Berberine protects against sepsis-related acute lung injury in rats via PPAR-γ signaling pathway upregulation and improvement at the cellular level: Functional, biochemical, and immunohistochemistry study.

This study aimed to assess the prophylactic effects of Berberine on experimentally induced lung sepsis and examine its effects on selected cytokines, genes, and protein expression besides the histopathological evaluation. Berberine significantly reduced the wet/dry lung ratio, the broncho-alveolar lavage fluid (BALF) protein, cells, neutrophils percentage, and cytokines levels. In addition, pretreatment with Berberine decreased the myeloperoxidase (MPO) and malondialdehyde (MDA) levels and decreased gene expression of nuclear factor kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), and the intracellular adhesion molecule 1 (ICAM-1) by RT-qPCR analysis, revealing Berberine's antioxidant and anti-inflammatory mode of action. Western blot analysis revealed increased peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in the Berberine pretreated group compared to the cecal ligation and puncture (CLP) group, in which the histopathological examination evidenced this improvement. In conclusion, Berberine improved lung sepsis via its PPAR-γ mediated antioxidant and anti-inflammatory effects.

Serum Apo Lipoprotein E, Apo Lipoprotein E Gene Polymorphisms, and Parkinson's Disease.

BACKGROUND: A central role for apolipoprotein E (APOE) has been suggested in modulating processes of neurodegeneration. OBJECTIVE: To study the association between serum APOE levels, APOE gene polymorphisms, and Parkinson's disease (PD). MATERIAL AND METHODS: Fifty-five patients with PD and 30 healthy subjects were enrolled. PD patients were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Modified Hoehn and Yahr scale, and Schwab-England Activities of Daily Living scale. Serum APOE level and genotyping for APOE polymorphisms were done for PD patients and controls using enzyme-linked immunosorbent assay and polymerase chain reaction, respectively. RESULTS: Mean serum APOE level was significantly higher in PD patients compared with healthy controls. APOE ε2/4 genotype was present in a significantly higher proportion of patients compared with controls. APOE ε4 allele was significantly associated with a higher score on the "mentation, behavior, and mood section" of UPDRS compared with ε2 allele. APOE ε2 allele was significantly associated with a shorter disease duration compared with ε3 and ε4 alleles. Mean serum APOE level was significantly higher in patients presenting predominantly by rigidity and bradykinesia compared with those presenting predominantly by tremors. Serum APOE level was positively correlated with mean scores of "mentation, behavior, and mood section" of UPDRS and disease duration. Serum APOE level was a significant predictor for the scores of "mentation, behavior, and mood section" of UPDRS. CONCLUSION: APOE ε2/4 genotype might be a susceptibility variant for PD. There may be a possible role for APOE in modulating the process of neurodegeneration in PD.

Comparing prophylactic effect of exercise and metformin on cognitive brain functions in rats with type 3 diabetes mellitus.

Introduction: Type 2 diabetes mellitus (DM) and Alzheimer's disease (AD) are two major medical conditions that constitute a significant financial burden on most healthcare systems. Due to AD sharing "insulin resistance" mechanistic features with DM, some scientists have proposed "type 3 DM" terminology for it. This study aims to compare the prophylactic effect of exercise and metformin on cognitive brain functions in rats with type 3 DM. Material and methods: Two groups of rats were included in the study: the control group (n = 15) and the streptozotocin-induced type 2 diabetic group (n = 45). The diabetic group was subdivided into three equal subgroups: a sedentary non-treated diabetic group, an exercised group, and a metformin-treated group. We estimated step-down avoidance task latency, serum glucose, insulin, free fatty acids (FFA), cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides (TG), brain Aß-42 and glucose, histological changes by toluidine blue, and immunohistochemistry for brain Aß-42 and tau-positive cells. Results: Serum glucose, FFA, TG, cholesterol, LDL, brain Aß-42, brain glucose, the number of hippocampal dark and degenerated cells, and brain Aß-42 and tau-positive cells, were all significantly lower. In contrast, serum insulin and HDL, the number of hippocampal granular cells, and latency of the step-down avoidance task were significantly higher in exercised and metformin-treated groups compared to the diabetic group. There were significantly higher values of serum insulin and brain/plasma glucose ratio and number of brain tau-positive cells in the metformin-treated group than in the exercised group. Conclusions: We can conclude that exercise can be as effective as metformin regarding prophylaxis against the deleterious effects of type 3 DM on cognitive brain functions.

Brain-derived Neurotrophic Factor Level and Gene Polymorphism as Risk Factors for Depression in Patients with type 2 Diabetes Mellitus- A Case-Controlled Study.

BACKGROUND: Diabetes mellitus and depression are comorbidities that can be caused by each other. Brain-derived neurotrophic factor (BDNF) functions as a neuronal growth factor. It maintains the functional integrity of the nervous system. AIM: To study the possible association between BDNF levels and gene polymorphism with depression in patients diagnosed with type 2 diabetes mellitus. METHODS: The Elisa technique measured BDNF, and rs6265 gene polymorphism was detected using real-time PCR. Depression was assessed utilizing a clinical interview tool designed to establish the diagnosis of depression and differentiate it from other psychiatric diseases. RESULTS: BDNF levels were significantly lower in patients with type 2 diabetes mellitus and symptoms of depression than in patients with type 2 diabetes mellitus and no symptoms of depression (82.6±16.1. Vs 122± 17.47, p˂ 0.001). There was a statistically significant difference in BDNF levels in patients with diabetes among the three genotypes of the BDNF gene (p-value < 0.001). Val/ Val carriers had the highest serum BDNF levels, and Met/ Met carriers had the lowest serum BDNF levels. Subgroup analysis showed statistically significant genotype-related differences in serum BDNF levels among the three subgroups in the Depression group. Val/ Val carriers had the highest serum BDNF levels, and Met/ Met carriers had the lowest serum BDNF levels. BDNF Val66Met polymorphism had no significant association with the presence of depression, yet there was a trend towards significance (p = 0.05) Conclusion: In this pilot, Low levels of BDNF were associated with depression in patients with type 2 diabetes. Carriers of the Met/ Met allele have the lowest serum BDNF levels. Multicenter studies with more participants are required.

CT volumetry study of microfat graft survival from different donor sites in augmenting the enophthalmic socket.

PURPOSE: To evaluate autologous fat grafts harvested from the abdomen versus the thigh for treating the enophthalmic socket using CT volumetry. METHODS: A randomized prospective interventional study including 20 patients suffering from unilateral enophthalmic socket. Pre-operative clinical assessment included photographs, exophthalmometry reading as well as CT volumetry for volume deficit calculations and the harvesting site was randomly allocated (abdomen or thigh). All patients completed 6 months of follow-up. Exophthalmometry change and percentage of retained fat with the globe included and without it at follow-up were measured. RESULTS: Microfat graft survival showed no statistically significant correlation with sex, age, or donor site. Mean percentage of retained fat with globe and without it were 14.75% and 25.31%, respectively. Difficulty of extraction and degree of volume deficit correlated significantly with percentage of fat retained. Exophthalmometer change correlated significantly with percentage of fat retained. CONCLUSION: Autologous fat grafting is a safe and effective technique for volume augmentation of enophthalmic sockets regardless of its harvesting site. CT volumetry has an important role in accurately measuring the volume deficit as well as the postoperative results.

Evaluating the hepatotoxic versus the nephrotoxic role of iron oxide nanoparticles: One step forward into the dose-dependent oxidative effects.

The present study has been designed to detect the dose-dependent effect of iron oxide nanoparticles (IONPs) on the liver and kidney of rats by evaluating three different doses 30, 300, 1000 mg/kg/day IONPs for 28 days. Forty rats were divided into four groups; I (control), II (low dose), III (medium dose) and IV (high dose). There also was a statistically-significant elevation in the serum levels of hepatic enzymes; AST and ALT in medium & high dose. The elevation of serum ALP, on the other hand, was significant in all IONPs doses. There was significant elevation in the levels of urea creatinine, and MDA in the medium and high doses of IONPs. The activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) showed significant decrease in the high dose only compared to the control group. The serum iron levels increased in a dose-dependent manner in the IONPs-treated groups with highly significant increase in the moderate and high dose groups. On comparing the effect of different doses of IONPs between the liver and kidney, the high dose revealed statistically significant difference (p < 0.05) in the area percent of collagen deposition (54.4 ± 3.9 versus 6.1 ± 2.6) and alpha smooth muscle actin (α-SMA) reaction (7.7 ± 1.5 versus 17.8 ± 4.3) in the liver relative to the kidney. The medium and high doses revealed statistically significant difference in optical density of Periodic acid Schiff (PAS) reaction (45 ± 3.4 versus 50.3 ± 1.8 in the medium dose, and 38.9 ± 6 versus 63 ± 3 in the high dose) and area percent of inducible nitric oxide synthase (iNOS) reaction (12.98 ± 2.7 versus 3.5 ± 0.5 in the medium dose, and 27.91 ± 1.5 versus 7.7 ± 0.6 in the high dose) in the liver relative to the kidney.

Potential impact of mesenchymal stem cells on nephrotoxicity induced by gamma irradiation and antiepileptic drugs cotherapy in rats.

The goal of this study was to assess the influence of bone marrow-derived mesenchymal stem cells (BM-MSCs) on the nephrotoxicity induced by fractionated doses of gamma irradiation (Rad) and the cotherapy of levetiracetam and oxcarbazepine in male rats. Adult rats were randomly divided into four groups. Group I: Control, Group II: antiepileptic drugs (AEDs), Group III: AEDs +Rad and Group IV: AEDs + Rad + MSCs. Rats treated with AEDs and exposed to fractionated doses of γ-irradiation displayed a discernible increase in serum urea, creatinine, kidney injury marker, kidney malondialdehyde, transforming growth factor beta (TGF-ß) and the relative expression of Smad3 along with a decrease in the relative expression of Smad7 and glutathione level. Alternatively, groups treated with BM-MSCs with AEDs and Rad showed a substantial modification in the majority of the evaluated parameters and looked to be successful in reducing the hazards of the combination therapy of AEDs and radiation. The reno-histopathological study supports the biochemical analysis. In conclusion, BM-MSCs exhibited therapeutic potential against nephrotoxicity induced by fractionated doses of γ-irradiation and AEDs. The outcome was brought about by the downregulation of the TGF-ß/Smad pathway. BM-MSCs might be suggested as a valuable therapeutic strategy to overcome kidney injury induced by gamma irradiation during AEDs cotherapy.

Tissue levels of suppressor of cytokine signaling-3 (SOCS-3) in mycosis fungoides.

Mycosis fungoides (MF) is a type of cutaneous T-cell lymphoma with proposed multifactorial etiology. Suppressor of cytokine signaling-3 (SOCS-3) is one of the proteins expressed in MF. Its exact role in disease pathogenesis has not yet been thoroughly investigated. This study aimed to assess the expression of SOCS-3 in patients' skin with mycosis fungoides to elucidate their possible role in the pathogenesis in MF. 30 patients with mycosis fungoides and 30 age and sex-matched healthy controls were included. After clinical examination, tissue levels of SOCS-3 were measured by ELISA. The level of expression of SOCS-3 was significantly upregulated in the lesional tissue compared to perilesional SOCS-3 level in patients' group (P < 0.001), and both levels were higher than the SOCS-3 level in control group (P < 0.001). In addition, there was a statistically significant positive correlation between lesional SOCS-3 level and itching in patients' group (P < 0.001). Regarding lesional and perilesional SOCS-3 levels in each stage, there was a significant increase in lesional SOCS-3 levels in comparison to perilesional level whether in stage Ia, Ib, and IIa; (P < 0.001), (P < 0.001) and (P < 0.001), respectively. Increased tissue levels of SOCS-3 patients with mycosis fungoides point to a role that SOCS-3 could play in its pathogenesis. Also, high levels of SOCS-3 in MF patients with itching suggest a role in the pathogenesis of this symptom. These findings may prove helpful in formulating a new treatment modality in addition to the current treatment of MF.

Mesenchymal Stem Cells and Selenium Nanoparticles Synergize with Low Dose of Gamma Radiation to Suppress Mammary Gland Carcinogenesis via Regulation of Tumor Microenvironment.

Breast cancer is one of the most prevalent and deadliest cancers among women in the world because of its aggressive behavior and inadequate response to conventional therapies. Mesenchymal stem cells (MSCs) combined with green nanomaterials could be an efficient tool in cell cancer therapy. This study examined the curative effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) with selenium nanoparticles (SeNPs) coated with fermented soymilk and a low dose of gamma radiation (LDR) in DMBA-induced mammary gland carcinoma in female rats. DMBA-induced mammary gland carcinoma as marked by an elevation of mRNA level of cancer promoter genes (Serpin and MIF, LOX-1, and COL1A1) and serum level of VEGF, TNF-α, TGF-ß, CA15-3, and caspase-3 with the reduction in mRNA level of suppressor gene (FST and ADRP). These deleterious effects were hampered after treatment with BM-MSCs (1 × 106 cells/rat) once and daily administration of SeNPs (20 mg/kg body weight) and exposure once to (0.25 Gy) LDR. Finally, MSCs, SeNPs, and LDR notably modulated the expression of multiple tumor promoters and suppressor genes playing a role in breast cancer induction and suppression.

Nicorandil mitigates amiodarone-induced pulmonary toxicity and fibrosis in association with the inhibition of lung TGF-ß1/PI3K/Akt1-p/mTOR axis in rats.

The long-term side effect of the antiarrhythmic drug, amiodarone (AMIO), such as lung toxicity, remains a critical clinical issue. The previous knowledge denotes diverse antioxidant, anti-inflammatory, and antifibrotic properties of the anti-anginal drug, nicorandil (NI). Therefore, we aimed to investigate the possible protective effect of NI on pulmonary tissue remodelling following AMIO-induced lung toxicity. The included rats were assigned into four equal groups (n = 8): (1) control, (2) control group that received NI 10 mg kg-1  day-1 , (3) model group that received AMIO in a dose of 60 mg kg-1  day-1 , and (4) treated group (AMIO-NI) that were treated with AMIO plus NI as shown above. Drug administration continued for 10 weeks. AMIO resulted in deteriorated (p < 0.001) pulmonary functions accompanied by respiratory acidosis. AMIO showed an obvious histological injury score with intense collagen deposition, disturbed nitric oxide synthase enzymes (NOS/iNOS), and increased alpha smooth muscle actin expression. Furthermore, AMIO upregulated the transforming growth factor (TGF-ß1)/phosphoinositide-3 kinase (PI3K)-Akt1-p/mammalian target of rapamycin (mTOR) axis, which determined the possible mechanism of AMIO on pulmonary remodelling. NI treatment significantly (p < 0.001) prevented the AMIO-induced lung toxicity, as well as inhibited the TGF-ß1/PI3K/Akt1-p/mTOR axis in the lung tissue of rats. The results were confirmed by an in-vitro study. CONCLUSION: The current results revealed that NI was effective in preserving the lung structure and functions. Amelioration of the oxidative stress and modulation of TGF-ß1/PI3K/Akt1-p/mTOR have been achieved. This study suggests NI administration as a preventive therapy from the serious pulmonary fibrosis side effect of AMIO.

Thymoquinone and quercetin protect against hepatic steatosis in association with SIRT1/AMPK stimulation and regulation of autophagy, perilipin-2, and cytosolic lipases.

BACKGROUND: We sought to investigate thymoquinone (TQ)/quercetin combination in preventing hepatic steatosis (HS). MATERIALS AND METHODS: The included rat groups; (1) Control, (2) HS model, (3) HS treated with TQ 10 mg.kg-1.d-1, (4) HS treated with quercetin 50 mg.kg-1.d-1, and (5) HS treated with both compounds for 4 weeks. RESULTS: TQ/quercetin co-treatment augmented the anti-steatosis potential of each ingredient. The results revealed more (p < 0.001) sirtuin (SIRT1)/AMP-activated protein kinase (p-AMPK) upregulation compared to each treatment in line with autophagy protein Atg7 enhancement, and suppressed pro-inflammatory and oxidation markers. They diminished the hepatic lipogenic enzymes and perilipin-2 and activated the cytosolic lipases adipose triglyceride lipase (ATGL). Histological and Biochemical analysis revealed diminished lipid deposition and improved liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) compared to the data of separate treatments. CONCLUSION: TQ and quercitin effectively upregulated SIRT1/p-AMPK and regulated hepatic perilipin-2/ATGL, inflammation and oxidative stress, preserved liver structure and function. TQ/quercetin combination additively prevents HS.

Assessment of prostaglandin F2-alpha (PGF2α) in lesional and nonlesional skin of vitiligo patients.

BACKGROUND: F2-isoprostane is one of the members of biologically active prostaglandins. It is considered a reliable marker of oxidative stress. This study aimed at investigating and studying the hypothesis of the possible role of prostaglandin F2-alpha (PGF2α) in the pathogenesis of vitiligo and to know if there is a possibility of using it in therapy. METHODS: This case-control study involved 30 patients with nonsegmental vitiligo and 30 healthy sex- and age-matched controls over a period of 7 months. Skin biopsies were taken from lesional and nonlesional vitiliginous skin of patients and from normal skin of controls for measurement of PGF2α in tissue by ELISA. RESULTS: The tissue levels of PGF2α in vitiligo patients were significantly higher in both lesional and nonlesional skin than in healthy controls (P < 0.001). The tissue levels of PGF2α in lesional skin were significantly higher than in nonlesional skin (P < 0.001). CONCLUSION: Based on the fact that PGF2α is a reliable biomarker of oxidative stress, in addition to our results that revealed higher tissue levels of PGF2α in vitiliginous skin than in healthy skin, we can conclude that PGF2α may be incriminated in the pathogenesis of vitiligo. This finding could help in the treatment of this disease by using anti-PGF2α drugs.

Necrostatin-1 mitigates renal ischaemia-reperfusion injury - time dependent - via aborting the interacting protein kinase (RIPK-1)-induced inflammatory immune response.

The recently defined necroptosis process participates in the pathophysiology of several tissue injuries. Targeting the necroptosis mediator receptor-interacting protein kinase (RIPK1) by necrostatin-1 in different phases of ischaemia-reperfusion injury (IRI) may provide new insight into the protection against renal IRI. The rat groups included (n = 8 in each group): 1) Sham; 2) Renal IRI; 3) Necrostatin-1 treatment 20 min before ischaemia induction in a dose of 1.65 mg/kg/intravenous; 4) Necrostatin-1 injection just before reperfusion; 5) Necrostatin-1 injection 20 min after reperfusion establishment; and 6) drug injection at both the pre-ischaemia and at reperfusion time in the same dose. Timing dependent, necrostatin-1 diminished RIPK1 (p < 0.001), and aborted the necroptosis-induced renal cell injury. Necrostatin-1 decreased the renal chemokine (CXCL1), interleukin-6, intercellular adhesion molecule (ICAM-1), myeloperoxidase, and the nuclear factor (NFκB), concomitant with reduced inducible nitric oxide synthase (iNOS), inflammatory cell infiltration, and diminished cell death represented by apoptotic cell count and the BAX/Bcl2 protein ratio. In group 6, the cell injury was minimal and the renal functions (creatinine, BUN and creatinine clearance) were almost normalised. The inflammatory markers were diminished (p < 0.001) compared to the IRI group. The results were confirmed by histopathological examination. In conclusion, RIPK1 inhibition ameliorates the inflammatory immune response induced by renal IRI. The use of two doses was more beneficial as the pathophysiology of cell injury is characterised.

Sensitivity of serum S100B protein as a disease activity marker in Egyptian patients with vitiligo (case-control study).

BACKGROUND: Vitiligo is a depigmented skin disease. S100B is a damage-associated molecular pattern protein proposed as a marker of melanocyte cytotoxicity. AIM: To detect the sensitivity of serum levels of S100B as a disease activity marker in vitiligo patients. METHODS: Four patient groups of both sexes: twenty segmental vitiligo, twenty non-segmental active vitiligo patients, twenty non-segmental stable vitiligo patients and thirty healthy controls age and sex-matched, patients were subjected to vitiligo disease activity score (VIDA score) and Vitiligo Extent Tensity Index (VETI) score. RESULTS: An increased level of S100B was observed in patients with vitiligo compared to control, there was statistically significant increase in its level in non- segmental-active than non-segmental stable and segmental-stable. Roc analysis for S100B to predict cases vs control was confirmed by getting cut off point 80.2 pg/ml, with high sensitivity 96.67 and high specificity 96.67. Roc analysis for S100B to predict non-segmental-active versus segmental and non-segmental was also confirmed by getting cut off point 118.3 pg/ml, with sensitivity 80.0 and specificity 77.50. CONCLUSION: S100B can be used as indicators for disease activity with high sensitivity and specificity in Egyptian vitiligo patients.

Association between long noncoding RNA taurine-upregulated gene 1 and microRNA-377 in vitiligo.

BACKGROUND: Taurine-upregulated gene 1 (TUG1) is one of the long noncoding RNAs (lncRNAs) that plays a role in melanogenesis. MicroRNA-377 (miRNA-377) is a conserved noncoding RNA that regulates angiogenesis and promotes oxidative stress. Peroxisome proliferator-activated receptors (PPARs) are components of the nuclear hormone receptor superfamily. PPAR-γ activators stimulate melanogenesis. Interleukin (IL)-17 has been implicated in the pathogenesis of several immunological diseases. This work aimed at detecting the expression levels of lncRNA TUG1, miRNA-377, PPAR-γ, and IL-17 among vitiligo subjects and to investigate their possible role in the pathogenesis of vitiligo. METHODS: This study was conducted on 30 healthy controls and 30 vitiligo patients. LncRNA TUG1 and miRNA-377 were detected in serum by real-time polymerase chain reaction (PCR). Also, expressions of PPAR-γ and IL-17 were assessed in tissue by real-time PCR. RESULTS: LncRNA TUG1 and PPAR-γ levels were significantly downregulated in the vitiligo group compared with the control group. On the other hand, miRNA-377 and IL-17 were significantly upregulated in the vitiligo group compared with the control group. CONCLUSION: This study demonstrated the dysregulated expressions of lncRNA TUG1 and miRNA-377 in patients with vitiligo suggesting that both contributed to the pathogenesis of vitiligo that might be through PPAR-γ downregulation and IL-17 upregulation.

Downregulation of interleukin 36γ and its cleaver cathepsin G following treatment with narrow-band ultraviolet B phototherapy in psoriasis vulgaris.

BACKGROUND: Growing evidence suggests the important role of IL-36 in the pathogenesis of psoriasis. Cathepsin G is a neutrophil-derived protease that can activate IL-36γ. OBJECTIVE: To assess the expression of IL-36γ and cathepsin G in psoriasis and to quantify the impact of treatment with narrow-band ultraviolet B phototherapy (NB-UVB) on their levels. METHODS: This case-control study involved 26 patients with moderate-severe psoriasis and 25 healthy volunteers. Psoriasis patients eligible for phototherapy received 24 NB-UVB sessions. Punch skin biopsies were obtained from all participants at recruitment and after phototherapy from patients. Real-time PCR was utilized for quantitative assessment of IL-36γ and cathepsin G expression in tissue samples. RESULTS: The expression of IL-36γ and cathepsin G was significantly higher in psoriasis before NB-UVB therapy compared to controls (p < .001). Both proteins decreased significantly with clinical improvement following NB-UVB therapy compared to baseline (p < .001). However, their expression after treatment was still higher than controls (p < .001). CONCLUSION: IL-36γ and cathepsin G expression is upregulated in psoriatic lesions, supporting their role as mediators of inflammation in psoriasis. Downregulation of IL-36γ and cathepsin G is a possible mechanism for psoriasis improvement after NB-UVB therapy. IL-36 and cathepsin G can be considered as therapeutic targets for psoriasis.

Vitamin D mitigates diabetes-associated metabolic and cognitive dysfunction by modulating gut microbiota and colonic cannabinoid receptor 1.

INTRODUCTION: Obesity is associated with elevated endocannabinoid tone, gut dysbiosis, and inflammation predisposing to diabetes. The endocannabinoid system mediates the effects of gut microbiota and regulates the gut barrier integrity. We examined the effects of vitamin D (VD) on colonic cannabinoid receptor 1(CB1R), tight junction proteins, gut dysbiosis, metabolic and cognitive dysfunction in a model of type 2 diabetes compared with metformin. METHODS: Rats received high-fat, high-sucrose diet (HFSD) and either VD (500 IU/kg/day; p.o.), or metformin (200 mg/kg/day; p.o.) for 8 weeks. After 6 weeks, streptozotocin (STZ) (40 mg/kg; i.p) was injected. Behavioral, cognitive, and metabolic assessments were carried out. Finally, fecal, blood, and tissue samples were collected to examine Bacteroidetes/Firmicutes ratio, colonic CB1R, zonula occludens-1 (ZO-1), occludin, and Toll-like receptor 4 (TLR4); serum lipopolysaccharides (LPS), peptidoglycan (PGN), tumor necrosis factor-alpha (TNF-ɑ), glucagon-like peptide-1 (GLP-1), lipids, and VD; hippocampal brain-derived neurotrophic factor (BDNF) and inflammatory markers. RESULTS: VD ameliorated HFSD/STZ-induced dysbiosis/gut barrier dysfunction as indicated by lower circulating LPS, PGN and TNF-ɑ levels, likely by downregulating colonic CB1R and upregulating ZO-1 and occludin expressions. Additionally, VD suppressed HFSD/STZ-induced hyperglycemia, hyperinsulinemia, dyslipidemia, and hippocampal neuroinflammation. These changes culminated in improved glycemic control and cognitive function. VD was more effective than metformin in decreasing serum LPS and TNF-ɑ levels; whereas metformin resulted in better glycemic control. CONCLUSION: Targeting gut microbiota by VD could be a successful strategy in the treatment of diabetes and associated cognitive deficit. The crosstalk between VD axis and the endocannabinoid system needs further exploration.

Evaluation of nootropic activity of telmisartan and metformin on diazepam-induced cognitive dysfunction in mice through AMPK pathway and amelioration of hippocampal morphological alterations.

Cognitive impairments such as dementia are considered the biggest challenges for public health. Benzodiazepines are often prescribed for treatment of anxiety disorder but they are associated with elevated risk of dementia. The present study has been designed to evaluate the neuroprotective effect of telmisartan and metformin on diazepam-induced cognitive dysfunction in mice. Piracetam was used as an established nootropic agent. Mice were divided into 8 groups, group1; control group which received normal saline. groups 2, 3 and 4 were received telmisartan 0.3 mg/kg/day, metformin 100 mg/kg/day and piracetam 200 mg/kg/day respectively. group 5; DZP group that injected with diazepam 2.5 mg/kg, groups 6, 7 and 8 were received diazepam 2.5 mg/kg + telmisartan 0.3 mg/kg/day, metformin 100 mg/kg/day and piracetam 200 mg/kg/day respectively. All drugs were administrated for 15 successive days. Cognitive skills of the animals were examined with Elevated plus maze and Passive Shock Avoidance tests. Investigations of oxidative stress markers were performed. Gene expression levels of TNF-α, NFκB, Caspase 3 and AMPK were analyzed using RT-PCR. Histological and immunohistochemical techniques were performed in hippocampus using H&E, cresyl violet stain, anti GFAP and anti COX-2 immunostain. The study revealed that administration of diazepam increased initial and retention transfer latency as well as it decreased step down latency that means it caused memory impairment. There was a significant increase in hippocampal expression levels of TNF-α, NFκB, and Caspase 3 and downregulation of AMPK expression levels associated with increased neurodegeneration, astrocytes activation and COX-2 immunohistochemical staining. This study indicates that diazepam caused a decline in cognitive function depending on hippocampal activity. Telmisartan, a common antihypertensive agent and metformin, a traditional antidiabetic drug improved this cognitive dysfunction through their anti-oxidant and anti-inflammatory effect as they decreased initial and retention transfer latency as well as it increased step down latency. Also they decreased TNF-α, NFκB, and Caspase 3 and upregulated AMPK expression, moreover they ameliorated the hippocampal morphological alterations, GFAP and COX-2 immunoexpression.

Impact of combined therapy of mesenchymal stem cells and sitagliptin on a metabolic syndrome rat model.

BACKGROUND: Emerging evidence suggests that mesenchymal stem cells (MSCs) have many anti-inflammatory and regenerative properties, which makes it a suitable candidate for the treatment of many diseases including metabolic syndrome (MetS). However, a major difficulty with stem cell therapy is to maintain cell viability, properties and function after implantation in vivo. This study aims to test the hypothesis that the combined therapy of MSCs and sitagliptin can effectively ameliorate MetS complications induced by high-fat and high-fructose diet (HFFD) in rats. METHODS: Rats were fed either standard diet (Control group) or HFFD. After 3 months, a group of HFFD animals was injected by a single dose of MSCs, another group received a daily oral dose of 10 mg/kg b.w. of sitagliptin, and the third group received the combined therapy of MSCs + sitagliptin for 1 month. RESULTS: Both MSCs and sitagliptin restored insulin sensitivity and reduced the HOMA-IR value in HFFD rats. The hepatic IRS-1 and Akt at both gene and protein levels, as well as the hepatic protein levels of IR and GLUT4 were improved. Downregulation of CHOP and NF-κB and upregulation of hepatic HO-1 expression and activity were also reported. Although MSCs and sitagliptin as monotherapy lead to remarkable effects, the dual application revealed the best results. Interestingly, histological findings confirmed these protective effects of the combined therapy against MetS complications. CONCLUSION: Combined therapy of MSCs and sitagliptin can efficiently ameliorate the insulin resistance and promote the regeneration of hepatocytes in the metabolic syndrome rat model.

Concerted outcome of metformin and low dose of radiation in modulation of cisplatin induced uremic encephalopathy via renal and neural preservation.

AIM: The therapeutic expediency of cisplatin was limited due to its nephrotoxic side effects, so this study planned to assess the nephrotic and neuroprotective impact of metformin (MET) and low-dose radiation (LDR) in cisplatin-prompted kidney injury and uremic encephalopathy (UE). METHODS: The effect of the 10-day MET treatment (200 mg/kg, orally) and/or fractionated LDR (0.25 Gy, of the total dose of 0.5 Gy, 1st and 7th day, respectively) on (5 mg/kg, intraperitoneally) cisplatin as a single dose was administered at the 5th day. Serum urea, creatinine and renal kidney injury molecule-1 were measured for the assessment of kidney function. Furthermore, the antioxidant potential in the renal and brain tissues was evaluated through, malondialdehyde and reduced glutathione estimation. Moreover, renal apoptotic markers: AMP-activated protein kinase, lipocalin, B-cell lymphoma 2 associated X protein, B-cell lymphoma 2, P53 and beclin 1 were estimated. UE was evaluated through the determination of serum inflammatory markers: nuclear factor kappa B, tumor-necrosis factor-α and interleukin 1 beta likewise, the cognitive deficits were assessed via forced swimming test, gamma-aminobutyric acid, n-methyl-d-aspartate and neuronal nitric oxide synthases besides AMP-activated protein kinase, light chain 3 and caspase3 levels in rats' cerebella. KEY FINDINGS: The obtained results revealed a noticeable improvement in the previously mentioned biochemical factors and behavioral tasks that was reinforced by histopathological examination when using the present remedy. SIGNIFICANCE: metformin and low doses of radiation afforded renoprotection and neuroprotection against cisplatin-induced acute uremic encephalopathy.