Effect of New Antidiabetics on Steatosis in Nerve Tissues and Nerve Conduction Velocity: Possible Role of Nerve Growth Factor (NGF)/Synaptophysin and Nrf2/HO-1 Pathways.

OBJECTIVES: The current study aims to investigate the impact of the GLP1 analog (semaglutide) and SGLT2 inhibitor (dapagliflozin) on nerve functions, morphology, and the underlying mechanisms involving nerve growth factor (NGF)/synaptophysin and Nrf2/HO-1 pathways in obese rats. METHODS: Forty male Sprague Dawley rats, aged six to eight weeks, were classified into five groups; normal group (high-fat diet {HFD} for 12 weeks, metformin group (HFD for 12 weeks + metformin in last four weeks), dapagliflozin group (HFD for 12 weeks +dapagliflozin in last four weeks, semaglutide group (HFD for 12 weeks + semaglutide in last four weeks). At the end of the experiment, the sciatic nerve was collected for nerve conduction study, oxidative stress marker (malondialdehyde, i.e., MDA), real-time polymerase chain reaction (PCR) study (for HO-1 and Nrf2), oil red O staining, electron microscopic examination and immunohistochemistry for NGF and synaptophysin. RESULTS: The HFD group showed a significant rise in blood glucose, serum lipids, homeostatic model assessment (HOMA) index, lipid deposition in nerve tissues, and lipid peroxidation (MDA) in nerve tissues with significant attenuation in nerve conduction velocity (NCV), the expression of Nrf2 and HO-1 genes and significant attenuation in area stained with NGF and synaptophysin. On the other hand, pretreatment with either dapagliflozin or semaglutide led to considerable enhancement in the deteriorated serum and nerve tissue parameters and reversed the pathological changes. CONCLUSION: New antidiabetic drugs like SGLT2 inhibitors (more powerful) and GLP1 analog might have neuroprotective beneficial effects besides controlling the glycemic state in obese rats. This effect may result from reduced oxidative stress and increased Nrf2 levels, HO-1, synaptophysin, and NGF in the nerve tissues of obese rats.

Effect of intermittent fasting on adriamycin-induced nephropathy: Possible underlying mechanisms.

PURPOSE: Intermittent fasting (IF) has been shown to induce a well-organized adaptive defense against stress inside the cells, which increases the production of anti-oxidant defenses, repair of DNA, biogenesis of mitochondria, and genes that combat inflammation. So, the goal of the current investigation was to identify the effects of IF on rats with adriamycin (ADR)-induced nephropathy and any potential underlying mechanisms. METHODS: Four groups of 40 mature Sprague-Dawley male rats were allocated as follow; control, fasting, ADR, and ADR plus fasting. After 8 weeks of ADR administration urine, blood samples and kidneys were taken for assessment of serum creatinine (Cr), BUN, urinary proteins, indicators of oxidative damage (malondialdehyde (MDA), reduced glutathione (GSH) and Catalase (CAT) levels), histopathological examinations, immunohistochemical examinations for caspase-3, Sirt1, aquaporin2 (AQP2) and real time PCR for antioxidant genes; Nrf2, HO-1 in kidney tissues. RESULTS: IF significantly improved serum creatinine, BUN and urinary protein excretion, oxidative stress (low MDA with high CAT and GSH), in addition to morphological damage to the renal tubules and glomeruli as well as caspase-3 production during apoptosis. Moreover, IF stimulates significantly the expression of Sirt1 and Nrf2/HO-1 and AQP2. CONCLUSION: AQP2, Sirt1, Nrf2/HO-1 signaling may be upregulated and activated by IF, which alleviates ADR nephropathy. Enhancing endogenous antioxidants, reducing apoptosis and tubulointerstitial damage, and maintaining the glomerular membrane's integrity are other goals.

Immunological changes in a cohort of COVID-19 survivors: Mansoura University experience.

Background: COVID-19 is a global pandemic that has affected millions of people all over the world since 2019. Infection with COVID-19 initiates a humoral immune response that produces antibodies against specific viral antigens, which in turn is supposed to provide immunity against reinfection for a period of time. The aim of this research was to study the kinetics of IgM and IgG antibodies against SARS-CoV-2. Methods: One hundred and seventeen post-COVID-19 participants were enrolled in the study.  Qualitative assessment of IgM and IgG antibodies over six months (three visits) post recovery was conducted. Results: The current study revealed a significant reduction in IgM and IgG titers between the first and second visits (p <0.001). After six months, the antibody titer had declined by 78.8% from the first visit for IgM and by 49.2% for IgG antibodies. Regarding younger age and male sex, statistically significant persistence of IgM antibodies was noticed at the six months follow up. Also, statistically significant persistent IgG immunity was found in male patients and diabetics by the end of the six months follow up. Conclusions: We observed a significant waning of IgM and IgG titers over a period of six months follow up.. The persistence of positive IgM and IgG antibodies by the end of six months was variable due to differences in age, gender and presence of diabetes mellitus.

Effect of Intermittent Fasting on Glucose Homeostasis and Bone Remodeling in Glucocorticoid-Induced Osteoporosis Rat Model.

BACKGROUND: The present study examined the effect of intermittent fasting (IF) on bone mineral content (BMC) and bone mineral density (BMD) and the markers of bone remodeling in a glucocorticoid-induced osteoporosis (GIO) rat model. METHODS: Forty male rats were allocated to 4 groups (N=10 per group): control group of normal rats; control+IF group (normal rats subjected to IF for 16-18 hr daily for 90 days); dexamethasone (DEX) group: (DEX [0.5 mg i.p.] for 90 days); and DEX+IF group (DEX and IF for 90 days). By the end of the experiment, BMD and BMC in the right tibia were measured. Serum levels of the following were measured: glucose; insulin; triglycerides (TGs); total cholesterol; parathyroid hormone (PTH); osteoprotegerin (OPG); receptor activator of nuclear factor-κB (RANK); bone-resorbing cytokines, including bone deoxypyridinoline (DPD), N-terminal telopeptide of collagen type I (NTX-1), and tartrate-resistant acid phosphatase 5b (TRAP-5b); and bone-forming cytokines, including alkaline phosphatase (ALP) and osteocalcin (OC). RESULTS: DEX administration for 90 days resulted in significantly increased serum levels of glucose, insulin, TGs, cholesterol, PTH, OPG, DPD, NTX-1, and TRAP-5b and significantly decreased BMD, BMC, and serum levels of RANK, OC, and ALP (all P<0.05). IF for 90 days significantly improved all these parameters (all P<0.05). CONCLUSIONS: IF corrected GIO in rats by inhibiting osteoclastogenesis and PTH secretion and stimulating osteoblast activity.

Prevalence of and risk factors for non-alcoholic fatty liver disease (NAFLD) and fibrosis among young adults in Egypt.

OBJECTIVE: Limited literature has examined the epidemiology of non-alcoholic fatty liver disease (NAFLD) and fibrosis among young adults in Egypt, a country with one of the highest obesity rates globally. We assessed the prevalence of steatosis and fibrosis among college students in Egypt. DESIGN: In this cross-sectional study, we recruited students unaware of having fatty liver via a call-for-participation at a private university in the Dakahlia governorate of Egypt. Primary outcomes were the prevalence of steatosis as determined by the controlled attenuation parameter component of transient elastography and fibrosis as determined by the liver stiffness measurement component of transient elastography. Secondary outcomes were clinical parameters and socioeconomic factors associated with the presence and severity of steatosis and fibrosis. RESULTS: Of 132 participants evaluated for the study, 120 (91%) were included (median (IQR) age, 20 (19-21) years; 65 (54.2%) female). A total of 38 participants (31.6%) had steatosis, among whom 22 (57.9%) had S3 (severe) steatosis. There was a higher risk for steatosis in persons with overweight (adjusted OR 9.67, 95% CI (2.94 to 31.7, p<0.0001) and obesity (adjusted OR 13.87, 95% CI 4.41 to 43.6, p<0.0001) compared with lean persons. Moreover, higher level of parental education was associated with progressing steatosis stages (S1-S3). Six (5%) participants had transient elastography values equivalent to F2-F3 fibrosis (four with F2 fibrosis (≥7.9 kPa), and two with F3 fibrosis (≥8.8 kPa)). CONCLUSION: In this cohort of college students in Egypt, around 1 in 3 had steatosis, and 1 in 20 had moderate-to-advanced fibrosis, an established risk factor for hepatic and extrahepatic morbidity and mortality. These data underscore the urgency to address the silent epidemic of NAFLD among young adults in the Middle East-North Africa region.

Impact of Dehydroepiandrosterone (DHEA) on Bone Mineral Density and Bone Mineral Content in a Rat Model of Male Hypogonadism.

OBJECTIVES: The present study examined the effect DHEA (dehydroepiandrosterone) on bone mineral content (BMC) and bone mineral density (BMD) and biomarkers of bone remodeling in orchidectomized male rats. MATERIAL AND METHODS: A total of 32 male rats were divided equally into four groups (n = 8): (i) control group (C), (ii) control treated with DHEA (Control + DHEA), (iii) orchidectomized (ORCH) group that underwent bilateral orchidectomy and (iv) orchidectomized (ORCH) rats treated with DHEA (ORCH+DHEA). DHEA treatment started 4 weeks after orchidectomy and continued for 12 weeks. After 12 weeks the bone mineral density (BMD) and bone mineral content (BMC) were assayed in the tibia and femur of the right hind limb of each rat. We also measured the serum levels of the bone turnover markers deoxypyridinoline (Dpd), N-telopeptide of type I collagen (NTx), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase 5b (TRAP-5b) and osteocalcin (OC) as well as receptor activator of nuclear factor kappa B (RANK) and osteoprotegerin (OPG). RESULTS: Orchidectomy in rats caused significant reduction in BMD, BMC, serum levels of testosterone, PTH (parathyroid hormone), OPG, OC and ALP with significant rise in serum levels of TRAP-5B, RANK, Dpd and NTx1 (p < 0.05). On the other hand, DHEA therapy for 12 weeks caused significant improvement in all studied parameters except NTx1 (p < 0.05). CONCLUSIONS: DHEA corrected hypogonadism-induced osteoporosis in male rats probably via inhibiting osteoclastogenesis, stimulating the activity of osteoblasts and stimulating the secretion of PTH and testosterone.

Exercise and Stevia Rebaudiana (R) Extracts Attenuate Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms.

BACKGROUND AND AIMS: In the current work, we studied the effects of exercise and stevia rebaudiana (R) extracts on diabetic cardiomyopathy (DCM) in type 2 diabetic rats and their possible underlying mechanisms. METHODS: Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group, b) DM group, type 2 diabetic rats received 2 ml oral saline daily for 4 weeks, c) DM+ Exercise, type 2 diabetic rats were treated with exercise for 4 weeks and d) DM+ stevia R extracts: type 2 diabetic rats received methanolic stevia R extracts. By the end of the experiment, serum blood glucose, HOMA-IR, insulin and cardiac enzymes (LDH, CK-MB), cardiac histopathology, oxidative stress markers (MDA, GSH and CAT), myocardial fibrosis by Masson trichrome, the expression of p53, caspase-3, α-SMA and tyrosine hydroxylase (TH) by immunostaining in myocardial tissues were measured. RESULTS: T2DM caused a significant increase in blood glucose, HOMA-IR index, serum CK-MB and LDH, myocardial damage and fibrosis, myocardial MDA, myocardial α-SMA, p53, caspase-3, Nrf2 and TH density with a significant decrease in serum insulin and myocardial GSH and CAT (p< 0.05). On the other hand, treatment with either exercise or stevia R extracts significantly improved all studied parameters (p< 0.05). Moreover, the effects of stevia R was more significant than exercise (p< 0.05). CONCLUSION: Both exercise and methanolic stevia R extracts showed cardioprotective effects against DCM and Stevia R offered more cardioprotective than exercise. This cardioprotective effect of these lines of treatment might be due to attenuation of oxidative stress, apoptosis, sympathetic nerve density and fibrosis and upregulation of the antioxidant transcription factor, Nrf2.

Comparative Study of the Effects of GLP1 Analog and SGLT2 Inhibitor against Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms.

The present study investigated the possible cardioprotective effects of GLP1 and SGLT2i against diabetic cardiomyopathy (DCM) in type 2 diabetic rats and the possible underlying mechanisms. METHODS: Thirty-two male Sprague Dawley rats were randomly subdivided into 4 equal groups: a) control group, b) DM group, type 2 diabetic rats with saline daily for 4 weeks, c) DM+ GLP1, as DM group with GLP1 analogue (liraglutide) at a dose of 75 µg/kg for 4 weeks, and d) DM+ SGLT2i as DM group with SGLT2 inhibitor (dapagliflozin) at a dose of 1mg/kg for 4 weeks. By the end of treatment (4 weeks), serum blood glucose, homeostasis model assessment insulin resistance (HOMA-IR), insulin, and cardiac enzymes (LDH, CK-MB) were measured. Also, the cardiac histopathology, myocardial oxidative stress markers (malondialdehyde (MDA), glutathione (GSH) and CAT) and norepinephrine (NE), myocardial fibrosis, the expression of caspase-3, TGF-ß, TNF-α, and tyrosine hydroxylase (TH) in myocardial tissues were measured. RESULTS: T2DM caused significant increase in serum glucose, HOMA-IR, serum CK-MB, and LDH (p < 0.05). Also, DM caused significant myocardial damage and fibrosis; elevation of myocardial MDA; NE with upregulation of myocardial caspase-3, TNF-α, TGF-ß, and TH; and significant decrease in serum insulin and myocardial GSH and CAT (p < 0.05). Administration of either GLP1 analog or SGLT2i caused a significant improvement in all studied parameters (p < 0.05). CONCLUSION: We concluded that both GLP1 and SGLT2i exhibited cardioprotective effects against DCM in T2DM, with the upper hand for SGLT2i. This might be due to attenuation of fibrosis, oxidative stress, apoptosis (caspase-3), sympathetic nerve activity, and inflammatory cytokines (TNF-α and TGF-ß).

Blockade of Renin Angiotensin System Ameliorates the Cardiac Arrhythmias and Sympathetic Neural Remodeling in Hearts of Type 2 DM Rat Model.

OBJECTIVE: The present study was designed to investigate the effects of renin angiotensin system (RAS) blockade on cardiac arrhythmias and sympathetic nerve remodelling in heart tissues of type 2 diabetic rats. METHODS: Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group: normal rats, b) DM group; after type 2 diabetes induction, rats received 2ml oral saline daily for 4 weeks, c) DM+ ACEi: after type 2 diabetes induction, rats were treated with enalapril (10 mg/kg, orally for 4 weeks) and d) DM+ ARBs: after type 2 diabetes induction, rats were treated with losartan (30 mg/kg, orally for 4 weeks). RESULTS: In type 2 diabetic rats, the results demonstrated significant prolongation in Q-T interval and elevation of blood sugar, HOMA-IR index, TC, TGs, LDL, serum CK-MB, myocardial damage, myocardial MDA, myocardial norepinephrine and tyrosine hydroxylase (TH) density with significant reduction in serum HDL, serum insulin and myocardial GSH and CAT. On the other hand, blockade of RAS at the level of either ACE by enalapril or angiotensin (Ag) receptors by losartan resulted in significant improvement in ECG parameters (Q-T), cardiac enzymes (CK-MB), cardiac morphology, myocardial oxidative stress (low MDA, high CAT and GSH) and myocardial TH density. CONCLUSION: RAS plays a role in the cardiac sympathetic nerve sprouting and cardiac arrhythmias induced by type 2 DM and its blockade might have a cardioprotective effect via attenuation of sympathetic nerve fibres remodelling, myocardial norepinephrine contents and oxidative stress.

Possible mechanisms underlying fatty liver in a rat model of male hypogonadism: A protective role for testosterone.

AIMS: To investigate the effects of testosterone (Test) deficiency and testosterone replacement therapy (TRT) on the development of non-alcoholic fatty liver disease (NAFLD) and associated peripheral insulin resistance (IR) in male rats and to illustrate the underlying mechanisms of action. MATERIALS AND METHODS: male Sprague Dawley rats were divided into 3 groups as follows: 1) sham-operated group (n = 11), 2) ORCD-induced group (n = 9) exposed to orchidectomy (ORCD), achieved by complete surgical removal of testicles, and 3) ORCD + Test treated group (n = 10) (11 ng/mL Test propionate, 3x/week, S.C.). RESULTS: Data revealed significant increases in final body, liver, visceral and subcutaneous fats weights with significant increases in fasting plasma glucose and insulin levels and HOMA-IR. Additionally, ORCD rats had higher UAC for measured glucose levels and insulin levels during OGTT and higher AUC for measured glucose levels during ITT. Interesting, higher serum and hepatic levels of TGs and CHOL and higher serum levels of LDL were seen in ORCD-induced rats. Mechanistically, significant increases in mRNA levels of SREBP-1, SREBP-2, ACC-1, FAS, HMGCOAR and HMGCOAS with significant increases in protein levels of both precursor and mature SREBP-1 and SREBP-2, PPAR-α, p-PPAR-α, CPT-1 and UCP-2 and significant lower protein levels p-AMPK and p-ACC-1 were detected in livers of ORCD rats. Test administration to ORCD-induced rats significantly ameliorated all of the above mentioned biochemical endpoints and reversed the effect of ORCD on mRNA and protein levels of these targets. In conclusion, Test deficiency could be an independent risk factor for the development of NAFLD by upregulation of lipid synthesis and disturb fatty acids oxidation whereas Test therapy is a protective strategy.