Targeting inflammation and redox perturbations by lisinopril mitigates Freund's adjuvant-induced arthritis in rats: role of JAK-2/STAT-3/RANKL axis, MMPs, and VEGF.

BACKGROUND: Cardiovascular disorders are major complications of rheumatoid arthritis (RA). Hence, finding effective agents that can target RA progression and its cardiovascular consequences is demanding. The present work aimed to explore the potential of lisinopril, an angiotensin-converting enzyme inhibitor, to mitigate adjuvant's-induced arthritis with emphasis on the pro-inflammatory signals, articular degradation cues, and angiogenesis alongside JAK-2/STAT-3 and Nrf2/HO-1 pathways. METHODS: Lisinopril (10 mg/kg/day) was administered by oral gavage for 3 weeks and the target signals were examined by biochemical assays, ELISA, histopathology, immunoblotting, and immunohistochemistry. RESULTS: Lisinopril attenuated the progression of arthritis as proven by lowering paw edema, arthritic index, and gait scores alongside diminishing the immune-cell infiltration/aberrant histopathology in the dorsal pouch lining. These favorable actions were associated with curtailing the production of inflammatory cytokines (TNF-α, IL-6, IL-1ß, and IL-17) and the pro-inflammatory angiotensin II alongside upregulating the anti-inflammatory angiotensin-(1-7) in the hind paw of arthritic rats. At the molecular level, lisinopril inhibited the upstream JAK-2/STAT-3 pathway by downregulating the protein expression of p-JAK-2/total JAK-2 and p-STAT-3/total STAT-3 ratio and the nuclear levels of NF-κBp65. Meanwhile, lisinopril curbed the downstream cartilage degradation signals matrix metalloproteinases (MMP-3 and MMP-9) and the bone erosion cue RANKL. Equally important, the protein expression of the angiogenesis signal VEGF was downregulated in the hind paw/dorsal lining. With respect to oxidative stress, lisinopril suppressed the paw lipid peroxides and boosted GSH and Nrf-2/HO-1 pathway. CONCLUSION: Lisinopril attenuated adjuvant-induced arthritis via inhibition of inflammation, articular degradation cues, and angiogenesis.

Ameliorative Potential of L-Alanyl L-Glutamine Dipeptide in Colon Cancer Patients Receiving Modified FOLFOX-6 Regarding the Incidence of Diarrhea, the Treatment Response, and Patients' Survival: A Randomized Controlled Trial.

Background and Objectives: Diarrhea induced by chemotherapy may represent a life-threatening adverse effect in cancer patients receiving chemotherapy. FOLFOX, an effective treatment for colon cancer, has been associated with diarrhea with high severity, particularly with higher doses. Management of diarrhea is crucial to increase the survival of cancer patients and to improve the quality of life. Glutamine is an abundant protein peptide found in blood and has a crucial role in boosting immunity, increasing protein anabolism, and decreasing the inflammatory effects of chemotherapy on the mucosal membranes, including diarrhea. This study aimed to provide evidence that parenteral L-alanyl L-glutamine dipeptide may have a positive influence on the incidence of diarrhea, treatment response, and the overall survival in colon cancer patients treated with modified FOLFOX-6 (mFOLFOX-6). Materials and Methods: Forty-four stage II and III colon cancer patients were included in this study where they were treated with the standard colon cancer chemotherapy mFOLFOX-6 and were randomly allocated into glutamine group and placebo group, each of 22 patients. Results: L-alanyl L-glutamine dipeptide was found to be significantly effective in decreasing the frequency and severity of diarrhea when compared to the placebo group, particularly after four and six cycles of mFOLFOX-6. There was no significant difference between the studied groups regarding to the overall survival. Conclusion: L-alanyl L-glutamine dipeptide can be considered as an add-on with chemotherapy to improve the quality of life and the overall survival of colon cancer patients.

Validated Simultaneous Gradient Ultra-Performance Liquid Chromatographic Quantification of Some Proton Pump Inhibitor Drug Residues in Saudi Pharmaceutical Industrial Wastewater.

Monitoring and quantification of active pharmaceutical ingredients (APIs) in the environment constitute important and challenging tasks, as they are directly associated with human health. Three commonly used proton pump inhibitors (PPIs), namely, omeprazole sodium (OMP), pantoprazole sodium (PNT), and lansoprazole sodium (LNZ) are well separated and quantified using ultra-performance liquid chromatography (UPLC) in pharmaceutical industrial wastewater. The separation of the studied drugs was performed on a stationary phase with a WatersTM column (100 × 2.1 mm, 1.7 µm). The mobile phase was composed of methanol:0.05 M potassium dihydrogen phosphate buffer (adjusted to pH 7.5 using NaOH) (50:50, v/v). The elution process was done in gradient mode by changing the relative proportions of the mobile phase components with time to get an optimum separation pattern. The flow rate of the developing system was adjusted to 0.8 mL/minute. Detection of the separated drugs was performed at 230 nm. The studied drugs were quantified in the concentration range of 10-200 ng/mL for all drugs. The cited method was fully validated according to the international conference on harmonization (ICH-Q2B) guidelines, then it was applied successfully for quantification of the studied PPIs in real wastewater samples after their solid phase extraction (SPE).

Fabrication of Membrane Sensitive Electrodes for the Validated Electrochemical Quantification of Anti-Osteoporotic Drug Residues in Pharmaceutical Industrial Wastewater.

Accurate and precise application of ion-selective electrodes (ISEs) in the quantification of environmental pollutants is a strenuous task. In this work, the electrochemical response of alendronate sodium trihydrate (ALN) was evaluated by the fabrication of two sensitive and delicate membrane electrodes, viz. polyvinyl chloride (PVC) and glassy carbon (GC) electrodes. A linear response was obtained at concentrations from 1 × 10-5 to 1 × 10-2 M for both electrodes. A Nernstian slope of 29 mV/decade over a pH range of 8-11 for the PVC and GC membrane electrodes was obtained. All assay settings were carefully adjusted to obtain the best electrochemical response. The proposed technique was effectively applied for the quantification of ALN in pure form and wastewater samples, acquired from manufacturing industries. The proposed electrodes were effectively used for the determination of ALN in real wastewater samples without any prior treatment. The current findings guarantee the applicability of the fabricated ISEs for the environmental monitoring of ALN.

Mechanistic perspective of morin protection against ketoprofen-induced gastric mucosal injury: Targeting HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways.

Ketoprofen is a widely used NSAID which incurs gastric mucosal damage. The high mobility group Box 1 (HMGB1) protein is a DNA-binding protein which exerts robust inflammatory actions, however, its role in ketoprofen-induced gastric damage has not been explored. Additionally, no previous studies have linked HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways in ketoprofen-induced gastropathy. The current work aimed to explore the potential of morin, a flavonoid with marked antioxidant/anti-inflammatory actions, to protect against ketoprofen-evoked gastric damage. Moreover, the underlying mechanisms, including the impact of morin on HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways were addressed. Immunoblotting and ELISA were used to examine the expression of target signals. Morin (50 mg/kg, p. o.) attenuated the severity of gastric injury via lowering of ulceration/hemorrhage and macroscopic damage scores. Meanwhile, it attenuated the histopathologic aberrations/damage scores. In the context of inflammation, morin suppressed TNF-α and myeloperoxidase levels and enhanced IL-10. Furthermore, it inhibited HMGB1/RAGE/NF-κB pathway through downregulating HMGB1, RAGE and phospho-NF-κBp65 protein expression. Morin successfully inhibited gastric mucosal oxidative stress through lowering of lipid peroxides and boosting of reduced glutathione, glutathione peroxidase and total antioxidant capacity. It also boosted DJ-1/Nrf2/HO-1 pathway via upregulating DJ-1, Nrf2 and HO-1 protein expression. Additionally, morin counteracted the apoptotic events by downregulating the proapoptotic Bax and Bax/Bcl-2 ratio and augmenting the PI3K/mTOR pathway through upregulating PI3Kp110α and phospho-mTOR protein expression. In conclusion, the current study demonstrates, for the first time, that morin shows a promise for the management of ketoprofen-induced mucosal insult through targeting of HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways.

Targeting MAPKs, NF-κB, and PI3K/AKT pathways by methyl palmitate ameliorates ethanol-induced gastric mucosal injury in rats.

Excessive drinking of alcohol has been frequently associated with gastric injury; however, its underlying molecular mechanisms have been inadequately investigated. Methyl palmitate (MP) has demonstrated marked hepato-, cardio- and pulmonary protective features; however, its effects on ethanol-induced gastric injury have not been studied. The aim of the present study was to evaluate the potential gastroprotective activity of MP against ethanol-evoked gastric mucosal damage in rats and associated molecular mechanisms, for example, mitogen-activated protein kinases (MAPKs), nuclear factor κB (NF-κB), and phosphoinositide 3 kinase/protein kinase B (PI3K/AKT) pathways. The rat stomachs were examined in terms of the inflammatory, oxidative, and apoptotic perturbations. Current data demonstrated that pretreatment with MP attenuated the gross gastric damage, scores of ulcer index, area of mucosal lesions and histopathology outcomes; actions which were similar to the reference antiulcer omeprazole. MP inhibited NF-κB expression, its nuclear translocation, and the expression of its downstream signals, for example, tumor necrosis factor-α and myeloperoxidase besides restoration of interleukin-10 levels. Western blot analysis revealed that MP counteracted the disruption of MAPKs signaling via lowering p-c-Jun N-terminal kinase 1/2 (p-JNK1/2) expression and restoring the phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) levels without affecting p-p38MAPK levels. Additionally, MP improved the antioxidant milieu via diminishing lipid peroxides and enhancing glutathione, glutathione peroxidase, total antioxidant capacity and mucosal nitric oxide. In the context of apoptosis, MP inhibited the cleavage of caspase-3 and poly(ADP-ribose)polymerase (PARP) and Bax protein expression with upregulating B cell lymphoma-2 expression (Bcl-2), thus, promoting gastric cellular survival. This was confirmed by MP activation of the PI3K/AKT pathway manifested by enhanced expression of PI3K p110α and p-AKT. Together, the present findings report the gastroprotective actions of MP mediated via its anti-inflammatory, antioxidant, and antiapoptotic actions. The underlying molecular mechanisms involve, at least partly, the modulation of MAPKs, NF-κB and PI3K/AKT transduction.

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.

Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways.

BACKGROUND/AIMS: The clinical utility of 5-fluorouracil (5-FU) is limited by its nephrotoxicity. Camel milk (CM) has previously displayed beneficial effects in toxicant-induced nephropathies. The current study aimed to investigate the potential of CM to attenuate 5-FU-induced nephrotoxicity in rats. METHODS: Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf-2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-κBp65, p53, Bax and PCNA were detected by Immunohistochemistry. To gain an insight into the molecular signaling mechanisms, we determined the effect of CM on MAPKs, NF-κB and PI3K/Akt/eNOS pathways by Western blotting. RESULTS: CM lowered 5-FU-triggered increase of creatinine, BUN, Kim-1 and NGAL renal injury biomarkers and attenuated the histopathological aberrations. It suppressed oxidative stress and augmented renal antioxidant armory (GSH, SOD, GPx, TAC) with restoration of NOX-1, Nrf-2 and HO-1 levels. CM also suppressed renal inflammation as indicated by inhibition of MPO, TNF-α, IL-1ß, IL-18 and MCP-1 proinflammatory mediators and downregulation of MMP-2 and MMP-9 expression with boosting of IL-10. Regarding MAPKs signaling, CM suppressed the phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 and inhibited NF-κB activation. For apoptosis, CM downregulated p53, Bax, CytC and caspase-3 proapoptotic signals with enhancement of Bcl-2 and PCNA. It also enhanced PI3K p110α, phospho-Akt and phospho-eNOS levels with augmentation of renal NO, favoring cell survival. Equally important, CM preconditioning enhanced 5-FU cytotoxicity in MCF-7, HepG-2, HCT-116 and PC-3 cells, thus, justifying their concomitant use. CONCLUSION: The current findings pinpoint, for the first time, the marked renoprotective effects of CM that were mediated via ROS scavenging, suppression of MAPKs and NF-κB along with activation of PI3K/Akt/eNOS pathway.

Targeting the proinflammatory cytokines, oxidative stress, apoptosis and TGF-ß1/STAT-3 signaling by irbesartan to ameliorate doxorubicin-induced hepatotoxicity.

Doxorubicin (DOX) is an anthracycline antibiotic that is used frequently for treatment of various types of malignancies. Hepatotoxicity is one of the serious complications of DOX. The aim of this study was to explore the effect of different doses of irbesartan on doxorubicin-induced hepatotoxicity in mice. Sixty male BALB/c mice were divided into six equal groups as follows: Control group; DOX group; Irbesartan (Small dose) group; Irbesartan (Large dose) group; DOX + Irbesartan (Small dose) group and DOX + Irbesartan (Large dose) group. Liver weight/body weight ratio, food intake, serum albumin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and total bilirubin were measured. Also, tissue antioxidant enzymes, transforming growth factor beta 1 (TGF-ß1), nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 (Nrf2/HO-1) content, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and signal transducer and activator of transcription-3 (STAT-3) were assessed. Parts of the hepatic tissues were subjected to histopathological examination. Irbesartan administration to DOX-treated mice induced significant decrease in serum ALT, AST, ALP, total bilirubin, tissue TGF-ß1, TNF-α, IL-6 and liver weight/body weight ratio associated with significant increase in food intake, serum albumin, tissue Nrf2/HO-1 content, STAT-3 and antioxidant enzymes and significant improvement in the histopathological picture compared to DOX group. This improvement was significant with DOX + Irbesartan large dose compared to DOX + Irbesartan small dose. In conclusion, irbesartan - in a dose-dependent manner - might represent a promising hope for cancer patients to ameliorate DOX-induced hepatotoxicity.

Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway.

BACKGROUND/AIMS: Camel milk (CM) has shown beneficial anti-inflammatory actions in several experimental and clinical settings. So far, its effect on rheumatoid arthritis (RA) has not been previously explored. Thus, the current work aimed to evaluate the effects of CM in Adjuvant-induced arthritis and air pouch edema models in rats, which mimic human RA. METHODS: CM was administered at 10 ml/kg orally for 3 weeks starting on the day of Freund's adjuvant paw inoculation. The levels of TNF-α and IL-10 were measured by ELISA while the protein expression of NF-κBp65, COX-2 and iNOS was detected by immunohistochemistry. The expression of MAPK target proteins was assessed by Western blotting. RESULTS: CM attenuated paw edema, arthritic index and gait score along with dorsal pouch inflammatory cell migration. CM lowered the TNF-α and augmented the anti-inflammatory IL-10 levels in sera and exudates of arthritic rats. It also attenuated the expression of activated NF-κBp65, COX-2 and iNOS in the lining of the dorsal pouch. Notably, CM inhibited the MAPK pathway signal transduction via lowering the phosphorylation of p38 MAPK, ERK1/2 and JNK1/2 in rat hind paws. Additionally, CM administration lowered the lipid peroxide and nitric oxide levels and boosted glutathione and total anti-oxidant capacity in sera and exudates of animals. CONCLUSION: The observed CM downregulation of the arthritic process may support the interest of CM consumption as an adjunct approach for the management of RA.

Chrysin alleviates testicular dysfunction in adjuvant arthritic rats via suppression of inflammation and apoptosis: comparison with celecoxib.

Long standing rheumatoid arthritis (RA) is associated with testicular dysfunction and subfertility. Few studies have addressed the pathogenesis of testicular injury in RA and its modulation by effective agents. Thus, the current study aimed at evaluating the effects of two testosterone boosting agents; chrysin, a natural flavone and celecoxib, a selective COX-2 inhibitor, in testicular impairment in rats with adjuvant arthritis, an experimental model of RA. Chrysin (25 and 50mg/kg) and celecoxib (5mg/kg) were orally administered to Wistar rats once daily for 21days starting 1h before arthritis induction. Chrysin suppressed paw edema with comparable efficacy to celecoxib. More important, chrysin, dose-dependently and celecoxib attenuated the testicular injury via reversing lowered gonadosomatic index and histopathologic alterations with preservation of spermatogenesis. Both agents upregulated steroidogenic acute regulatory (StAR) mRNA expression and serum testosterone with concomitant restoration of LH and FSH. Furthermore, they suppressed inflammation via abrogation of myeloperoxidase, TNF-α and protein expression of COX-2 and iNOS besides elevation of IL-10. Alleviation of the testicular impairment was accompanied with suppression of oxidative stress via lowering testicular lipid peroxides and nitric oxide. With respect to apoptosis, both agents downregulated FasL mRNA expression and caspase-3 activity in favor of cell survival. For the first time, these findings highlight the protective effects of chrysin and celecoxib against testicular dysfunction in experimental RA which were mediated via boosting testosterone in addition to attenuation of testicular inflammation, oxidative stress and apoptosis. Generally, the 50mg/kg dose of chrysin exerted comparable protective actions to celecoxib.

OSU-CG5, a novel energy restriction mimetic agent, targets human colorectal cancer cells in vitro.

AIM: Energy-restriction mimetic agents (ERMAs) are small-molecule agents that target various aspects of energy metabolism, which has emerged as a promising approach in cancer therapy. In the current study, we tested the ability of OSU-CG5, a novel ERMA, to target human colorectal cancer (CRC) in vitro. METHODS: Two human CRC cell lines (HCT-116 and Caco-2) were tested. Cell viability was assessed using MTT assay. Caspase-3/7 activities were measured using Caspase-Glo 3/7 assay kit. Western blot analysis was used to measure the expression of relevant proteins in the cells. Glucose consumption of the cells was detected using glucose uptake cell-based assay kit. RESULTS: OSU-CG5 dose-dependently inhibited HCT-116 and Caco-2 cell proliferation with the IC50 values of 3.9 and 4.6 µmol/L, respectively, which were 20-25-fold lower than those of resveratrol, a reference ERMA. Both OSU-CG5 (5, 10, and 20 µmol/L) and resveratrol (50, 100, and 200 µmol/L) dose-dependently increased caspase-3/7 activity and PARP level in the cells. Furthermore, both OSU-CG5 and resveratrol induced dose-dependent energy restriction in the cells: they suppressed glucose uptake and Akt phosphorylation, decreased the levels of p-mTOR and p-p70S6K, increased the levels of ER stress response proteins GRP78 and GADD153, and increased the level of ß-TrCP, which led to the downregulation of cyclin D1 and Sp1. CONCLUSION: OSU-CG5 exhibits promising anti-cancer activity against human CRC cells in vitro, which was, at least in part, due to energy restriction and the consequent induction of ER stress and apoptosis.

Omarigliptin/rosinidin combination ameliorates cyclophosphamide-induced lung toxicity in rats: The interaction between glucagon-like peptide-1, TXNIP/NLRP3 inflammasome signaling, and PI3K/Akt/FoxO1 axis.

Cyclophosphamide is an anti-neoplastic drug that has shown competence in the management of a broad range of malignant tumors. In addition, it represents a keystone agent for management of immunological conditions. Despite these unique properties, induction of lung toxicity may limit its clinical use. Omarigliptin is one of the dipeptidyl peptidase-4 inhibitors that has proven efficacy in management of diabetes mellitus. Rosinidin is an anthocyanidin flavonoid that exhibited promising results in management of diseases characterized by oxidative stress, inflammation, and apoptosis. The present work investigated the possible effects of omarigliptin with or without rosinidin on cyclophosphamide-induced lung toxicity with an exploration of the molecular mechanisms that contribute to these effects. In a rodent model of cyclophosphamide elicited lung toxicity, the potential efficacy of omarigliptin with or without rosinidin was investigated at both the biochemical and the histopathological levels. Both omarigliptin and rosinidin exhibited a synergistic ability to augment the tissue antioxidant defenses, mitigate the inflammatory pathways, restore glucagon-like peptide-1 levels, modulate high mobility group box 1 (HMGB1)/receptors of advanced glycation end products (RAGE)/nuclear factor kappa B (NF-κB) axis, downregulate the fibrogenic mediators, and create a balance between the pathways involved in apoptosis and the autophagy signals in the pulmonary tissues. In conclusion, omarigliptin/rosinidin combination may be introduced as a novel therapeutic modality that attenuates the different forms of lung toxicities induced by cyclophosphamide.

Activation of AMPK/mTOR-Driven Autophagy and Suppression of the HMGB1/TLR4 Pathway with Pentoxifylline Attenuates Doxorubicin-Induced Hepatic Injury in Rats.

Despite being an effective chemotherapeutic agent, the clinical use of doxorubicin (DOX) is limited by several organ toxicities including hepatic injury. Pentoxifylline (PTX) is a methylxanthine derivative with marked anti-inflammatory and anti-apoptotic features. It is unknown, however, whether PTX can mitigate DOX-evoked hepatotoxicity. This study aims to explore the potential hepatoprotective impact of PTX in DOX-induced hepatic injury and the underlying molecular mechanisms. Histopathology, immunohistochemistry, and ELISA were used to examine liver tissues. The current findings revealed that PTX administration to DOX-intoxicated rats mitigated the pathological manifestations of hepatic injury, reduced microscopical damage scores, and improved serum ALT and AST markers, revealing restored hepatic cellular integrity. These favorable effects were attributed to PTX's ability to mitigate inflammation by reducing hepatic IL-1ß and TNF-α levels and suppressing the pro-inflammatory HMGB1/TLR4/NF-κB axis. Moreover, PTX curtailed the hepatic apoptotic abnormalities by suppressing caspase 3 activity and lowering the Bax/Bcl-2 ratio. In tandem, PTX improved the defective autophagy events by lowering hepatic SQSTM-1/p62 accumulation and enhancing the AMPK/mTOR pathway, favoring autophagy and hepatic cell preservation. Together, for the first time, our findings demonstrate the ameliorative effect of PTX against DOX-evoked hepatotoxicity by dampening the hepatic HMGB1/TLR4/NF-κB pro-inflammatory axis and augmenting hepatic AMPK/mTOR-driven autophagy. Thus, PTX could be utilized as an adjunct agent with DOX regimens to mitigate DOX-induced hepatic injury.

Carvedilol alleviates adjuvant-induced arthritis and subcutaneous air pouch edema: modulation of oxidative stress and inflammatory mediators.

Rheumatoid arthritis (RA) is a systemic inflammatory disease with cardiovascular complications as the leading cause of morbidity. Carvedilol is an adrenergic antagonist which has been safely used in treatment of several cardiovascular disorders. Given that carvedilol has powerful antioxidant/anti-inflammatory properties, we aimed to investigate its protective potential against arthritis that may add further benefits for its clinical usefulness especially in RA patients with concomitant cardiovascular disorders. Two models were studied in the same rat; adjuvant arthritis and subcutaneous air pouch edema. Carvedilol (10mg/kg/day p.o. for 21days) effectively suppressed inflammation in both models with comparable efficacy to the standard anti-inflammatory diclofenac (5mg/kg/day p.o.). Notably, carvedilol inhibited paw edema and abrogated the leukocyte invasion to air pouch exudates. The latter observation was confirmed by the histopathological assessment of the pouch lining that revealed mitigation of immuno-inflammatory cell influx. Carvedilol reduced/normalized oxidative stress markers (lipid peroxides, nitric oxide and protein thiols) and lowered the release of inflammatory cytokines (TNF-α & IL-6), and eicosanoids (PGE2 & LTB4) in sera and exudates of arthritic rats. Interestingly, carvedilol, per se, didn't present any effect on assessed biochemical parameters in normal rats. Together, the current study highlights evidences for the promising anti-arthritic effects of carvedilol that could be mediated through attenuation of leukocyte migration, alleviation of oxidative stress and suppression of proinflammatory cytokines and eicosanoids.

OSU-A9 inhibits angiogenesis in human umbilical vein endothelial cells via disrupting Akt-NF-κB and MAPK signaling pathways.

Since the introduction of angiogenesis as a useful target for cancer therapy, few agents have been approved for clinical use due to the rapid development of resistance. This problem can be minimized by simultaneous targeting of multiple angiogenesis signaling pathways, a potential strategy in cancer management known as polypharmacology. The current study aimed at exploring the anti-angiogenic activity of OSU-A9, an indole-3-carbinol-derived pleotropic agent that targets mainly Akt-nuclear factor-kappa B (NF-κB) signaling which regulates many key players of angiogenesis such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Human umbilical vein endothelial cells (HUVECs) were used to study the in vitro anti-angiogenic effect of OSU-A9 on several key steps of angiogenesis. Results showed that OSU-A9 effectively inhibited cell proliferation and induced apoptosis and cell cycle arrest in HUVECs. Besides, OSU-A9 inhibited angiogenesis as evidenced by abrogation of migration/invasion and Matrigel tube formation in HUVECs and attenuation of the in vivo neovascularization in the chicken chorioallantoic membrane assay. Mechanistically, Western blot, RT-PCR and ELISA analyses showed the ability of OSU-A9 to inhibit MMP-2 production and VEGF expression induced by hypoxia or phorbol-12-myristyl-13-acetate. Furthermore, dual inhibition of Akt-NF-κB and mitogen-activated protein kinase (MAPK) signaling, the key regulators of angiogenesis, was observed. Together, the current study highlights evidences for the promising anti-angiogenic activity of OSU-A9, at least in part through the inhibition of Akt-NF-κB and MAPK signaling and their consequent inhibition of VEGF and MMP-2. These findings support OSU-A9's clinical promise as a component of anticancer therapy.

Targeting the Endoplasmic Reticulum Stress-Linked PERK/GRP78/CHOP Pathway with Magnesium Sulfate Attenuates Chronic-Restraint-Stress-Induced Depression-like Neuropathology in Rats.

Magnesium sulfate has demonstrated marked neuroprotection in eclampsia, hypoxia, stroke, and post-traumatic brain injury rodent models. However, its potential impact against chronic-restraint-stress (CRS)-induced depression-like neuropathology and associated alterations in endoplasmic reticulum (ER) stress have not been adequately examined. The present study aimed to investigate the neuroprotective potential of magnesium sulfate in a rat model of CRS-triggered depression-like behavioral disturbance and the underlying molecular mechanisms. Herein, CRS was induced by placing rats into restraining tubes for 6 h/day for 21 days and the animals were intraperitoneally injected with magnesium sulfate (100 mg/kg/day) during the study period. After stress cessation, the depression-like behavior was examined by the open-field test, sucrose preference test, and forced swimming test. The present data demonstrated that CRS triggered typical depression-like behavioral changes which were confirmed by the Z-normalization scores. Mechanistically, serum circulating corticosterone levels spiked, and the hippocampi of CRS-exposed animals demonstrated a significant decline in serotonin, norepinephrine, and dopamine neurotransmitters. At the molecular level, the hippocampal pro-inflammatory TNF-alpha and IL-1ß cytokines and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-HG) increased in stressed animals. In tandem, enhancement of hippocampal ER stress was evidenced by the activation of iNOS/PERK/GRP78/CHOP axis seen by increased protein expression of iNOS, PERK, GRP78, and CHOP signal proteins in the hippocampi of stressed rats. Interestingly, magnesium sulfate administration attenuated the depression-like behavioral outcomes and the histopathological changes in the brain hippocampi. These favorable actions were driven by magnesium sulfate's counteraction of corticosterone spike, and hippocampal neurotransmitter decline, alongside the attenuation of neuroinflammation, pro-oxidation, and ER stress. In conclusion, the current results suggest the promising neuroprotective/antidepressant actions of magnesium sulfate in CRS by dampening inflammation, ER stress, and the associated PERK/GRP78/CHOP pathway.

Neuroprotective Impact of Linagliptin against Cadmium-Induced Cognitive Impairment and Neuropathological Aberrations: Targeting SIRT1/Nrf2 Axis, Apoptosis, and Autophagy.

Cadmium is an environmental contaminant associated with marked neurotoxicity and cognitive impairment. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated promising neuroprotection against cerebral ischemia and diabetic dementia. However, there has been no study of its effect on cadmium-induced cognitive deficits. In the present work, linagliptin's prospective neuroprotective effects against cadmium-evoked cognitive decline were examined in vivo in rats. The molecular pathways related to oxidative stress, apoptosis, and autophagy were investigated. Histology, immunohistochemistry, ELISA, and biochemical assays were performed on brain hippocampi after receiving linagliptin (5 mg/kg/day). The current findings revealed that cadmium-induced learning and memory impairment were improved by linagliptin as seen in the Morris water maze, Y-maze, and novel object recognition test. Moreover, linagliptin lowered hippocampal neurodegeneration as seen in histopathology. At the molecular level, linagliptin curtailed hippocampal DPP-4 and augmented GLP-1 levels, triggering dampening of the hippocampal neurotoxic signals Aß42 and p-tau in rats. Meanwhile, it enhanced hippocampal acetylcholine and GABA and diminished the glutamate spike. The behavioral recovery was associated with dampening of the hippocampal pro-oxidant response alongside SIRT1/Nrf2/HO-1 axis stimulation. Meanwhile, linagliptin counteracted hippocampal apoptosis markers and inhibited the pro-apoptotic kinase GSK-3ß. In tandem, linagliptin activated hippocampal autophagy by lowering SQSTM-1/p62 accumulation, upregulating Beclin 1, and stimulating AMPK/mTOR pathway. In conclusion, linagliptin's antioxidant, antiapoptotic, and pro-autophagic properties advocated its promising neuroprotective impact. Thus, linagliptin may serve as a management approach against cadmium-induced cognitive deficits.

Targeting Autophagy, Apoptosis, and Oxidative Perturbations with Dapagliflozin Mitigates Cadmium-Induced Cognitive Dysfunction in Rats.

Cognitive decline and Alzheimer-like neuropathology are common manifestations of cadmium toxicity. Thanks to its antioxidant/anti-apoptotic features, dapagliflozin has demonstrated promising neuroprotective actions. However, its effect on cadmium-induced neurotoxicity is lacking. The present work aimed to examine whether dapagliflozin could protect rats from cadmium-evoked cognitive decline. In this study, the behavioral disturbances and hippocampal biomolecular alterations were studied after receiving dapagliflozin. Herein, cadmium-induced memory/learning decline was rescued in the Morris water maze, novel object recognition task, and Y-shaped maze by dapagliflozin. Meanwhile, the hippocampal histopathological abnormalities were mitigated. The molecular mechanisms revealed that dapagliflozin lowered hippocampal expression of p-tau and Aß42 neurotoxic proteins while augmenting acetylcholine. The cognitive enhancement was triggered by hippocampal autophagy stimulation, as indicated by decreased SQSTM-1/p62 and Beclin 1 upregulation. Meanwhile, a decrease in p-mTOR/total mTOR and an increase in p-AMPK/total AMPK ratio were observed in response to dapagliflozin, reflecting AMPK/mTOR cascade stimulation. Dapagliflozin, on the other hand, dampened the pro-apoptotic processes in the hippocampus by downregulating Bax, upregulating Bcl-2, and inactivating GSK-3ß. The hippocampal oxidative insult was mitigated by dapagliflozin as seen by lipid peroxide lowering, antioxidants augmentation, and SIRT1/Nrf2/HO-1 pathway activation. In conclusion, dapagliflozin's promising neuroprotection was triggered by its pro-autophagic, anti-apoptotic, and antioxidant properties.

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.