time point. RESULTS:By day 14, wound surface area values in the BG (0.059 ± 0.034) and CG (0.073 ± 0.063) groups were significantly lower than in the control group (0.128 ± 0.074; p < 0.05)(p < 0.05). No significant difference was found between BG and CG (p > 0.05). Histopathologically, epithelialization, fibrosis, and angiogenesis were significantly improved, while edema, hemorrhage, and inflammatory infiltration were reduced in the treatment groups (p < 0.05). Immunohistochemical analysis revealed that BG and CG were associated with downregulation of Caspase-3 (BG: 0.50 ± 0.16; CG: 0.90 ± 0.16) and TNF-α (BG: 1.60 ± 0.16; CG: 1.20 ± 0.20), while upregulating VEGF (BG: 2.70 ± 0.15; CG: 2.60 ± 0.16) and TGF-α expression (BG: 2.20 ± 0.20; CG: 1.60 ± 0.16). CONCLUSION:Both colostrum-based and carnosine-based gels enhanced wound healing by promoting epithelial regeneration, collagen formation, and angiogenesis while modulating inflammation and apoptosis. BepanGel showed slightly superior performance in several parameters, suggesting its potential as an effective topical agent in wound management.

Sepsis-related hepatic injury arises from intertwined inflammatory, oxidative, and apoptotic mechanisms. This study aimed to evaluate the hepatoprotective effects of gallic acid (GA), a natural polyphenol, in a lipopolysaccharide (LPS)-induced rat model, with a particular focus on the SIRT-1/p53 axis and mitochondrial stress. Thirty-two adult male Wistar rats were divided into four groups (Control, LPS, GA + LPS, and GA; n = 8 each). GA (100 mg/kg, endotoxin-free, ≥98% purity; Sigma-Aldrich, USA) or saline was administered intraperitoneally 15 min before LPS (5 mg/kg, Escherichia coli O111:B4). Six hours after induction, liver tissues were examined histopathologically, and immunohistochemical expression of interleukin-6 (IL-6), nuclear factor kappa B (NF-κB), and Toll-like receptor 4 (TLR-4) was assessed, along with transcriptional levels of p53, sirtuin-1 (SIRT-1), BCL-2-associated X protein (BAX), B-cell lymphoma 2 (BCL-2), and caspase-3 (CAS-3) using reverse transcription polymerase chain reaction. Serum aspartate aminotransferase (AST) and alanine transaminase (ALT) levels were also measured biochemically. LPS administration caused severe hepatic injury characterized by congestion, hemorrhage, neutrophil infiltration, necrosis, and elevated AST/ALT levels, accompanied by upregulation of IL-6, NF-κB, TLR-4, and pro-apoptotic genes, and downregulation of SIRT-1 and BCL-2. GA co-treatment significantly ameliorated these alterations, reducing inflammatory and apoptotic markers, restoring SIRT-1, and suppressing p53 activation. Collectively, GA exerts hepatoprotective effects through modulation of the TLR-4/NF-κB/IL-6 pathway and restoration of the SIRT-1/p53 regulatory axis, highlighting its immunopharmacological potential in sepsis-induced hepatic dysfunction.

Methotrexate (MTX)-induced pulmonary toxicity severely limits its clinical use and effective preventive strategies are lacking. This study evaluated the protective effects of agomelatine (AGO), a melatonergic antidepressant, against MTX-induced lung injury, focusing on its dual-pathway action targeting both immune cell infiltration and apoptotic signaling. Thirty-two female Wistar rats were assigned to: Control, AGO (20 mg/kg/day, p.o., 7 days), MTX (single i.p. dose, 20 mg/kg), and MTX + AGO groups. Lung tissues were examined by histopathology, immunohistochemistry (CD45+, CD68+), and RT-qPCR (BAX, BCL2). MTX administration caused marked pulmonary damage (histopathological score: 2.75 ± 0.25, p < 0.001), significant infiltration of CD45+ leukocytes and CD68+ macrophages and an elevated BAX/BCL2 ratio (3.5 ± 0.4 vs. 1.0 ± 0.2 in Control, p < 0.001). AGO cotreatment significantly ameliorated these alterations via its dual activity, lowering the histopathological score (1.25 ± 0.25, p < 0.01), reducing CD45+/CD68 immunopositivity, and restoring the BAX/BCL2 ratio toward cell survival (1.4 ± 0.3, p < 0.01 vs. MTX). These findings provide integrated immunohistochemical and molecular evidence supporting the concurrent modulation of immune cell infiltration and apoptotic signaling by AGO in MTX-induced lung injury. Given its established clinical use and favorable safety profile, AGO may represent a potential adjunctive candidate to reduce the risk of MTX-related pulmonary complications, through concurrent targeting of immune and apoptotic pathways.

Exposure to electric fields has been associated with oxidative stress, inflammation and apoptosis in various tissues. However, the duration-dependent effects of electric field exposure on renal tissue and the balance between adaptive cytoprotective responses and tissue injury remain unclear. This study aimed to investigate the histopathological, immunohistochemical and molecular effects of different durations of 10 kV/m electric field exposure on rat kidney tissue, with particular emphasis on oxidative stress, apoptosis and inflammatory pathways. Forty Wistar rats were randomly assigned to five groups: control, 1 min, 5 min, 15 min and 30 min exposure. Histological analysis (hematoxylin–eosin staining) revealed that the 30 min exposure group exhibited severe hyperemia, hemorrhage, inflammatory cell infiltration and tubular degeneration. Immunohistochemical findings demonstrated markedly increased expression of caspase-3 (Cas-3), nuclear factor kappa B (NF-κB) and tumor suppressor protein p53 (p53) in the 30 min group, indicating activation of apoptotic and inflammatory pathways. Gene expression analysis by quantitative real-time PCR showed significant upregulation of sirtuin-1 (SIRT1), nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) in the 1, 5 and 15 min groups, suggesting adaptive cytoprotective activation. In contrast, these protective markers were sharply downregulated in the 30 min group, coinciding with extensive tissue damage. Short-term electric field exposure induces adaptive cytoprotective responses in renal tissue, whereas prolonged exposure (30 min) overwhelms these mechanisms, leading to increased oxidative stress, inflammation, apoptosis and significant histopathological damage.

Acute neuroinflammation plays a critical role in the pathogenesis of various central nervous system (CNS) disorders. Theranekron (TH), a homeopathic preparation derived from Tarantula cubensis venom, has demonstrated anti-inflammatory potential in several experimental models. This study aimed to evaluate the therapeutic efficacy of TH in a lipopolysaccharide (LPS) induced acute neuroinflammation model, focusing on oxidative stress parameters, histopathological changes, immunohistochemical markers, and key neuroinflammatory pathways involving the NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome. Thirty-two Wistar Albino rats were randomly divided into four groups: control, LPS (5 mg/kg, intraperitoneally), TH (0.2 ml, single dose, subcutaneously), and LPS + TH. Theranekron (0.2 mL, s.c.) was administered 30 min after LPS injection. Six hours after LPS administration, brain tissues were collected for the biochemical analyses of total antioxidant species (TAS), total oxidant species (TOS), and oxidative stress index (OSI)with histopathological and immunohistochemical analyses of tyrosine hydroxylase (TyrH) caspase-3 (Cas-3), tumor necrosis factor-alpha (TNF-α); and gene expression analyses of NLRP3, caspase 1 (Cas-1), interleukin-1 beta (IL-1β), and interleukin 18 (IL-18). LPS administration significantly increased Cas-3, TNF-α immunoexpression, TOS, OSI, and the expression of NLRP3, Cas-1, IL-1β, and IL-18 genes, while reducing TyrH immunoexpression and TAS levels. TH treatment reversed these alterations; demonstrating strong anti-inflammatory, antioxidant, and neuroprotective effects in the cerebral cortex, hippocampus and cerebellum. This study provides compelling evidence that TH exerts potent neuroprotective effects by suppressing NLRP3 inflammasome activation, reducing oxidative stress, and restoring neurochemical homeostasis in an LPS-induced neuroinflammation model. These findings highlight TH as a promising therapeutic candidate for CNS inflammatory disorders, warranting further molecular and clinical investigation.

High fructose corn syrup (HFCS) consumption may lead to oxidative stress–related neurodegeneration. Dexpanthenol (DEX), with antioxidant and cytoprotective properties, may exert neuroprotective effects; however, its efficacy against HFCS-induced neurotoxicity remains unclear. This study examined DEX’s effects against HFCS-induced neurotoxicity across multiple pathways. Rats were randomly assigned to four experimental groups (n = 8, for each group): Control, HFCS (20