Curcumin and ustekinumab cotherapy alleviates induced psoriasis in rats through their antioxidant, anti-inflammatory, and antiproliferative effects.

INTRODUCTION: Psoriasis is a chronic multifactorial inflammatory disease that affects 3% of people worldwide. Ustekinumab is a selective anti-IL-12/23 biologic that alleviates psoriasis, and curcumin is a natural, effective dietary turmeric extract applied to treat numerous diseases through its antioxidant and anti-inflammatory effects. OBJECTIVE: The current study evaluated the therapeutic effects of curcumin and ustekinumab cotherapy (CUC) on imiquimod (IQ)-induced psoriasis in a rat model. MATERIALS AND METHODS: Twenty rats were divided into four groups, G1 (control group), G2 (IQ-treated group), G3 (IQ + ustekinumab), and G4 (IQ + CUC). Clinical, histopathological (HP), immunohistochemical (IHC), antioxidant, and biochemical investigations evaluated the efficacy of these drugs for treating IQ induced-psoriasis. RESULTS: Rats of G2 exhibited clinical signs of psoriatic skin lesions (erythema, scaling, and skin thickening) with epidermal changes (acanthosis and parakeratosis). Additionally, the biochemical analysis revealed significant (p < 0.05) reductions in the levels of antioxidant biomarkers (SOD, GPx, and CAT) with significant (p < 0.05) elevations in psoriasis-related cytokines (TNF-α, IL-17A, IL-12P40, and IL-23). In contrast, CUC alleviated the psoriatic changes in G4 better than ustekinumab monotherapy in G3. CONCLUSIONS: Ustekinumab inhibits the inflammatory cytokines IL-12P40 and IL-23, while curcumin has antioxidant effects (increasing SOD, GPx, and CAT levels) with anti-inflammatory effects (decreasing the proinflammatory cytokine TNF-α and IL-17). Therefore, CUC could be an excellent cost-effective regimen that can improve the treatment of psoriasis by the synergistic effects of CUC.HighlightsIQ-induces psoriasis by elevating TNF-α, IL-17A, IL-12, and IL-23 and decreasing GPx, SOD, and CATUstekinumab exhibits anti-inflammatory effects by inhibiting IL-12 and IL-23Curcumin inhibits TNF-α and IL-17A, and increases GPx, SOD, and CAT levelsCUC mitigates psoriasis by synergistic antioxidant and anti-inflammatory effectsCUC inhibits TNF-α, IL-17A, IL-12, and IL-23 and increases GPx, SOD, and CAT levels.

An Ethanolic Extract of Cucurbita pepo L. Seeds Modifies Neuroendocrine Disruption in Chronic Stressed Rats and Adrenal Expression of Inflammatory Markers and HSP70.

Background: Pumpkins (Cucurbita pepo L.) were described to have antioxidant, anti-inflammatory, anti-fatigue, and antidepressant-like effect. The adrenal gland is an important stress-responsive organ that maintains homeostasis during stress. Objectives: This study aimed to assess the efficacy of the administration of Cucurbita pepo L. (CP) extract in relieving behavioral, biochemical, and structural changes in the adrenal gland induced by exposure to chronic unpredictable mild stress (CUMS) and to explore the mechanism behind this impact. Materials and Methods: Forty male albino rats were divided into 4 groups (n = 10): control, CUMS, fluoxetine-treated, and CP-treated groups. Behavioral changes, corticosterone level, pro-inflammatory cytokines TNF-α and IL-6, and oxidant/antioxidant profile were assessed in the serum at the end of the experiment. Adrenal glands were processed for histopathological and immunohistochemical assessment. Gene expression of caspase-3 and Ki67 and heat shock protein 70 (HSP70) were assessed in adrenal glands using RT-PCR. Results: The CP extract significantly reduced the corticosterone level (p < 0.001), immobility time (p < 0.001), and inflammatory and oxidative changes associated with CUMS-induced depression compared to the untreated group. The CP extract alleviated CUMS-induced adrenal histopathological changes and significantly reduced apoptosis (p < 0.001) and significantly upregulated antioxidant levels in the serum. Conclusion: Cucurbita pepo L. effectively ameliorated the chronic stress-induced behavioral, biochemical, and adrenal structural changes mostly through its antioxidant and anti-inflammatory effects.

Garlic Extract Alleviates Trastuzumab-Induced Hepatotoxicity in Rats Through Its Antioxidant, Anti-Inflammatory, and Antihyperlipidemic Effects.

BACKGROUND: Trastuzumab is a new biological drug that has been used to treat breast and gastric cancer; however, its cardiotoxicity and hepatotoxicity limit its use. Garlic has antioxidant, anti-inflammatory, antihyperlipidemic, and anticancer effects. The present study aimed to evaluate the effects of garlic on trastuzumab-induced hepatotoxicity in a rat model. METHODS: Twenty rats were divided into four equal groups as vehicle control (G1), garlic (G2), trastuzumab (G3), and trastuzumab+garlic (G4). All rats were sacrificed after eight weeks of treatment, followed by blood collection and excision of liver tissues for further analyses. The liver specimens were processed for histopathological (HP), immunohistochemical (expression of TNF-α and PCNA), immunofluorescent expression of Chk2 and p53, biochemical, and flow cytometry investigations to evaluate the extent of hepatocyte injury. The biochemical analysis was conducted for the activity of tissue antioxidants (GPX1, CAT, and SOD2), serum lipid profile, and liver enzymes, whereas ROS was performed by flow cytometry. RESULTS: The results revealed remarkable structural changes in hepatocytes of G3 with significant increases in the numbers of inflammatory cells and positive PCNA cells, area % of collagen fibers, and immuno-expression of TNF-α, as well as a significant reduction in the nuclear expression of Chk2. In addition, significant reductions were noticed in the antioxidant enzymes (SOD2, CAT, and GPX1) activity of G3. In contrast, the levels of lipid profile tests (triglycerides, total cholesterol, LDLC, and HDLC), liver enzymes (ALT, AST, and ALP), and ROS revealed significant increases in rats of G3. Likewise, garlic administration in G4 restored all mentioned changes to their average levels deviated by trastuzumab. CONCLUSION: Based on the current results, garlic demonstrates hepatoprotective effects against trastuzumab-induced toxicity in rats. The study suggested for the first time that the coadministration of garlic with trastuzumab for treating breast or gastric cancer can augment their efficacy with minimal toxicity.

Could Mesna and Celery Seed Cotherapy Modulate Oxidative Stress and Inflammation of the Urinary Bladder Induced by Ifosfamide in Rabbits?

BACKGROUND: Ifosfamide (IFS) has potential complications such as nephropathy and hemorrhagic cystitis (HC). Although mesna can prevent IFS-induced cystitis by direct binding and neutralization of acrolein, HC symptoms have still been observed clinically in most of these cases. Celery is a powerful healing vegetable that has antioxidant, anti-inflammatory, and anticancer effects. The current study evaluated the synergistic effects of mesna and celery seed on IFS-induced HC in rabbits. METHODS: Twenty male rabbits (four groups) were administered distilled water, IFS, mesna, and mesna+celery seed cotherapy (MCC) for three weeks. The serum and urinary bladder of experimental rabbits underwent biochemical (TNF-α, MDA, iNOS, SOD, GPx, and CAT), histopathological and ultrastructural investigations to evaluate the structural changes of the urinary bladder (UB). RESULTS: IFS injection resulted in severe cystitis with a remarkable increase in the scale of hematuria, elevations of TNF-α, MDA, and iNOS activity, and reduced activity of SOD, GPx, and CAT antioxidants. Additionally, the structure of UB exhibited evident mucosal edema and ulceration. In contrast, the MCC regimen group revealed partial synergistic improvement of all mentioned parameters. CONCLUSION: IFS induced cystitis by releasing acrolein, which exerted a significant role in the pathogenesis of HC. In contrast, the MCC intake partially ameliorated the UB damage through its antioxidant and anti-inflammatory effects.

Brain-derived Neurotropic factor (BDNF) mediates the protective effect of Cucurbita pepo L. on salivary glands of rats exposed to chronic stress evident by structural, biochemical and molecular study.

BACKGROUND: Acute and chronic stresses affect the salivary glands, representing the source of plasma BDNF during stressful conditions. Pumpkin is a medicinal plant with an evident antioxidant, anti-inflammatory and potential antidepressant effects. OBJECTIVE: To assess the structural and biochemical effects induced by exposure to chronic unpredictable mild stress (CUMS) on salivary glands of albino rats, and to evaluate the role of pumpkin extract (Pump) in ameliorating this effect. METHODOLOGY: Four groups (n=10 each) of male albino rats were included in this study: the control, CUMS, Fluoxetine-treated and Pump-treated. The corticosterone, the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the oxidant/antioxidant profile were all assessed in the serum. The level of BDNF mRNA was measured in the salivary glands using qRT-PCR. Histopathological changes of the salivary glands were also assessed. RESULTS: The depressive-like status was confirmed behaviorally and biochemically. Exposure to CUMS significantly up-regulated (p<0.001) the level of serum corticosterone. CUMS induced degenerative changes in the secretory and ductal elements of the salivary glands evident by increased apoptosis. Both Fluoxetine and Pumpkin significantly up-regulated (p<0.001) BDNF expression in the salivary glands and ameliorated the CUMS-induced histopathological and biochemical alterations in the salivary glands. Pumpkin significantly (p<0.001) increased the serum levels of antioxidant enzymes SOD, GPX and CAT, and reduced the serum levels of the pro-inflammatory cytokines TNF-α, IL-6. CONCLUSION: Pumpkin ameliorates the depressive-like status induced in rats following exposure to chronic stress through exerting a promising anti-inflammatory, antioxidant and anti-depressant-like effects. The pumpkin, subsequently, improved stress-induced structural changes in the salivary glands that might be due to up-regulation of BDNF expression in the glands.

Umbelliferone alleviates hepatic ischemia/reperfusion-induced oxidative stress injury via targeting Keap-1/Nrf-2/ARE and TLR4/NF-κB-p65 signaling pathway.

Umbelliferone (UMB; 7-hydroxycoumarin) is a natural compound that exhibited a diversity of pharmacological activities. Its protective effects against various ischemia/reperfusion (IR) injuries, including heart, kidney, and testis, have been observed. However, their effect on hepatic IR is still not investigated yet. Here, this study was conducted to examine the potential protective role of UMB during the early phase of hepatic IR injury via targeting Keap-1/Nrf-2/ARE and its closely related signaling pathway, TLR4/NF-κB-p65. Experimentally, forty Wistar albino rats were randomly divided into 4 groups: Sham control group (received 1% carboxymethyl cellulose as a vehicle), UMB group (30 mg/kg/day, P.O.), IR group (subjected to complete hepatic IR injury), and IR + UMB group. Our results revealed that oral UMB effectively reduced the serum levels of ALT, AST, ALP, and LDH along with the restoration of oxidant/antioxidant status. At the molecular level, UMB markedly activated Nrf-2 expression and its down-streaming targets: HO-1, NQO1, GCLC, SOD3, and TNXRD1, along with Keap-1 down-regulation. Besides, UMB significantly down-regulated NF-κB-p65 and TLR4 expressions with subsequent decreased TNF-α and IL-1ß levels coupled with the up-regulation of the IL-10 level. Finally, biochemical findings were confirmed by attenuation of histopathological changes in liver tissues. Together, UMB is a promising agent for the amelioration of liver tissues against IR-induced oxidative injury through activation of the Keap-1/Nrf-2/ARE signaling pathway along with suppression of its closely related signaling pathways: TLR4/NF-κB-p65. Illustrated diagram explored the prospective underlying protective mechanism of UMB against IR-induced hepatic damage.

Rebamipide potentially mitigates methotrexate-induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study.

Methotrexate (MTX) is a widely used chemotherapeutic agent; nevertheless, the nephrotoxicity associated with its use has limited its clinical use. Rebamipide (REB) is a gastro-protective agent with diverse promising biological activities. Here, we investigated the renoprotective effects of REB against MTX-induced nephrotoxicity in rats. Male Wistar rats were allocated into four groups: the normal control group, the REB group (100 mg kg-1 day-1 , PO, for 12 days), the MTX group (which received a single injection of 20 mg/kg, ip), and the REB + MTX group (which received 100 mg kg-1 day-1 REB for 7 days before and 5 days after being injected with 20 mg/kg MTX). Interestingly, MTX triggered kidney injury, characterized by renal dysfunction along with histopathological alterations. Moreover, increased reactive oxygen species level and inflammatory response were detected in the kidney of MTX-treated rats. However, REB prevented MTX-induced oxidative kidney injury and boosted an antioxidant balance. Mechanistically, REB markedly activated the NRF-2 protein and upregulated the expression of both SIRT-1 and FOXO-3 genes. Additionally, REB administration strongly inhibited the inflammatory response by downregulating both NF-κB-p65 and TLR-4. Finally, the coadministration of REB and MTX activated the mTOR/PI3K/AKT signaling pathway. Simultaneously, REB treatment attenuated the reduction in glomerular size, the widening of the capsular spaces, and the tubular cell damage due to MTX administration. Taken together, these results indicate the potential of REB as adjuvant therapy to prevent nephrotoxicity in patients receiving MTX treatment.

Brain-derived Neurotropic factor (BDNF) mediates the protective effect of Cucurbita pepo L. on salivary glands of rats exposed to chronic stress evident by structural, biochemical and molecular study

Abstract Acute and chronic stresses affect the salivary glands, representing the source of plasma BDNF during stressful conditions. Pumpkin is a medicinal plant with an evident antioxidant, anti-inflammatory and potential antidepressant effects. Objective To assess the structural and biochemical effects induced by exposure to chronic unpredictable mild stress (CUMS) on salivary glands of albino rats, and to evaluate the role of pumpkin extract (Pump) in ameliorating this effect. Methodology Four groups (n=10 each) of male albino rats were included in this study: the control, CUMS, Fluoxetine-treated and Pump-treated. The corticosterone, the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the oxidant/antioxidant profile were all assessed in the serum. The level of BDNF mRNA was measured in the salivary glands using qRT-PCR. Histopathological changes of the salivary glands were also assessed. Results The depressive-like status was confirmed behaviorally and biochemically. Exposure to CUMS significantly up-regulated (p<0.001) the level of serum corticosterone. CUMS induced degenerative changes in the secretory and ductal elements of the salivary glands evident by increased apoptosis. Both Fluoxetine and Pumpkin significantly up-regulated (p<0.001) BDNF expression in the salivary glands and ameliorated the CUMS-induced histopathological and biochemical alterations in the salivary glands. Pumpkin significantly (p<0.001) increased the serum levels of antioxidant enzymes SOD, GPX and CAT, and reduced the serum levels of the pro-inflammatory cytokines TNF-α, IL-6. Conclusion Pumpkin ameliorates the depressive-like status induced in rats following exposure to chronic stress through exerting a promising anti-inflammatory, antioxidant and anti-depressant-like effects. The pumpkin, subsequently, improved stress-induced structural changes in the salivary glands that might be due to up-regulation of BDNF expression in the glands.

Pentoxifylline alleviated cardiac injury via modulating the cardiac expression of lncRNA-00654-miR-133a-SOX5 mRNA in the rat model of ischemia-reperfusion.

Pentoxifylline (PTX) protects from many cardiovascular complications. It plays a critical role in stem cell proliferation and differentiation. Here, the effect of PTX administration on cardiac ischemia and dysfunction was explored. PTX in 3 doses (20, 30, and 40 mg/kg), was administered in vivo 5 min before a 45 min occlusion of the left anterior descending artery, followed by a 120 min reperfusion in male Wistar rats. The left ventricular end-diastolic pressure and dP/dtmax were assessed. Blood and cardiac tissue samples were collected for measuring the levels of cardiac enzymes and the expression of lncRNA-00654-miR-133a-SOX5. Samples of left ventricles were collected and processed for light microscopic, immunohistochemical staining for c-kit (a marker for cardiac progenitor cells) and transmission electron microscopic examination. PTX administration showed improvements in cardiac function tests, enzymes, and myocytes. Microscopic features showed minimal cardiac edema, hemorrhage, cellular inflammatory infiltration and fibrosis in addition to increased c-kit + cells in cardiac tissue samples. Notably, this treatment also produced a dose-dependent decrease in lncRNA-00654 with an increase in SOX5 mRNA and miRNA-133a-3p expressions. In conclusion, PTX has the potential to alleviate cardiac injury and increase the number of c-kit + cells following ischemia-reperfusion in the rat model via modulation of lncRNA-00654 and miR-133a-SOX5 mRNA expressions.

Hesperidin suppressed hepatic precancerous lesions via modulation of exophagy in rats.

The enormous cost of modern medicines warrants alternative strategies for the better management of hepatocellular carcinoma. Recently, exosomes have been shown to relay the oncogenic information through the horizontal transfer of RNAs between the cells. In this study, we modulated exosomal production and autophagy (exophagy) by the administration of hesperidin and evaluated its effect on the development of hepatic precancerous lesion (HPC) in rats. Diethylnitrosamine and 2-acetylaminofluorene were used in vivo to induce HPC in rats. Rats were allocated into five groups: naïve, HPC, and three hesperidin treated (50, 100, and 200 mg/kg/d; orally) for 4 consecutive days per week for 16 weeks. Liver tissues and blood samples were collected for histopathological, immunohistochemical, and transmission electron microscope examinations, liver function, alfa-fetoprotein level, and isolation of exosomal and autophagy RNAs. Hesperidin administration showed hepato-protective effects and improved the microscopic hepatic features with a decrease in glutathione S-transferase placental precancerous foci and the abundance of exosomes in liver tissues. Hesperidin improved liver function with a significant decrease in alfa-fetoprotein levels. Hesperidin dose-dependently decreased exosomal RAB11A messsenger RNA and long noncoding RNA-RP11-583F2.2 along with the increase in exosomal miR-1298, involved in the exophagy process. In conclusion, hesperidin likely suppresses liver carcinogenesis in rat model via the modulation of exosomal secretion and autophagy.