Whole-Body Vibration Impacts on the Degree of Toe Angle and Its Correlation to the Knee Osteoarthritis Index during Level Walking among Female University Students: A Randomized Controlled Trial.

Whole-body vibration (WBV) training is used for ankle rehabilitation as it stimulates muscle spindles to excite tonic vibration reflexes, and improves muscle strength, power, joint proprioception, balance, and flexibility. Thus, this study aims to determine the impact of whole-body vibration on the degree of the toe angle and the correlation between the toe angle and knee osteoarthritis index during level walking among female university students. A randomized controlled trial was conducted with 42 participants divided into two groups. The control group performed only home-based exercise (HBE) after education, and the study group received WBV with HBE. The functional status of participants to predict osteoarthritis was evaluated using the Western Ontario and McMaster osteoarthritis index (WOMAC), where the toe angle degree and WOMAC index were assessed before and six weeks after training. The results showed a significant improvement in the toe-in angle of HBE + WBV compared to the HBE group (p = 0.02), and in HBE + WBV, an improvement of the toe angle showed a 43% decrease in the WOMAC index (p = 0.001). In conclusion, WBV for the ankle and foot training program positively affected the degree of the toe angle, that directly affected the subtalar and ankle joint mechanics. Trial registration in the Pan African Clinical Trial Registry PACTR202304816093190 (registered retrospectively, date of registration: 18 April 2023).

Hesperidin and hesperetin against heavy metal toxicity: Insight on the molecular mechanism of mitigation.

Toxic heavy metals (THMs) are non-essential hazardous environmental pollutants with intractable health challenges in humans and animals. Exposure to lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), nickel (Ni), and chromium (Cr) are ubiquitous and unavoidable due to food contamination, mining, and industrial mobilization. They are triggers of tissue impairment and aberrant signaling pathways that cascade into several toxicities and pathologies. Each of Pb, Cd, Hg, As, Ni, and Cr aggravate oxidative inflammation, protein dysregulation, apoptotic induction, DNA damage, endocrine deficits, and mitochondrial dysfunction contributing to the pathophysiology of diseases. Hesperidin (HSD) and hesperetin (HST) are flavonoids from citrus fruits, and systematic investigations suggest their potential to combat the molecular alterations and toxicities induced by THMs. They mitigate heavy metal toxicity via antioxidant, anti-inflammatory, and anti-apoptotic effects via scavenging free radicals and modulation of ATPases, cell cycle proteins, and various cellular signaling pathways, including Nrf2/HO-1/ARE, PI3K/mTOR/Akt, MAPK/caspase-3/Bax/Bcl-2, iNOS/NF-κB/TNF-α/COX-2. This review summarized the mechanistic effects of heavy metal toxicity and the insights on molecular mechanisms underlying mitigation of heavy metal toxicity by HSD and HST. Hesperidin and hesperetin are potential flavonoids for the modulation of pathological signaling networks associated with THMs. Therefore, HSD and HST can be suggested as natural dietary agents and blockers of harmful effects of THMs.

Astrocytes profiling in acute hepatic encephalopathy: Possible enrolling of glial fibrillary acidic protein, tumor necrosis factor-alpha, inwardly rectifying potassium channel (Kir 4.1) and aquaporin-4 in rat cerebral cortex.

Hepatic encephalopathy (HE) is a neurological disarray manifested as a sequel to chronic and acute liver failure (ALF). A potentially fatal consequence of ALF is brain edema with concomitant astrocyte enlargement. This study aims to outline the role of astrocytes in acute HE and shed light on the most critical mechanisms driving this role. Rats were allocated into two groups. Group 1, the control group, received the vehicle. Group 2, the TAA group, received TAA (300 mg/kg) for 3 days. Serum AST, ALT, and ammonia were determined. Liver and cerebral cortical sections were processed for hematoxylin and eosin staining. Additionally, mRNA expression and immunohistochemical staining of cortical GFAP, TNFα, Kir4.1, and AQP4 were performed. Cortical sections from the TAA group demonstrated neuropil vacuolation and astrocytes enlargement with focal gliosis. GFAP, TNFα, and AQP4 revealed increased mRNA expression, positive immunoreactivity, and a positive correlation to brain water content. In contrast, Kir 4.1 showed decreased mRNA expression and immunoreactivity and a negative correlation to brain water content. In conclusion, our findings revealed altered levels of TNFα, Kir 4.1, GFAP, and AQP4 in HE-associated brain edema. A more significant dysregulation of Kir 4.1 and TNFα was observed compared to AQP4 and GFAP.

α-Lipoic Acid Protects against Cyclosporine A-Induced Hepatic Toxicity in Rats: Effect on Oxidative Stress, Inflammation, and Apoptosis.

The clinical application of cyclosporine A (CsA) as an immunosuppressive agent is limited by its organ toxicity. We aimed to evaluate the effectiveness of α-lipoic acid against CsA-induced hepatotoxicity and to delineate the underlying molecular mechanisms. Male Wistar rats (n = 24, 8 per each group) received the vehicle, CsA (25 mg/kg) and/or ALA (100 mg/kg, p.o.) for 3 weeks. Biochemical markers of liver function (serum ALT, AST, ALP < GGT), oxidative stress (MDA, TAC, SOD, GSH, Nrf2/HO-1), inflammation (NF-κB, CD68, iNOS, NO, COX-2), and apoptosis (caspase-3) were assessed in serum and tissue. Liver histological analysis using H&E and Sirius red was performed. The development of liver injury in CsA-treated animals was indicated by elevated levels of liver enzymes, oxidants/antioxidants imbalance, inflammatory cells infiltration, up-regulated expression of inflammatory mediators, and apoptosis. These changes were associated with altered architecture of hepatic cells and fibrous connective tissue. ALA co-administration protected against CsA-induced liver damage and ameliorated biochemical changes and cellular injury. In conclusion, ALA demonstrated hepatoprotective potential against CsA-induced liver injury through combating oxidative stress, inflammation, and apoptosis, highlighting ALA as a valuable adjunct to CsA therapy.

Effect of Diacerein on HOTAIR/IL-6/STAT3, Wnt/ß-Catenin and TLR-4/NF-κB/TNF-α axes in colon carcinogenesis.

Colorectal cancer (CRC) is a common malignancy with high mortality and poor prognosis. Diacerein (DIA) is an anti-inflammatory used for treatment of osteoarthritis. We delineated some underlying molecular mechanisms of DIA's anti-carcinogenic effect in CRC using in vivo and in vitro models. Human Caco-2 cells were treated with DIA followed by MTT and Annexin V assays and CRC was experimentally induced using 1,2-dimethylhydrazine. DIA (50 mg/kg/day, orally) was administrated for 8 weeks. The MTT assay confirmed cytotoxic effect of DIA in vitro and Annexin V confirmed its apoptotic effect. DIA resulted in regression of tumour lesions with reduced colonic TLR4, NF-κB and TNF-α protein levels and down-regulated VEGF expression, confirming anti-angiogenic impact. DIA triggered caspase-3 expression and regulated Wnt/ß-Catenin pathway, by apparently interrupting the IL-6/STAT3/ lncRNA HOTAIR axis. In conclusion, DIA disrupted IL-6/STAT3/ lncRNA HOTAIR axis which could offer an effective therapeutic strategy for the management of CRC.

Origanum majorana L. Extract Attenuated Benign Prostatic Hyperplasia in Rat Model: Effect on Oxidative Stress, Apoptosis, and Proliferation.

Benign prostatic hyperplasia (BPH) is a widespread androgenic illness influencing elderly men. It is distinguished by prostatic epithelial and stromal muscle cell proliferation. Inflammation, oxidative stress, and apoptosis have all been interrelated to the development of BPH. Marjoram (Origanum majorana L.) is a herb with reported antiproliferative, proapoptotic, and antioxidative properties, which have not yet been studied in relation to BPH. Consequently, in this work, an ethanolic extract of O. majorana was prepared in two doses (250 and 500 mg/kg/day) to be injected into castrated rats after induction of a testosterone-BPH model. Testosterone propionate (TP) was subcutaneously injected (0.5 mg/kg/day) for one week after castration to induce BPH. Forty adult Wistar male rats were randomly allocated into five groups: control, BPH model, high and low O. majorana doses (250, 500 mg/kg/day), and finasteride (FN) (0.8 mg/kg/day) as a positive control. Treatment was continued with drugs/normal saline for 28 days. Rat's body and prostate were weighed, prostate index (PI) and % of prostate growth inhibition were calculated, serum dihydrotestosterone (DHT), prostatic content of superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC), and malondialdehyde (MDA), DN damage, histopathological changes, immune expression of proliferating cell nuclear antigen (PCNA), caspase-3, α-SMA, and TGF-ß1 were assessed. In addition, molecular quantitative PCR and ELISA analyses were performed to identify the expression of mRNAs and related proteins of both caspase-3 and TGF-ß1 in prostate tissue from O. majorana-treated and untreated groups. Rats with BPH had significantly higher prostate weights and PI, higher DHT, DNA damage (8-hydroxyguanine, 8-OH-dG), and MDA levels with prominent PCNA, α-SMA, and TGF-ß expression, but lower SOD, CAT, and TAC activity and caspase-3 expression. O. majorana (250 and 500 mg/kg/day)-treated groups revealed a decrease in prostate weights and PI, lower levels of DHT, suppressed oxidative stress, reduced tissue proliferation and fibrosis, and restored antioxidant and proapoptotic activity. Additionally, quantitative PCR and ELISA analysis showed that treatment with O. majorana significantly upregulated the expression of caspase-3 and downregulated the expression of TGF-ß in prostate tissues of BPH rats. The data were confirmed by the immunohistological reactivity of these targeted markers in the prostate tissues. These effects were more significant with O. majorana 500 mg/mL/rat. In conclusion, the current study indicates the efficient use of O. majorana in the treatment of testosterone-induced BPH through its antiproliferative, proapoptotic, and antioxidative mechanisms.

Sexual Dimorphism Impact on the Ground Reaction Force Acting on the Mediolateral Direction During Level Walking: Hip Abductor Muscle Biomechanics and Its Correlation to GRF Moment Arm.

The female pelvis morphology represents an evolved compensation between two opposing needs: a broad pelvis enough to deliver a sizeable brained offspring while remaining narrow enough to allow for effective bipedal gait. The precise expectation of hip abductor force generation is critical in anthropological studies and experimental practice of human stride mechanics. Hip implants and surgical procedures for hip anatomy reconstruction are based on the static single-leg stance paradigm. The current work investigated the impact of sexual dimorphism on the ground reaction force (GRF) acting on the mediolateral direction during level walking, emphasizing the difference in hip abductor muscle biomechanics and its correlation to ground reaction force moment arm, R. The ground reaction force in the mediolateral direction, hip abduction and adduction moments during the gait cycle and ground reaction force moment arm, R were measured. The current study concludes that the male individuals exhibit significantly higher mass-specific mediolateral ground reaction force during level walking. In contrast, hip abductor moments/kg body weight, medialization of the trochanter, R, and hip coronal were more significant in female individuals. We conclude that increased abductor moment and medialization of the greater trochanter will increase R, hip coronal and decrease abductor moment arm, r, in female individuals, affecting the effective mechanical advantage (EMA) of hip abductors in single-limb stance during level walking.

Mechanism of chromium-induced toxicity in lungs, liver, and kidney and their ameliorative agents.

Heavy metal Chromium (Cr), can adversely affect humans and their health if accumulated in organs of the body, such as the lungs, liver, and kidneys. Cr (VI) is highly toxic and has a higher solubility in water than Cr (III). One of the most common routes for Cr exposure is through inhalation and is associated with liver, lung, kidney damage, widespread dermatitis, GI tract damage, human lung cancer, cardiomyopathies, and cardiovascular disease. The increase in ROS production has been attributed to most of the damage caused by Cr toxicity. Cr-induced ROS-mediated oxidative stress has been seen to cause a redox imbalance affecting the antioxidant system balance in the body. The Nrf2 pathway dysregulation has been implicated in the same. Deregulation of histone acetylation and methylation has been observed, together with gene methylation in genes such as p16, MGMT, APC, hMLH1, and also miR-143 repression. Several ultra-structural changes have been observed following Cr (VI)-toxicity, including rough ER dilation, alteration in the mitochondrial membrane and nuclear membrane, pycnotic nuclei formation, and cytoplasm vacuolization. A significant change was observed in the metabolism of lipid, glucose, and the metabolism of protein after exposure to Cr. Cr-toxicity also leads to immune system dysregulations with changes seen in the expression of IL-8, IL-4, IgM, lymphocytes, and leukocytes among others. P53, as well as pro-and anti-apoptotic proteins, are involved in apoptosis. These Cr-induced damages can be alleviated via agents that restore antioxidant balance, regulate Nrf-2 levels, or increase anti-apoptotic proteins while decreasing pro-apoptotic proteins.

Mixed Contaminants: Occurrence, Interactions, Toxicity, Detection, and Remediation.

The ever-increasing rate of pollution has attracted considerable interest in research. Several anthropogenic activities have diminished soil, air, and water quality and have led to complex chemical pollutants. This review aims to provide a clear idea about the latest and most prevalent pollutants such as heavy metals, PAHs, pesticides, hydrocarbons, and pharmaceuticals-their occurrence in various complex mixtures and how several environmental factors influence their interaction. The mechanism adopted by these contaminants to form the complex mixtures leading to the rise of a new class of contaminants, and thus resulting in severe threats to human health and the environment, has also been exhibited. Additionally, this review provides an in-depth idea of various in vivo, in vitro, and trending biomarkers used for risk assessment and identifies the occurrence of mixed contaminants even at very minute concentrations. Much importance has been given to remediation technologies to understand our current position in handling these contaminants and how the technologies can be improved. This paper aims to create awareness among readers about the most ubiquitous contaminants and how simple ways can be adopted to tackle the same.

Role of Dapagliflozin and Liraglutide on Diabetes-Induced Cardiomyopathy in Rats: Implication of Oxidative Stress, Inflammation, and Apoptosis.

The current study aims to assess the protective effects of dapagliflozin (Dapa; a sodium-glucose cotransporter-2 inhibitor) and/or liraglutide (Lira; a glucagon-like peptide 1 agonist) in an experimental model of diabetic cardiomyopathy (DCM). A single dose of streptozotocin (STZ) was administrated to male Sprague-Dawley rats by intraperitoneal injection at a dose of 50 mg/kg to induce diabetes mellitus (DM). Dapa (1 mg/kg, orally), Lira (0.4 mg/kg, s.c.), and Dapa-Lira combination were administrated for 8 weeks once-daily. Blood samples were evaluated for glucose level and biochemical markers of cardiac functions. Cardiac tissue was dissected and assessed for redox homeostasis (malondialdehyde (MDA), glutathione (GSH), and catalase (CAT)), pro-inflammatory mediators (NF-κB and tumor necrosis factor-α (TNF-α)), and apoptotic effectors (caspase-3). Moreover, the effect of treatments on the cardiac cellular structure was studied. Dapa and/or Lira administration resulted in significant improvement of biochemical indices of cardiac function. Additionally, all treatment groups demonstrated restoration of oxidant/antioxidant balance. Moreover, inflammation and apoptosis key elements were markedly downregulated in cardiac tissue. Also, histological studies demonstrated attenuation of diabetes-induced cardiac tissue injury. Interestingly, Dapa-Lira combination treatment produced a more favorable protective effect as compared to a single treatment. These data demonstrated that Dapa, Lira, and their combination therapy could be useful in protection against DM-accompanied cardiac tissue injury, shedding the light on their possible utilization as adjuvant therapy for the management of DM patients.

Canagliflozin reduces the contractile response of isolated heart of normal adult rats / Canagliflozin reduce la respuesta contráctil del corazón aislado de ratas adultas normales

SUMMARY: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a unique class of glucose-declining renal-targeted drugs. The SGLT2i Canagliflozin (CANA) is an anti-hyperglycemic drug that reduces various cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. This study aimed to explore the potential effects of CANA on the isolated healthy adult rat hearts to show if CANA has positive inotropic or cardiac depressant effects via analyzing the amplitude and frequency of cardiac contractions. In isolated normal adult rat hearts, the effects of CANA on cardiac contractility were examined. In a dose-response curve, CANA led to a significant cardiac depressant effect in a dose-dependent manner. This cardiac depressant effect of CANA (10-6 M) was not prevented by atropine. However, this cardiac depressant effect was partially antagonized by both Isoproterenol (10-5 M) and Calcium chloride (10-6 M), suggesting beta-adrenoceptor and calcium channel blocking actions. In addition, the cardiac depressant effect of CANA (10-6 M) was mitigated in part by Nitric oxide synthase inhibitor, L-NAME, suggesting that its action probably depends to some extent on the accumulation of nitric oxide, which decreases the rise of intracellular Calcium. Data from this study demonstrate that CANA has a significant cardiac relaxant effect in isolated hearts of healthy adult rats by different possible mechanisms. This inhibitory effect on cardiac contractility may help improve the diastolic ventricular filling providing a therapeutic potential to help the other cardioprotective mechanisms of CANA in the prevention and treatment of heart failure.

RESUMEN: Los inhibidores del cotransportador de sodio- glucosa 2 (SGLT2i) representan una clase única de fármacos dirigidos a los riñones que disminuyen la glucosa. El SGLT2i Canagliflozin (CANA) es un fármaco antihiperglucémico que reduce varios resultados cardiovasculares y renales en pacientes con diabetes mellitus tipo 2. Este estudio tuvo como objetivo explorar los efectos potenciales de CANA en corazones aislados de ratas adultas sanas para indicar si CANA tiene efectos inotrópicos o depresores cardíacos positivos mediante el análisis de la amplitud y la frecuencia de las contracciones cardíacas. En corazones aislados de ratas adultas normales, se examinaron los efectos de CANA sobre la contractilidad cardíaca. En una curva de dosis-respuesta, CANA condujo a un efecto depresor cardíaco significativo de manera dependiente de la dosis. Este efecto depresor cardíaco de CANA (10-6 M) no fue impedido por la atropina. Sin embargo, este efecto depresor cardíaco fue parcialmente antagonizado tanto por el isoproterenol (10-5 M) como por el cloruro de calcio (10-6 M), lo que sugiere acciones bloqueadoras de los receptores beta adrenérgicos y de los canales de calcio. Además, el efecto depresor cardíaco de CANA (10-6 M) fue mitigado en parte por el inhibidor de la sintasa de óxido nítrico, L-NAME, lo que sugiere que su acción probablemente depende en cierta medida de la acumulación de óxido nítrico, lo que disminuye el aumento de calcio intracelular. Los datos de este estudio demuestran que CANA tiene un efecto relajante cardíaco significativo en corazones aislados de ratas adultas sanas por diferentes mecanismos posibles. Este efecto inhibitorio sobre la contractilidad cardíaca puede ayudar a mejorar el llenado ventricular diastólico proporcionando un potencial terapéutico para ayudar a los otros mecanismos cardioprotectores de CANA en la prevención y tratamiento de la insuficiencia cardíaca.

Renovation of Intestinal Barrier by Polydatin in Experimentally Induced Ulcerative Colitis: Comparative Ultrastructural Study with L-Carnosine.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with intestinal epithelial barrier impairment. Polydatin (PD), a natural product isolated from Polygonum cuspidatum, is known to have an anti-inflammatory, antioxidant, and antiapoptotic effect. We attempted to compare the protective impact of PD pretreatment on alterations to the intestinal epithelial barrier and the colonic wall's ultrastructure accompanying ulcerative colitis to other conventional drugs in practice, primarily L-carnosine, which has not been addressed before. The rats were divided into 5 groups; 3 of them were treated with sulphasalazine (500 mg/kg), L-carnosine (30 mg/kg), and PD (45 mg/kg). All groups were administered their respective drugs 3 days before the UC was induced by acetic acid intra-rectally, and the treatment was continued until the 11th day. The disease activity index (DAI) was estimated, and a macroscopic scoring was established for the harvested colonic tissue. The tissues were extracted and processed for hematoxylin and eosin staining, caspase-3 immunohistochemical staining, electron microscopy, and biochemical analysis evaluating proinflammatory markers (IL-1ß, TNF-α, and IL-6), myeloperoxidase (MPO), oxidative stress, and lipid peroxidation. Histopathological examination of colonic tissue showed that PD pretreatment effectively restored mucosal epithelial cells, intercellular tight junctions, goblet cells, and maintained the intestinal epithelial and endothelial barriers. PD suppressed MPO, proinflammatory markers, and malondialdehyde but enhanced superoxide dismutase and glutathione levels. It also hampered apoptosis, as evidenced by a reduction in caspase-3 expression. PD showed a significantly better response in preserving the intestinal epithelial barrier against acetic acid-induced colitis as compared to sulphasalazine and L-carnosine. These findings demonstrate the therapeutic role of PD for patients with UC.

Effect of meloxicam (cyclooygenase-2 inhibitor) versus vitamin D3 (cholecalciferol) as ameliorating agents of progressive doxorubicin-induced nephrotoxicity in rats.

Doxorubicin (DOX)-induced nephropathy hampered its antineoplastic efficiency. The objective of the current work is to assess the prospective ameliorating effects of meloxicam versus vitamin D3 (Vit D3, cholecalciferol) against progressive DOX-induced nephropathy in rats trying to ascertain the possible mechanism underlying such amelioration. Ninety Male Wistar rats were randomly distributed to five experimental groups for 3 weeks, with saline, meloxicam (daily), DOX (single dose), Vit D3+DOX, or both meloxicam and DOX. We measured levels of urinary protein, serum creatinine, malondialdehyde (MDA) and renal reduced glutathione (GSH). In addition, tumor necrosis factor-alpha (TNF-α) expression and renal histopathology were assessed. Meloxicam alone treated group revealed no significant difference in urinary protein and serum creatinine. It also presented non-significant reduction in the MDA content while an increase in the reduced GSH content in contrast to the control group, which is more evident after the first week. Renal sections of rats received meloxicam only showed no significant histological changes and negative immunoreactivity compared to the control group. DOX induced a significant increase in urinary protein, serum creatinine, decrease reduced GSH, increased renal MDA and disrupted renal morphometric parameters and histology with increased TNF-α expression. Combination groups of Vit D3+DOX and meloxicam+DOX showed improvement of all DOX disturbed parameters. Meloxicam showed better results most likely due to anti-inflammatory and antioxidant activities superimposing the immune-modulatory effect of Vit D3. So, it is recommended to use meloxicam in patients receiving DOX as a renoprotective agent in addition to its analgesic effects required by cancer patients.