Search Results (1,736)

Background/Objectives: Overweight and obesity have consistently increased in prevalence. Early exposure to foods high in fats and sugar through maternal conditions may increase vulnerability to developing metabolic diseases and cognitive impairments in adulthood. In this regard, we aim to evaluate the effects that perinatal exposure to cafeteria diet (CAF) and physical activity (PA) has on anxiety-like, depressive-like behavior, memory and diet preference in male and female offspring. Methods: Seventy female and male offspring rats were divided into five groups according to maternal conditions: (1) CONTROL, fed only standard diet (SD) with no voluntary PA, (2) SED+SD, fed only SD with no voluntary PA, (3) SED+CAF, fed SD and CAF with no voluntary PA, (4) PA+SD, fed only SD with voluntary PA, and (5) PA+CAF, fed SD and CAF with voluntary PA. Starting on PND 24, offspring rats were exposed to SD and CAF (except for rats from the CON maternal group) and evaluated for seven weeks for diet preference, and at week seven for anxiety-like, depressive-like behavior and memory. Results: After seven weeks of exposure to CAF, maternal conditions showed significantly different effects on adult male and female offspring for diet preference and memory impairments. Furthermore, maternal PA significantly reduced anxiety-like and depressive-like behaviors in the offspring. Conclusions: Our results suggest that maternal conditions and postweaning CAF exposure have a joint influence on diet preference, anxiety-like and depressive-like behavior. Additionally, perinatal CAF exposure impairs memory in male and female offspring, regardless of maternal PA conditions. However, maternal PA was associated with reduced affective behaviors induced by lifelong CAF, presenting as a promising non-pharmacological intervention to promote favorable long-term behavioral outcomes in offspring. Full article

Background: Bladder dysfunction is a complicated condition that substantially impairs quality of life for both men and women. Due to the adverse effects and limited efficacy of current therapies, new strategies must be rapidly developed. Female bladder dysfunction arises from multifaceted etiologies distinct from the predominantly male benign prostatic hyperplasia (BPH) that is the focus of existing drug development. In this study, we investigated the therapeutic potential of Quisqualis indica extract (QIE), a traditional medicinal herb that attenuates BPH-induced lower urinary symptoms (LUTS), to elucidate its underlying mechanisms in a female bladder dysfunction model. Methods and Results: A bladder dysfunction model was established by inducing partial bladder outlet obstruction (pBOO) in female Sprague Dawley rats, followed by the oral administration of QIE for 7 weeks. Voiding pattern analysis and cystometry were conducted to evaluate indicators such as voiding frequency, voiding volume, and intravesical pressure. Histological analysis of excised bladder tissue quantified smooth muscle hypertrophy and collagen deposition. Gene expression profiling of inflammatory cytokines and fibrosis-related markers within the bladder tissue was performed to assess tissue remodeling. Furthermore, pharmacological contraction studies examined the direct effects of QIE on detrusor muscle responsiveness to muscarinic and purinergic agonists. QIE administration significantly improved the elevated voiding pressure and abnormal inter-contraction intervals observed in the pBOO rats, restoring normal voiding patterns. Histological examination revealed a marked decrease in muscle hypertrophy and collagen deposition. Expression levels of pro-inflammatory cytokines (TNFα, IL-1β) and fibrosis-associated genes (TGF-β, α-SMA) were downregulated. Pharmacological contraction assays demonstrated that QIE attenuated the hypercontractile response of bladder smooth muscle to a muscarinic agonist, with concurrent reduced expression of muscarinic receptors (M₂, M₃) at the mRNA level. Conclusions:QIE ameliorates key aspects of bladder dysfunction, voiding abnormalities, inflammation, fibrosis, and hypercontractility by modulating muscarinic receptor signaling and fibrotic pathways. This study suggests that QIE warrants further investigation as a natural product-based therapeutic candidate for female bladder dysfunction. Full article

Background/Objectives: Sarcomas exhibit marked intratumoural heterogeneity at the molecular, cellular and tissue levels, thereby limiting drug delivery and treatment response. Herein, we evaluated the effects of free doxorubicin (FDOX) and liposomal doxorubicin (LDOX) combined with inductive moderate hyperthermia (IMH) on intratumoural heterogeneity in an experimental sarcoma model using magnetic resonance imaging (MRI), histology and immunohistochemistry image analysis. Methods: Female non-inbred rats bearing sarcoma-45 were divided into six groups: control (no treatment), IMH, FDOX, LDOX, FDOX + IMH and LDOX + IMH. FDOX or LDOX was administered every other day for a total of five times, beginning from day 2 after inoculation. IMH was applied locally following drug administration using a 42 MHz radiofrequency electromagnetic field. Treatment-induced changes were assessed by T₁- and T₂-weighted MRI, haematoxylin–eosin–orange (H&E) staining, and Ki-67 and p53 immunohistochemistry. Moran’s spatial autocorrelation index was used as a measure of tumour phenotypic heterogeneity in medical images. Results: Combination treatment with different doxorubicin formulations resulted in distinct patterns of intratumoural heterogeneity in MRI and in H&E-, Ki-67- and p53-stained images. FDOX or LDOX combined with IMH produced greater deviations from the control group in multimodal spatial organisation of sarcoma-45 than the corresponding drug treatments alone. LDOX + IMH reduced tumour growth by 34% relative to the control group and was associated with distinct histological and immunohistochemical remodelling, including connective tissue replacement and the lowest Ki-67 staining level. The lowest p53 staining levels were observed in the LDOX and LDOX + IMH groups. Conclusions: FDOX and LDOX combined with IMH induced distinct tumour remodelling patterns in sarcoma-45. Multimodal analysis of intratumoural heterogeneity in sarcomas may provide additional quantitative information for assessing treatment response. Full article

Introduction: Endothelial dysfunction (ED) is a key pathogenetic mechanism underlying cardiovascular and cerebrovascular diseases and is increasingly recognized as a common link between ischemic heart pathology and cerebral vascular impairment. In addition to postnatal risk factors, adverse intrauterine conditions, particularly prenatal hypoxia (PH), may program long-term endothelial alterations. The aim of this study was to investigate the structural and molecular features of ED in the myocardial and cerebral vessels in experimental chronic heart failure (CHF) and PH, as well as to evaluate the endothelioprotective potential of pharmacological agents targeting the nitric oxide system. Methods: This study was conducted on Wistar rats using experimental models of CHF (doxorubicin administration, cumulative dose 15 mg/kg) and PH (sodium nitrite 50 mg/kg administered to pregnant females on gestational days 16–21). The endothelial status of cerebral and myocardial vessels was assessed using immunohistochemistry, ELISA, morphometric analysis, and real-time PCR. Key markers of endothelial function, inflammation, nitric oxide metabolism, oxidative stress, and angiogenesis were evaluated. The endothelioprotective potential of nitric oxide-modulating pharmacological agents was also evaluated. Results: CHF and PH induced pronounced structural and functional endothelial alterations in the microcirculatory and muscular-type vessels of the heart and brain. These changes were characterized by reduced endothelial cell density, suppressed eNOS expression, increased iNOS expression, nitric oxide deficiency, elevated nitrotyrosine levels, and activation of proinflammatory cytokines. VEGF levels were significantly decreased, while apoptotic features of endothelial cells were intensified. Angiolin and Hypertril demonstrated the most pronounced endothelioprotective effects among the tested agents. Conclusions: CHF and PH induce persistent ED in cerebral and myocardial vessels through disruption of the nitric oxide system, oxidative stress, and inflammatory activation. PH may act as an early trigger increasing susceptibility to cardiovascular and cerebrovascular diseases later in life. These findings support the rationale for targeted endothelioprotective therapy in ischemic cardiovascular pathology. Full article

Underweight in pregnant women adversely affects the next generation. Although young female underweight has become an important issue even in developed countries, the precise mechanisms that induce an underweight status in young women remains unknown. To examine the influence of feeding timing in young women on the following underweight conditions, we examined the effects of chronic light–dark cycle-reversed feeding restriction on post-restriction dietary behaviors using adult and young adult female rats. Eight- and 24-week-aged female Wistar rats were classified into three groups: (1) the control group (without time or calorie restriction), (2) the night-time-fed group that was fed only during the active phase, and (3) the daytime-fed group that was fed only during the non-active phase. After a 4-week feeding restriction, all groups were additionally fed ad libitum for 7 weeks with daily food intake and weight gain measurements. After sacrifice, mRNA expressions of neuropeptide Y (NPY), agouti-related protein (AgRP), orexin-A, pro-opiomelanocortin (POMC), and thyrotropin-releasing hormone (TRH) in the hypothalamus and leptin in the fatty tissues were examined by real-time PCR. Daytime-fed groups decreased food intake during restriction. After stress relief, adult rats showed a rebound increase in food intake beyond the level of the control group, whereas young adult rats showed no significant rebound response. At the end of the non-restricted period, both adult and young adult rats in the daytime-fed group reduced NPY expression in the hypothalamus. These findings indicate that recovery responses in food intake against chronic light–dark cycle-reversed stress are different between adult and young adult rats. The lower response in young adult rats may provide clues to elucidating a new mechanism for underweight status in young females. Full article

Background: Although fentanyl significantly contributes to opioid-related morbidity and mortality, little is known about the epigenetic changes that may influence long-term neuronal adaptations. Objective: The effects of repeated fentanyl administration on class IIa histone deacetylase (HDAC) expression-activity were studied using the radiotracer [¹⁸F]TFAHA and positron emission tomography (PET) imaging in a model of fentanyl-induced behavioral sensitization. Methods: Female and male Wistar rats received 14 days of fentanyl (20 μg/kg) or saline injections and a 14-day drug-free period followed by a single fentanyl or saline challenge dose on day 28. Locomotor activity (LMA) was measured on days 0, 1, 14, and 28 with PET imaging being performed at baseline and again on day 28 following the fentanyl/saline challenge and LMA. The percent change in standard uptake value (body weight corrected) between pre- and post-administration was calculated as a measure of class IIa HDAC expression-activity. Results: Repeated fentanyl exposure resulted in significantly increased LMA in both sexes compared to controls. Females displayed an earlier onset (day 1) and a greater magnitude of behavioral sensitization on days 14 and 28 compared to males. Fentanyl significantly decreased class IIa HDAC expression-activity across time in the whole brain and in reward-related brain regions without sex differences. Conclusions: Prolonged fentanyl exposure induces robust sex-specific locomotor sensitization with varying magnitude over time, suggesting differential neuroadaptive processes. Fentanyl also appears to induce epigenetic changes in the brain independent of sex and region. The effect of fentanyl on class II HDACs may not directly impact the expression of behavioral sensitization. Full article

Endothelial VEGFR-2 plays a central role in vascular remodeling during intestinal inflammation, yet its activation during the early stages of colitis remains poorly characterized. Because Akt is a major downstream effector of VEGFR-2 signaling and a key mediator of endothelial responses, we investigated whether VEGFR-2 phosphorylation and Akt activation occur during the early phase of TNBS-induced colitis before the development of extensive mucosal injury. Acute colitis was induced in adult female Wistar rats by intracolonic administration of TNBS. Colonic tissues were collected on days 2, 4, and 6 after induction. Histological analyses and macrophage (CD68⁺ cells) infiltration were performed to characterize disease progression. VEGFR-2 expression and phosphorylation at Tyr1175 were evaluated on day 4 by Western blot, immunoprecipitation, and immunofluorescence. Akt activation was also assessed. TNBS-induced colitis is characterized by histological injury and increased CD68⁺ macrophage infiltration on day 4, with severe tissue damage observed on day 6. On day 4, colitis is associated with increased endothelial VEGFR-2 expression, enhanced VEGFR-2 phosphorylation at Tyr1175, and Akt activation. Early TNBS-induced colitis is associated with endothelial VEGFR-2 phosphorylation and Akt activation before the onset of extensive mucosal destruction on day 6. These findings support activation of the VEGFR-2/Akt signaling axis as an early vascular response during intestinal inflammation and suggest its potential contribution to disease progression. Full article

Introduction: Chronic kidney disease (CKD) involves a progressive loss of renal function and is characterized by chronic oxidative stress and kidney fibrosis. Tetrahydrocurcumin (THCu), a metabolite of curcumin, may possess antioxidant benefits in CKD. This study evaluated the transcriptomic changes and therapeutic potential of THCu against kidney damage and fibrosis in the 5/6 nephrectomy rat CKD model. Methods: Adult female Sprague–Dawley rats were randomized into CKD groups and three THCu doses were tested (100, 300 and 500 mg/kg). A liposomal formulation of THCu was given twice daily via oral gavage for 4 weeks. Serum creatinine and proteinuria were measured, and kidney fibrosis was assessed on histology. Kidney lysates were processed for total RNA sequencing to analyze differential gene expression in the experimental groups. The data were screened for outliers prior to ANOVA and correlation analyses. Results: In the untreated CKD group, serum creatinine and proteinuria were increased compared to control animals. Transcriptomic profiling revealed that untreated CKD animals exhibited marked upregulation across three key gene categories: immune cell activation, kidney injury and fibrosis, and inflammation and oxidative stress. THCu treatment mitigated these pathways by which there was downregulation of markers of immune cell activation as well as the kidney injury marker Kim1, while the fibrosis markers Col1a1 and Col3a1 were decreased to expression levels similar to non-CKD control animals. Furthermore, the highest dose of THCu at 500 mg/kg triggered a cellular detoxification and metabolic clearance response, with highly significant upregulation of Abcb11 and Gls2. Antioxidant benefit was evidenced by upregulation of Gpx1 in the high-dose THCu group compared to the untreated CKD group. Pathway enrichment analysis demonstrated that the high-dose THCu group restored key metabolic and signaling pathways disrupted in renal fibrosis, including small and organic solute metabolism, fatty acid oxidation, lipid biosynthesis, and peptide hormone response. Furthermore, the treatment upregulated essential anion and organic solute transport functions. Proteinuria was reduced with THCu therapy; however, serum creatinine and urine creatinine clearance were not significantly modified in comparison to untreated CKD rats. Conclusions: Oral THCu therapy demonstrated promising transcriptional changes in antioxidant and anti-fibrotic pathways in a rat CKD model. Confirmatory protein-level studies are needed to clarify benefits on kidney function. Full article

Objective: Diabetes mellitus (DM) is a major metabolic disorder associated with hyper-glycemia and oxidative stress. Traditional medicinal plants remain important sources of bioactive compounds with potential antidiabetic activity. Salacia reticulata and Caralluma tuberculata are two important medicinal plants that have been reported to have antidiabetic effects. The growing burden of type 2 diabetes and the need for therapies that address both hyperglycemia and oxidative stress underscore the necessity to investigate these two medicinal plants. Therefore, the current study evaluated the antihyperglycemic, antioxidant, and protective effects of Salacia reticulata and Caralluma tuberculata in an alloxan-induced diabetic female rat model. Methods: Ethanolic extracts of S. reticulata and C. tuberculata were characterized by total phenolic content (TPC), total flavonoid content (TFC), DPPH radical-scavenging assay, and UPLC–MS/MS metabolite profiling. Female Wistar rats (n = 42) were randomly assigned to seven groups (n = 6/group), including normal control, diabetic control, extract-treated non-diabetic groups, diabetic extract-treated groups, and a metformin-treated diabetic group. Diabetes was induced by alloxan (130 mg/kg), followed by oral treatment for 8 days with extracts or metformin (500 mg/kg/day). Fasting blood glucose, oral glucose tolerance, serum malondialdehyde (MDA), antioxidant markers (SOD1, GSH, and CAT), and liver and kidney histopathology were assessed. Results: Both plant extracts significantly reduced fasting blood glucose compared with baseline, with S. reticulata showing a greater reduction (22.8%) than C. tuberculata (12.3%), and a response comparable to metformin (27.4%). Diabetic rats exhibited increased MDA and reduced antioxidant enzyme activities. C. tuberculata significantly lowered MDA levels and increased SOD1 activity, suggesting moderate antioxidant effects, whereas S. reticulata showed higher phenolic and flavonoid contents and the highest DPPH scavenging activity. UPLC–MS/MS identified 33 compounds in S. reticulata and 24 in C. tuberculata. Histopathological findings supported improvement of diabetes-associated renal and hepatic damage. Conclusions: Within the eight-day experimental period, both extracts demonstrated significant acute antidiabetic and antioxidant effects with distinct redox–metabolic profiles. However, further long-term studies are recommended to evaluate their sustained efficacy, safety, and potential as complementary therapeutic agents for diabetes management. Full article

Background/Objectives: Dietary fiber and polyphenols are recognized modulators of intestinal and immune homeostasis; however, evidence regarding their combined impact under physiological conditions remains limited. This study aimed to evaluate whether a diet enriched with fermentable fiber and polyphenols modulates mucosal and systemic immune biomarkers, as well as microbiota composition and function in healthy adult female rats. Methods: Wistar rats were fed either a reference diet (REF group) or a fiber- and polyphenol-enriched diet (FP group) for nine weeks. At the end of the intervention, plasma lipid profile, systemic and mucosal immune status (assessed by immunoglobulin (Ig) content in several compartments), cecal microbiota composition (determined by 16S rRNA sequencing), cecal short-chain fatty acids (SCFAs) and cecal Ig-coated bacteria, among other variables, were quantified. Results: The FP group exhibited a higher IgG concentration in plasma and elevated IgG2c levels in mucosal compartments compared with REF animals. The FP diet did not alter either intestinal morphology or hematologic and lipid variables; however, FP rats exhibited increased fecal moisture and reduced fecal pH. With regard to cecal microbiota, the FP group displayed higher microbial evenness, distinct β-diversity clustering, and shifts in the abundance of multiple genera. In addition, elevated cecal SCFA concentrations, particularly for acetate and propionate, were found in the FP group. Conclusions: Long-term intake of fermentable fiber and polyphenols promotes microbial fermentation and enhances humoral immunity without inducing structural or systemic physiological alterations. These findings support the role of plant-based foods in promoting immune and gut microbiota homeostasis under healthy conditions. Full article

Background and Objectives: The aim of this study is to evaluate the effects of oridonin on a cisplatin-induced ovarian injury rat model. Materials and Methods: Thirty female rats were divided into three groups. Group 1: control; group 2: cisplatin; group 3: cisplatin plus oridonin group. In groups 2 and 3, the rats were injected with 2.5 mg/kg (twice weekly) cisplatin intraperitoneally (i.p.) for 4 weeks. In Group 3, rats received oridonin (10 mg/kg/day, i.p.). At the end of the study, the ovaries were removed in all groups. Histopathologic analysis and follicle counting were performed. Plasma anti-Müllerian hormone (AMH), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-α) levels were measured, while ovarian transforming growth factor-beta 1 (TGF-β1), SMAD family member 3 (SMAD3), and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels were evaluated. Results: Oridonin alleviated cisplatin-induced histopathological changes in the ovarian tissue. The numbers of primordial, primary, secondary, and tertiary follicles were significantly decreased, while ovarian fibrosis was significantly increased in Group 2 compared with Group 1 (p < 0.05). Co-treatment with oridonin statistically significantly increased follicle counts at all developmental stages and markedly reduced ovarian fibrosis in group 2 compared with group 3. Compared with Group 1, AMH decreased, whereas MDA, TNF-α, TGF-β1, SMAD3, and TIMP-1 increased in Group 2 (p < 0.001); these alterations were markedly attenuated in Group 3. Conclusions: These findings suggest that oridonin may exert protective effects against cisplatin-induced ovarian injury. Full article

Maternal exposure to airborne particulate matter smaller than $2.5$ μm (${\mathrm{PM}}_{2.5}$) has been associated with adverse fetal outcomes, although its effects on intramembranous ossification remain poorly understood. This study evaluated the impact of gestational and pregestational exposure to wood-smoke-derived ${\mathrm{PM}}_{2.5}$ on fetal neurocranial ossification in Sprague–Dawley rats. Females were allocated to four exposure conditions combining filtered air (FA) and non-filtered air (NFA): FA/FA, FA/NFA, NFA/FA, and NFA/NFA. Fetuses were collected at gestational day 21 and analyzed using fetal morphometry, radiography, micro-computed tomography, whole-mount alizarin red skeletal staining, histology, and immunohistochemistry for HIF-1$\alpha$, COL-1, BMP-2, FGF-R1, and TGF-$\beta$. Continuous exposure (NFA/NFA) was associated with reduced fetal weight, shorter crown–rump length, impaired craniofacial mineralization, widened cranial sutural regions, and reduced mineral density, particularly in the occipital and interparietal bones. Histologically, exposed fetuses exhibited abundant osteoid, reduced osteocyte incorporation, and diffuse osteoblastic distribution, consistent with delayed osteogenic maturation. Immunohistochemistry showed increased HIF-1$\alpha$ immunoreactivity, altered TGF-$\beta$ regulation, and reduced COL-1 expression in continuously exposed fetuses, whereas BMP-2 and FGF-R1 showed no significant changes. These findings suggest that maternal exposure to wood-smoke-derived PM_2.5 is associated with delayed fetal neurocranial intramembranous ossification, particularly under continuous exposure. The observed immunohistochemical profile, elevated HIF-1$\alpha$, reduced COL-I, and altered TGF-$\beta$, is consistent with a hypoxia-associated imbalance between extracellular matrix deposition and mineral maturation; however, the underlying mechanistic pathway was not directly functionally tested and should be regarded as a biologically plausible inferential model requiring further experimental validation. Full article

Background and Objectives: Seroma formation is the most common postoperative complication following mastectomy and axillary dissection, negatively affecting wound healing and delaying adjuvant therapy. Despite numerous surgical and pharmacological approaches, no universally effective strategies have been established. This study aimed to comparatively evaluate the effects of porcine dermal collagen (PDC), tranexamic acid (TXA), and thymoquinone (TQ) on seroma formation and tissue repair. Materials and Methods: A randomized controlled experimental study was conducted using 40 female Wistar albino rats that underwent modified radical mastectomy and axillary dissection. All surgical and postoperative procedures were performed in accordance with the institutional animal welfare and ethical guidelines, including postoperative analgesic administration. The animals were divided into four groups: control, PDC, TXA, and TQ (n = 10 each). Seroma volume was measured on postoperative day 14. Histopathological evaluation, immunohistochemical analysis (FGF2, VEGF, TGF-β1, p53), and quantitative real-time PCR were performed to assess tissue remodeling and molecular responses. Results: All treatment groups demonstrated a significant reduction in seroma volume compared to the control group, with the most pronounced decrease observed in the TQ and TXA groups (p < 0.0001), while PDC showed a moderate effect (p < 0.01). Histopathological analysis revealed increased collagen deposition and fibrin formation in the PDC and TQ groups, whereas TXA exhibited a more limited remodeling profile than the others. Immunohistochemical and molecular analyses showed significant upregulation of VEGF across all groups, with broader and more consistent increases in the PDC and TQ groups. TGF-β1 and FGF2 expression demonstrated region-specific increases, particularly in the thoracic tissue. p53 expression remained relatively stable in the TXA group but was elevated in specific regions in the PDC and TQ groups. Importantly, the increased inflammatory infiltration, edema, vascular proliferation, and fibrin deposition observed in the TQ group may reflect not only active tissue remodeling processes but also prolonged inflammatory activation and enhanced fibrotic responses and should therefore be interpreted cautiously. Conclusions: PDC, TXA, and TQ differentially modulate postoperative seroma formation via distinct biological mechanisms. While TXA primarily exerts a targeted anti-seroma effect and PDC enhances extracellular matrix stabilization, TQ is associated with broader angiogenic, inflammatory, and tissue remodeling responses within this preclinical rat model. These findings should be considered exploratory and hypothesis-generating, and additional mechanistic studies and clinical investigations are necessary before definitive therapeutic conclusions can be established regarding the use of TQ in human breast surgery settings. Full article

Background/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease. Full article

Animals with knockout of the dopamine transporter gene (DAT-KO) display hyperdopaminergic phenotypes, including attention-deficit/hyperactivity-like behaviors. A previous behavioral analysis of heterozygous rats with partial knockout (DAT-HET) suggested increased susceptibility to addictive behaviors. The aim of this study was to investigate elements of addictive behaviors and the mechanisms underlying dopamine release in DAT-HET rats. Offspring derived from DAT-knockout breeding underwent genotyping and behavioral assessment using the marble burying test, a manipulative behavior test using nesting material, and a modified version of the Iowa Gambling Task. Feeding behavior was studied using a binge-eating model. Reinforcing properties were investigated using intracranial self-stimulation under fixed-ratio (FR) and variable-ratio (VR) schedules. Dopamine (DA) release and clearance dynamics were assessed using fast-scan cyclic voltammetry (FSCV). DAT-HET rats exhibited moderate hyperactivity, increased impulsive choice, and compulsive responses. Male DAT-HET rats also showed increased compulsive overeating compared with wild-type (WT) rats of both sexes and female DAT-HET rats. In addition, DAT-HET rats demonstrated a preference for VR self-stimulation, which resembles risk- and thrill-seeking behavior in humans. In DAT-KO rats, impaired DA clearance resulted from complete loss of dopamine transporter function. In DAT-HET rats, increased DA release amplitude was observed, and dopamine persisted longer in the extracellular space than in WT rats. These findings underscore the importance of the DAT-HET model for studying impulsivity, compulsivity, and factors underlying the predisposition to addictive behavior. Full article