Probiotics mixture and taurine attenuate L-arginine-induced acute pancreatitis in rats: Impact on transient receptor potential vanilloid-1 (TRPV-1)/IL-33/NF-κB signaling and apoptosis.

Acute pancreatitis (AP) is an inflammatory disorder of acinar cells. It may develop into severe chronic pancreatitis with a significant mortality rate. The current study aimed to assess the therapeutic effect of a Lactobacillus (LAB) mixture against rat AP. Six groups were created including control, taurine (300 mg/kg; i.p.) for 7 days, LAB mixture for 7 days, L-arginine (2.5 g/kg; i.p.) 2 doses with 1 h interval on 1st day, L-arginine+taurine, and L-arginine+LAB. Serum amylase and lipase activities were measured. Pancreatic tissue was used for histopathological examination, oxidative stress biomarkers including malondialdehyde (MDA) and reduced glutathione (GSH), and inflammatory biomarkers including myeloperoxidase (MPO) and interleukin (IL)-33 assessment. qRT-PCR was used for transient receptor potential vanilloid-1 (TRPV-1) investigation and Western blot analysis for measuring nuclear factor kappa-B (NF-κBp65) and the apoptosis biomarker; caspase-3. Taurine and LAB reduced lipase and significantly ameliorated induced oxidative stress by normalizing MDA and GSH contents. They counteracted inflammation by reducing MPO, IL-33, NF-κBp65, and TRPV-1. In addition, taurine and LAB counteracted apoptosis as proved by reduced caspase-3 expression. Taken together, these findings indicate that taurine and the use LAB mixture can mitigate AP by L-arginine via influencing TRPV-1/IL-33/NF-κB signaling together with exhibiting potent antioxidant and anti-inflammatory effects.

Stimulation of Autophagy by Dapagliflozin Mitigates Cadmium-Induced Testicular Dysfunction in Rats: The Role of AMPK/mTOR and SIRT1/Nrf2/HO-1 Pathways.

Cadmium (Cd) is a widespread environmental pollutant that triggers testicular dysfunction. Dapagliflozin is a selective sodium-glucose co-transporter-2 inhibitor with notable antioxidant and anti-apoptotic features. It has shown marked cardio-, reno-, hepato-, and neuroprotective effects. Yet, its effect on Cd-evoked testicular impairment has not been examined. Hence, the goal of the current study was to investigate the potential positive effect of dapagliflozin against Cd-induced testicular dysfunction in rats, with an emphasis on autophagy, apoptosis, and oxidative insult. Dapagliflozin (1 mg/kg/day) was given by oral gavage, and testicular dysfunction, impaired spermatogenesis, and biomolecular events were studied via immunohistochemistry, histopathology, and ELISA. The current findings demonstrated that dapagliflozin improved relative testicular weight, serum testosterone, and sperm count/motility and reduced sperm abnormalities, signifying mitigation of testicular impairment and spermatogenesis disruption. Moreover, dapagliflozin attenuated Cd-induced histological abnormalities and preserved testicular structure. The testicular function recovery was prompted by stimulating the cytoprotective SIRT1/Nrf2/HO-1 axis, lowering the testicular oxidative changes, and augmenting cellular antioxidants. As regards apoptosis, dapagliflozin counteracted the apoptotic machinery by downregulating the pro-apoptotic signals together with Bcl-2 upregulation. Meanwhile, dapagliflozin reactivated the impaired autophagy, as seen by a lowered accumulation of SQSTM-1/p62 and Beclin 1 upregulation. In the same context, the testicular AMPK/mTOR pathway was stimulated as evidenced by the increased p-AMPK (Ser487)/total AMPK ratio alongside the lowered p-mTOR (Ser2448)/total mTOR ratio. Together, the favorable mitigation of Cd-induced testicular impairment/disrupted spermatogenesis was driven by the antioxidant, anti-apoptotic, and pro-autophagic actions of dapagliflozin. Thus, it could serve as a tool for the management of Cd-evoked testicular dysfunction.

Ameliorative effect of bone marrow-derived mesenchymal stem cells on burn-induced hepatic and metabolic derangements in rats.

AIMS: The current study aims to investigate the therapeutic potential of bone marrow-derived mesenchymal stem cells (MSCs) as a solo therapy in ameliorating both skin lesions and liver injury induced by cutaneous severe burn injury (SBI) in rats. MAIN METHODS: In anesthetized male adult Wistar albino rats, 30 % total burn surface area and established hepatic injury was achieved via direct contact of each experimental animal's dorsum with heated metal rod (100 °C) for 10 s. On the next day following burn, human MSCs or mouse MSCs was administered locally around the burn site and intraperitonially (0.5 × 106 cells/rat for each route) and outcomes were investigated at 4 and 14 days following burn induction. KEY FINDINGS: Both types of MSCs significantly improved skin and liver histology, decreased liver enzymes, and ameliorated oxidative stress in hepatocytes of SBI-rats. Further, SBI-induced rises in hepatic apoptotic marker (caspase-3, Bax) and serum inflammatory markers (TNF-α, IL-1ß, and IL-6) were reduced following either human or mouse MSC administration. In addition, MSCs augmented insulin receptor substrate-1, phosphorylated protein kinase-B (phospho-Akt), while alleviating serum glucose levels in SBI-rats. These previous effects persisted even at the 14-day time point. SIGNIFICANCE: Following single administration, bone marrow-derived MSCs is capable of counteracting SBI-induced skin lesions as well as related hepatic complications, specifically via mitigating postburn hyperglycemia and hyperinflammation.

Ellagic acid attenuates testicular disruption in rheumatoid arthritis via targeting inflammatory signals, oxidative perturbations and apoptosis.

BACKGROUND AND PURPOSE: Reduced male fertility has been regarded as a serious complication of rheumatoid arthritis. Phytochemicals have been described as protective agents against rheumatoid arthritis-linked testicular impairment. The current study aimed to investigate the potential protective effects of ellagic acid on rheumatoid arthritis-evoked testicular dysfunction vis-à-vis the reference anti-inflammatory celecoxib. EXPERIMENTAL APPROACH: Ellagic acid (50 mg/kg/day) and celecoxib (5 mg/kg/day) were administered orally for 20 days in adjuvant-induced arthritic rats. KEY FINDINGS: Current data revealed that ellagic acid counteracted rheumatoid arthritis-evoked testicular histopathologic changes, disrupted sperm characteristics and low gonadosomatic index with comparable efficacy to celecoxib. Ellagic acid also enhanced the testicular steroidogenesis via upregulating the gene expression of 3ß-hydroxysteroid dehydrogenase, 17ß-hydroxysteroid dehydrogenase and steroidogenic acute regulatory protein with consequent boosting of serum testosterone. Notably, ellagic acid attenuated the testicular inflammatory responses through suppression of myeloperoxidase, tumor necrosis factor-α and cyclo-oxygenase-2 protein expression together with enhancing the anti-inflammatory signal interleukin 10. Ellagic acid also curbed the redox alterations via lowering the production of lipid peroxides and nitric oxide and elevation of the anti-oxidant reduced glutathione. In support of cell survival, ellagic acid combated testicular apoptosis through downregulating caspase-3 protein expression. SIGNIFICANCE: The present work accentuates the beneficial actions of ellagic acid in rheumatoid arthritis-incurred testicular impairment and disrupted spermatogenesis via combating the inflammatory, oxidative and apoptotic aberrations.

Venlafaxine and carvedilol ameliorate testicular impairment and disrupted spermatogenesis in rheumatoid arthritis by targeting AMPK/ERK and PI3K/AKT/mTOR pathways.

Testicular impairment has been commonly described in long-standing rheumatoid arthritis (RA) patients. Since depression and cardiovascular disorders are the most disturbing co-morbidities of RA, investigating the efficacy of the anti-depressant venlafaxine or the beta-blocker carvedilol in RA-associated testicular dysfunction may add to their clinical utility for RA patients. Previously, both agents have demonstrated significant in vivo anti-oxidant and anti-inflammatory actions. In the current study, venlafaxine (50 mg/kg/day) and carvedilol (10 mg/kg/day) were orally administered to adjuvant arthritic rats for 20 days. Interestingly, venlafaxine and carvedilol effectively suppressed paw edema and mitigated the testicular histopathological aberrations and the disrupted spermatogenesis. Both drugs enhanced testicular steroidogenesis through upregulation of 3ß-HSD, 17ß-HSD and StAR gene expression with concomitant augmentation of serum testosterone. They also blunted the inflammatory burden via attenuation of myeloperoxidase, TNF-α and the protein expression of NF-κBp65 along with elevation of IL-10. They attenuated testicular oxidative perturbations via lowering lipid peroxides and nitric oxide and boosting glutathione levels. With regard to apoptosis, the two agents lowered the protein expression of caspase-3, cleaved caspase-3, cleaved PARP, Bax and p53, promoting germ cell survival. They also modulated the AMPK/ERK signaling via lowering of p-AMPK and upregulation of p-ERK1/2 along with PI3K/AKT/mTOR transduction by enhancing the PI3Kp110α, p-AKT and p-mTOR protein expression. Together, the present work demonstrates the beneficial effects of venlafaxine and carvedilol in RA testicular dysfunction and impaired spermatogenesis via modulation of AMPK/ERK and PI3K/AKT/mTOR signaling and intervention with the testicular oxidative stress, inflammation and apoptosis.

Caffeic acid and ellagic acid ameliorate adjuvant-induced arthritis in rats via targeting inflammatory signals, chitinase-3-like protein-1 and angiogenesis.

Rheumatoid arthritis (RA) is a chronic inflammatory arthropathy that principally attacks the joints. The present study aimed to explore the potential anti-arthritic effects of caffeic acid and ellagic acid in adjuvant-induced arthritis, compared to celecoxib. The current study also explored the underlying molecular mechanisms e.g., pro-inflammatory signals including chitinase-3-like protein-1 (CHI3L1); a glycoprotein that correlates with RA joint destruction besides angiogenesis, oxidative stres and apoptosis. Interestingly, caffeic and ellagic acids attenuated the severity of arthritis with comparable efficacy to celecoxib. Both agents effectively mitigated paw edema and inflammatory cell infiltration and protected the joint tissues against pannus formation along with cartilage and bone destruction. Notably, they also lowered the paw expression of NF-κB and the downstream effector CHI3L1 and its synthesis inducer IL-1ß. They also lowered the levels of the tissue remodeling factor MMP-9 and the angiogenic signal VEGF in rat paws. Both agents also suppressed serum oxidative stress via diminishing lipid peroxides and nitric oxide together with augmentation of reduced glutathione in arthritic animals. Regarding apoptosis, they attenuated paw caspase-3 levels, favoring cell survival. Together, these favorable findings may advocate the use of caffeic and ellagic acids as adjunct modalities for the management of RA to mitigate joint damage.

Mechanistic insights into the augmented effect of bone marrow mesenchymal stem cells and thiazolidinediones in streptozotocin-nicotinamide induced diabetic rats.

This study was designed to assess whether the protective effects of bone marrow-derived mesenchymal stem cells (MSCs) against diabetes could be enhanced by pioglitazone (PIO), a PPARγ agonist. Combined MSCs and PIO treatments markedly improved fasting blood glucose, body weight, lipid profile levels, insulin level, insulin resistance, ß cell function. Those protective effects also attenuated both pancreatic lesions and fibrosis in diabetic rats and decreased the depletion of pancreatic mediators of glycemic and lipid metabolism including peroxisome proliferator-activated receptor alpha (PPARα), PGC-1α, GLP-1 and IRS-2. Cardiac biogenesis of diabetic groups was also improved with MSCs and/or PIO treatments as reflected by the enhanced up-regulation of the expressions of cardiac IRS1, Glucose transporter 4, PGC-1, PPARα and CPT-1 genes and the down-regulated expression of lipogenic gene SREBP. The combination of MSCs and PIO also potentiated the decrease of abnormal myocardial pathological lesions in diabetic rats. Similarly, the inhibitory effects of MSCs on diabetic cardiac fibrosis and on the up regulations of TGF-ß, collagen I and III gene expressions were partial but additive when combined with PIO. Therefore, combined therapy with PIO and BMCs transplantation could further potentiate the protective benefit of MSCs against diabetes and cardiac damage compared to MSCs monotherapy.

Bone marrow and adipose mesenchymal stem cells attenuate cardiac fibrosis induced by methotrexate in rats.

Mesenchymal stem cells (MSCs) are an ideal adult stem cell with capacity for self-renewal and differentiation with an extensive tissue distribution. The present study evaluates the therapeutic effects of bone marrow mesenchymal stem cells (BM-MSCs) or adipose-derived mesenchymal stem cells (AD-MSCs) against the development of methotrexate (MTX)-induced cardiac fibrosis versus dexamethasone (DEX). Rats were allocated into five groups; group 1, received normal saline orally; group 2, received MTX (14 mg/kg/week for 2 weeks); groups 3 and 4, treated once with 2 × 106 cells of MTX + BM-MSCs and MTX + AD-MSCs, respectively; and group 5, MTX + DEX (0.5 mg/kg, for 7 days, P.O.). MTX induced cardiac fibrosis as marked changes in oxidative biomarkers and elevation of triglyceride, cholesterol, aspartate aminotransferase, gamma-glutamyl transferase, creatine kinase, and caspase-3, as well as deposited collagen. These injurious effects were antagonized after treatment with MSCs. So, MSCs possessed antioxidant, antiapoptotic, as well antifibrotic effects, which will perhaps initiate them as notable prospective for the treatment of cardiac fibrosis.

Significant curative functions of the mesenchymal stem cells on methotrexate-induced kidney and liver injuries in rats.

Mesenchymal stem cells (MSCs) curative effects on methotrexate (MTX)-induced kidney and liver injuries remain elusive. Therefore, rats were divided into five groups, rats received MTX orally (14 mg/kg) as a single dose/week for 2 weeks, groups 3 and 4 were injected once with 2 × 106 cells bone marrow MSCs and adipose-derived MSCs, respectively. The last group administered dexamethasone (DEX) (0.5 mg/kg, p.o) for 7 days. MTX caused marked increase in malondialdehyde and nitrite/nitrate concentrations. However, MTX administration decreased reduced glutathione content plus catalase activity. In addition, MTX caused a significant increment in kidney and liver biomarkers levels. Moreover, MTX showed renal tubules vacuolation and necrosis of hepatocytes, as well expression of caspase-3 and nuclear factor kappa beta in kidney and liver tissues were observed. MSCs treatment alleviated previous side effects induced by MTX. MSCs improved nephrotoxicity and hepatotoxicity induced by MTX to a better extent as compared with DEX.