Liraglutide attenuates obese-associated breast cancer cell proliferation via inhibiting PI3K/Akt/mTOR signaling pathway.

This study aims to explore the anti-proliferative, pro-apoptotic, and anti-migration activities of liraglutide (LGT) in MCF-7 breast cancer (BC) cells in subjects with obesity, particularly its effects on the PI3K/Akt/mTOR/AMPK pathway. The role of AMPK/SIRT-1, an essential regulator of adipokine production, in the effect of LGT on the production of adipose-derived adipokine was also assessed. MCF-7 cells were incubated in conditioned medium (CM) generated from adipose-derived stem cells (ADSCs) of obese subjects. MCF-7 cells were then treated with LGT for 72 h. Anti-proliferative, pro-apoptotic, and anti-migration activities were investigated using alamarBlue, annexin V stain, and scratch assay, respectively. Protein levels of phosphorylated PI3K, p-Akt, p-mTOR, and p-AMPK were investigated using immunoblotting. Levels of adipokines in ADSCs were determined using RT-PCR before and after transfection of ADSCs using the specific small interference RNA sequences for AMPK and SIRT-1. LGT evoked anti-proliferative, apoptotic, and potential anti-migratory properties on MCF-7 cells incubated in CM from obese ADSCs and significantly mitigated the activity of the PI3K/Akt/mTOR survival pathway-but not AMPK-in MCF-7 cells. Furthermore, the anti-proliferative effects afforded by LGT were similar to those mediated by LY294002 (PI3K inhibitor) and rapamycin (mTOR inhibitor). Our results reveal that transfection of AMPK/SIRT-1 genes did not affect the beneficial role of LGT in the expression of adipokines in ADSCs. In conclusion, LGT elicits anti-proliferative, apoptotic, and anti-migratory effects on BC cells in obese conditions by suppressing the activity of survival pathways; however, this effect is independent of the AMPK/SIRT1 pathway in ADSCs or AMPK in BC cells.

Pentoxifylline and thiamine ameliorate rhabdomyolysis-induced acute kidney injury in rats via suppressing TLR4/NF-κB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis.

Acute kidney injury (AKI) is a common complication of rhabdomyolysis (RM), a syndrome characterized by skeletal muscle damage resulting in renal tubular oxidative stress, inflammation, and activated toll like receptor-4 (TLR-4) and NOD-like receptor protein-3 (NLRP-3) inflammasome. Pyroptosis is a programmed cell death mediated by NLRP-3 leading to the activation of caspase-1 and gasdermin D (GSDMD), the hallmark of pyroptosis. This study aims to investigate the renoprotective effects of two antioxidants; pentoxifylline (PTX) and thiamine (TM) via targeting the aforementioned pathways. RM-AKI was induced in male Albino Wistar rats by intramuscular injection of glycerol (50% v/v, 10 ml/kg). PTX (100 mg/kg, oral) and TM (25 mg/kg, i.p) were administered for 12 days prior glycerol injection and continued for 3 days following induction of RM-AKI. Serum creatinine, blood urea nitrogen (BUN), creatin kinase, lipid peroxides, total antioxidant activity, inflammatory markers (tumor necrosis factor-α, interleukin-1ß, and nuclear factor kappa B), TLR4, NLRP-3, caspase-1, GSDMD and c-myc (an apoptotic marker) were estimated. Compared to AKI model, co-administered drugs revealed a significant improvement in renal function and pathology as indicated by the reduction in serum creatinine, BUN and protein cast accumulation. The elevations of oxidative stress, and inflammatory markers as well as the over-expression of c-myc were alleviated. Protein levels of TLR4, NLRP3, cleaved caspase-1, and GSDMD were significantly elevated in RM-AKI model, and this elevation was attenuated by the tested drugs. In conclusion, PTX and TM could be a potential renoprotective approach for patients with RM through targeting TLR4/NF-κB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis pathways.

Headspace Solid Phase Micro-Extraction of Volatile Constituents Produced from Saudi Ruta chalepensis and Molecular Docking Study of Potential Antioxidant Activity.

Ruta chalepensis L., commonly known as Shazab in Saudi Arabia, is one of the famous culinary plants belonging to the Rutaceae family. It is commonly used in ethnomedicine in treating numerous diseases. This study was performed to characterize the essential oil isolated from Saudi species using a relatively new advanced headspace solid-phase microextraction technique. Following that, the antioxidant activity of the extracted oil was assessed using in vitro techniques such as the DPPH and nitric oxide scavenging tests, as well as the reducing power FRAP study and the molecular docking tool. The essential oil yield of the dried plant was 0.83% (v/w). Gas chromatography joined with a mass spectrometer was used to determine the chemical composition of the pale-yellow essential oil. Sixty-eight constituents were detected, representing 97.70% of the total oil content. The major constituents were aliphatic ketones dominated by 2-undecanone (37.30%) and 2-nonanone (20.00%), with minor constituents of mono and sesquiterpenoids chemical classes. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is one of the major causes of many contemporary diseases due to its ability to create a reactive oxygen species (ROS). Thus, molecular docking was used to confirm that some oil phytoconstituents have good docking scores compared to the standard antioxidant drug (Vitamin C), indicating great binding compatibility between the (NADPH) oxidase receptor site and the ligand. In conclusion, our findings suggest that the oil could be used safely and as a cost-effective remedy in treating various modern diseases caused by free radical formation.

The inhibitory mechanisms of losartan and vitamin D on amiodarone-induced lung inflammation in rats: Role of mitogen-activated protein kinases/activator protein-1.

Amiodarone (AMD), an antiarrhythmic drug, is used cautiously due to its lung toxicity that is characterized by alveolar inflammation followed by fatal fibrosis. AMD induces lung inflammation via increasing the alveolar macrophages and disturbing the balance of T-helper-1 (Th1) and Th2 cells cytokines. In this study, the role of the mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) pathway in AMD-induced lung inflammation was evaluated. Also, the anti-inflammatory and antifibrotic effects of losartan and/or vitamin D were investigated following 7, 14, and 28 days of AMD administration. AMD resulted in lung injury, inflammatory infiltration, and increased pulmonary levels of inflammatory cytokines starting from Week 1 of exposure. A significant increase in serum levels of interleukin-4 along with a significant reduction of interferon-gamma, in addition to strong expression of CD68, were reported after 14 and 28 days of AMD administration reflecting Th1/Th2 cytokines imbalance and the accumulation of alveolar macrophages, respectively. The phosphorylation of MAPKs (ERK1/2, JNK, p38) and AP-1 was significantly enhanced starting from Week 1 of exposure. Marked expression of transforming growth factor beta-1 and massive deposition of collagen were detected after 28 days reflecting late fibrosis. All these abnormalities were significantly mitigated by vitamin D and its combination with losartan. Losartan alone has less prominent anti-inflammatory effects particularly after 28 days; however, it efficiently prevented late fibrosis. This study concludes that MAPKs/AP-1 pathway is involved in AMD-induced lung inflammation and that vitamin D and/or losartan could be used as a prophylactic agent to prevent AMD-induced lung toxicity.

Biotin, coenzyme Q10, and their combination ameliorate aluminium chloride-induced Alzheimer's disease via attenuating neuroinflammation and improving brain insulin signaling.

Insulin is important for brain function and neuronal survival. Insulin signaling is initiated by the phosphorylation of insulin receptor substrate-1 (IRS-1) at tyrosine (pTyr) residue. However, IRS-1 is inhibited by phosphorylation at serine (pSer). In Alzheimer's disease (AD), oxidative stress and accumulation of amyloid beta (Aß) induce neuroinflammation, which augments pSer-IRS-1 and reduces pTyr-IRS-1 disturbing insulin signaling pathway. Coenzyme Q10 (CoQ10) and biotin possess antioxidant and anti-inflammatory properties, and, in this study, their impact on insulin signaling is investigated in an aluminium chloride (AlCl3 ) model of AD. AD was induced by oral administration of AlCl3 (75 mg/kg) for 60 days. Biotin (2 mg/kg), CoQ10 (10 mg/kg), and their combination were supplemented concomitantly with AlCl3 for 60 days. Memory test and histological examination were performed. Brain levels of lipid peroxides, antioxidants (reduced glutathione and superoxide dismutase), inflammatory markers (tumor necrosis factor-α, interleukin-6 [IL-6], IL-1, and nuclear factor κB), and phosphorylated Akt (survival kinase) as well as protein levels of Aß, IRS-1 (pTyr and pSer), and caspase-3 (apoptotic marker) were determined. AlCl3 resulted in impaired memory, significant increase in Aß, lipid peroxides, inflammatory markers, caspase-3, and pSer-IRS-1, with significant reduction of the antioxidants, pTyr-IRS-1, and p-Akt reflecting Aß-induced inflammation and defective insulin signaling. Histological examination revealed focal aggregations of inflammatory cells and neuronal degeneration. The biochemical deviations and histological changes were attenuated by the concomitant treatment with biotin and, to greater extent, with CoQ10 and the combination. In conclusion, biotin and CoQ10 could protect against AD via attenuating inflammatory response and enhancing insulin signaling.

Roles of some antioxidants in modulation of cardiac myopathy induced by sodium nitrite via down-regulation of mRNA expression of NF-κB, Bax, and flt-1 and suppressing DNA damage.

The underlying pathology of cardiac damage involves various molecular and signaling pathways. Therefore, this study aimed to explore the role of Quercetin (Querc), alone or in combination with Melatonin (Melat) against cardiac damage induced by sodium nitrite (Sod nit), as well as to elucidate different signaling pathways. Querc and Melat were injected intraperitoneally (i.p.), followed by induction of hypoxia in rats by using a single dose of Sod nit (60 mg/kg, s.c.). Treatment with Sod nit significantly decreased hemoglobin (Hb) levels in blood. Pretreatment of hypoxic rats with Querc and/or Melat elevated the declined Hb concentration. The forementioned antioxidants also successfully ameliorated the alteration of heat shock protein 70 (HSP-70) and markers of cardiac injury, including troponin T (Trop. T), creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF α), and C-reactive protein (CRP) in the rats serum. Furthermore, RT-PCR revealed that these antioxidants successfully modulated mRNA expression of NF-κB, Bax, Bcl-2, and flt-1. They also regulated vascular endothelial growth factor (VEGF), the apoptosis marker caspase 3, and oxidative DNA damage in cardiac tissue, compared to Sod nit-intoxicated rats. The present biochemical results are reinforced by histopathological examination. IN CONCLUSION: The results reflected that treatment with Querc in combination with Melat was most effective in improving Sod nit-toxicity induced cardiac damage, thus confirming the promising role of this combination as an effective treatment for cardiac damage induced by other cardio-toxic agents.

Attenuation of DNA damage and mRNA gene expression in hypoxic rats using natural antioxidants.

This study aimed to explore the efficiency of carnosine (Cs) and/or l-arginine (Agn) in the downregulation of apoptotic and inflammatory molecule expression and DNA damage caused hepatic injury in response to sodium nitrite (Sd)-induced hypoxia in rats. Rats were injected with Sd; Agn or/and Cs were administrated prior to Sd intoxication. Sd significantly decreased hemoglobin concentration and Bcl-2 mRNA expression, while increased expressions of apoptotic markers (Bax and caspase), tumor necrosis factor-α, nuclear factor kappa B, and C-reactive protein and the oxidative DNA damage in hepatic tissue. Moreover, administration of Agn or/and Cs exhibited a modulation of the previous parameters. However, concurrent treatment with the forementioned antioxidants modulated these levels. It was concluded that the treatment with the combination of Agn and Cs was the most effective regimen in ameliorating Sd toxicity accompanied by hypoxic stress.

Quercetin inhibits sodium nitrite-induced inflammation and apoptosis in different rats organs by suppressing Bax, HIF1-α, TGF-ß, Smad-2, and AKT pathways.

The objective of this work is to study the protective effects of Quercetin against sodium nitrite-induced hypoxia on liver, lung, kidney and cardiac tissues, also to explore novel mechanism of this compound. Male albino rats were injected with sodium nitrite (75 mg/kg). Quercetin (200 mg kg-1 ,- i.p.) was administrated 24 and 1 h respectively prior to sodium nitrite intoxication, hypoxia significantly decreased hemoglobin concentration, while increased expressions of HIF, Bax, Smad-2, TGF-ß, and AKT. However, administration of Quercetin played a modulatory role against the previous mentioned apoptotic factors protein expressions in all the studied tissues. On the other hand, Bcl-2 was downregulated by NaNO2 , whereas concurrent treatment with Quercetin increased its expression. It was concluded that Quercetin possesses an anti-apoptotic action induced by NaNO2 -intoxication via different mechanisms. Quercetin administration is recommended in areas of high altitudes to combat the hazard effect of hypoxia in different organs and in some diseases accompanied by hypoxic stress.

The antifibrotic and fibrolytic properties of date fruit extract via modulation of genotoxicity, tissue-inhibitor of metalloproteinases and nuclear factor- kappa B pathway in a rat model of hepatotoxicity.

BACKGROUND: Hepatic fibrosis and its end point; cirrhosis, are the major cause of liver failure and death in patients with chronic liver disease. Therefore, the need for an effective treatment is evident. This study was designed to assess the potential effects of aqueous extract of date fruits, either flesh (DFE) or pits (DPE), on oxidative DNA damage and liver inflammation induced by carbon tetrachloride (CCl4) and whether they are related to inhibition of nuclear factor-κB pathway. In addition, the fibrolytic potential was evaluated via measuring matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases -1 and -2. METHODS: Rats were divided into the following groups: normal control, model control (CCl4 only), CCl4 + DFE, CCl4 + DPE and CCl4 + coffee. Coffee was used as a positive control. Fibrosis was induced by chronic administration of CCl4 (0.4 ml/kg) 3× a week for 8 weeks, and rats were treated with 6 ml/kg/day of DFE or DPE for 8 weeks. Liver homogenate was prepared for evaluation of oxidative stress, DNA damage, inflammatory and fibrolytic markers. Data are analyzed using one-way analysis of variance followed by a Tukey-Kramer post hoc test. RESULTS: Both DFE and DPE significantly attenuated CCl4-induced oxidative damage as indicated by reducing lipid, protein and DNA oxidation in addition to increasing the levels of hepatic catalase activity. Both extracts blocked the accumulation of collagen I in the liver and ameliorated the increased expression of collagen III and α-smooth muscle actin suggesting suppression of profibrotic response induced by CCl4. DFE and DPE also upregulated the expression of heme oxygenase-1 and attenuated the nuclear factor-κB activation and cycloxygenase-2 expression reflecting their anti-inflammatory potential. Additionally, both flesh and pits extracts attenuated the increase in the tissue inhibitor of metalloproteinases -1 and -2 suggesting their fibrolytic activity. CONCLUSION: Our data suggest that DFE or DPE can prevent liver fibrosis by suppressing genotoxicity and nuclear factor-κB inflammatory pathway and by promoting collagen degradation.

Renoprotective Effects of Fenofibrate via Modulation of LKB1/AMPK mRNA Expression and Endothelial Dysfunction in a Rat Model of Diabetic Nephropathy.

This study was conducted to investigate whether the renoprotective effects of fenofibrate are mediated via attenuation of endothelial dysfunction and modulating the mRNA expression of adenosine monophosphate-activated protein kinase (AMPK) and its downstream kinase liver kinase B1 (LKB1) in rats with diabetic nephropathy (DN). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg kg(-1)). Fenofibrate (100 mg kg(-1), p.o.) was given to diabetic rats daily for 12 weeks. Treatment with fenofibrate significantly improved the renal function as revealed by the significant reductions in urinary albumin excretion and serum levels of creatinine and urea, in addition to the significant increase in creatinine clearance compared with the diabetic control group. Hyperglycemia-induced oxidative damage was ameliorated by treatment with fenofibrate as indicated by the significantly increased levels of glutathione and catalase together with the significant decrease in lipid peroxidation. Administration of fenofibrate caused significant increases in renal nitric oxide (NO) production and mRNA expression of endothelial NO synthase (eNOS), AMPK and LKB1, reflecting improvement of endothelial function. Our results give further insights into the mechanisms underlying the protective role of fenofibrate in DN via modulation of AMPK, LKB1 and eNOS mRNA expression.

The combination of zinc and glibenclamide limits cardiovascular complications in diabetic rats via multiple mechanisms.

Cardiovascular complications have become a major cause of mortality for diabetic patients. Glibenclamide is an effective hypoglycemic agent, but failed to alleviate diabetic complications. This study aimed to evaluate whether the addition of zinc to glibenclamide could mitigate such complications. Diabetes was induced using streptozotocin (60 mg/kg, i.p.). Cardiovascular complications were detected by the significant rise of cardiac enzymes, serum lipids, myocardial oxidative stress and cardiac levels of tumor necrosis factor-α (TNF-α, a marker for inflammation) as well as massive histological changes in the heart wall in diabetic control compared to non-diabetic group. Levels of serum nitric oxide and cardiac vascular endothelial growth factor (VEGF, an angiogenic marker) were lower in diabetic rats. Addition of zinc sulfate (30mg/kg) to glibenclamide (600ßg/kg) resulted in significant improvement in cardiac biomarkers, oxidative status and serum lipids. Highly significant reduction in cardiac TNF-α (P<0.001), in addition to significant rise in nitric oxide (P< 0.05) and VEGF (P<0.01) were observed. Cellular infiltration and myocardial edema were ameliorated. These results suggest that a combined treatment of zinc and glibenclamide might be a potential therapy for preventing the risk of cardiovascular complications and reducing the mortality rate among diabetic patients.

The Protective Effects of Vitamin B Complex on Diclofenac Sodium-Induced Nephrotoxicity: The Role of NOX4/RhoA/ROCK.

Diclofenac sodium (DIC) is a widely used non-steroidal anti-inflammatory drug. Unfortunately, its prolonged use is associated with nephrotoxicity due to oxidative stress, inflammation, and fibrosis. We aimed to investigate the nephroprotective effects of vitamin B complex (B1, B6, B12) against DIC-induced nephrotoxicity and its impact on NOX4/RhoA/ROCK, a pathway that plays a vital role in renal pathophysiology. Thirty-two Wistar rats were divided into four groups: (1) normal control; (2) vitamin B complex (16 mg/kg B1, 16 mg/kg B6, 0.16 mg/kg B12, intraperitoneal); (3) DIC (10 mg/kg, intramuscular); and (4) DIC plus vitamin B complex group. After 14 days, the following were assayed: serum renal biomarkers (creatinine, blood urea nitrogen, kidney injury molecule-1), oxidative stress, inflammatory (tumor necrosis factor-α, interleukin-6), and fibrotic (transforming growth factor-ß) markers as well as the protein levels of NOX4, RhoA, and ROCK. Structural changes, inflammatory cell infiltration, and fibrosis were detected using hematoxylin and eosin and Masson trichrome stains. Compared to DIC, vitamin B complex significantly decreased the renal function biomarkers, markers of oxidative stress and inflammation, and fibrotic cytokines. Glomerular and tubular damage, inflammatory infiltration, and excessive collagen accumulation were also reduced. Protein levels of NOX4, RhoA, and ROCK were significantly elevated by DIC, and this elevation was ameliorated by vitamin B complex. In conclusion, vitamin B complex administration could be a renoprotective approach during treatment with DIC via, at least in part, suppressing the NOX4/RhoA/ROCK pathway.

The protective role of sesame oil against Parkinson's-like disease induced by manganese in rats.

Chronic exposure to manganese (Mn) results in motor dysfunction, biochemical and pathological alterations in the brain. Oxidative stress, inflammation, and dysfunction of dopaminergic and GABAergic systems stimulate activating transcription factor-6 (ATF-6) and protein kinase RNA-like ER kinase (PERK) leading to apoptosis. This study aimed to investigate the protective effect of sesame oil (SO) against Mn-induced neurotoxicity. Rats received 25 mg/kg MnCl2 and were concomitantly treated with 2.5, 5, or 8 ml/kg of SO for 5 weeks. Mn-induced motor dysfunction was indicated by significant decreases in the time taken by rats to fall during the rotarod test and in the number of movements observed during the open field test. Also, Mn resulted in neuronal degeneration as observed by histological staining. The striatal levels of lipid peroxides and reduced glutathione (oxidative stress markers), interleukin-6 and tumor necrosis factor-α (inflammatory markers) were significantly elevated. Mn significantly reduced the levels of dopamine and Bcl-2, while GABA, PERK, ATF-6, Bax, and caspase-3 were increased. Interestingly, all SO doses, especially at 8 ml/kg, significantly improved locomotor activity, biochemical deviations and reduced neuronal degeneration. In conclusion, SO may provide potential therapeutic benefits in enhancing motor performance and promoting neuronal survival in individuals highly exposed to Mn.

Preventive effects of selenium yeast, chromium picolinate, zinc sulfate and their combination on oxidative stress, inflammation, impaired angiogenesis and atherogenesis in myocardial infarction in rats.

PURPOSE: Accumulating evidences suggest a critical role of trace metal dyshemostasis in oxidative stress and cardiac dysfunction after myocardial infarction (MI). This study investigated the cardioprotective effects of selenium yeast (Se), chromium picolinate Cr(pic)3, zinc sulfate (Zn) and their combination on isoproterenol (ISO)-induced MI. METHODS: Rats were divided into six groups: normal control, ISO control, Se-pretreated (0.1 mg/kg), Cr(pic)3-pretreated (400 µg/kg), Zn-pretreated (30 mg/kg) and metal combination-pretreated groups. All metals were administered for 28 days and at the 27th day, MI was induced by subcutaneous injection of ISO (85 mg/kg) once for two consecutive days. RESULTS: ISO control group showed hyperlipidemia, elevation of cardiac biomarkers and lipid peroxidation and increased immunostaining of p47 phox NADPH oxidase subunit in addition to decreased levels of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Cardiac levels of tumor necrosis factor-α (TNF-α) were increased, while vascular endothelial growth factor (VEGF, the major angiogenic factor) was decreased. Pretreatment with Se normalized the cardiac enzymes, lipid peroxidation, GSH, SOD, CAT, GPx, TNF-α and VEGF (P<0.001) and reduced the immunostaining of p47 phox subunit. However, Se failed to correct the dyslipidemia. Cr(pic)3 significantly improved lipid profile (P<0.001) and all other biochemical deviations except for VEGF. Zn, but to lesser extent, reduced the oxidative damage and TNF-α levels and improved both dyslipidemia and angiogenesis. Combination therapy exhibited less prominent protection compared to individual metals. CONCLUSION: Daily supplementation with trace metals is promising for improving myocardial performance via preventing oxidative damage, induction of angiogenesis, anti-inflammatory and/or anti-hyperlipidemic mechanisms.

Autophagy and necroptosis in cisplatin-induced acute kidney injury: Recent advances regarding their role and therapeutic potential.

Cisplatin (CP) is a broad-spectrum antineoplastic agent, used to treat many different types of malignancies due to its high efficacy and low cost. However, its use is largely limited by acute kidney injury (AKI), which, if left untreated, may progress to cause irreversible chronic renal dysfunction. Despite substantial research, the exact mechanisms of CP-induced AKI are still so far unclear and effective therapies are lacking and desperately needed. In recent years, necroptosis, a novel subtype of regulated necrosis, and autophagy, a form of homeostatic housekeeping mechanism have witnessed a burgeoning interest owing to their potential to regulate and alleviate CP-induced AKI. In this review, we elucidate in detail the molecular mechanisms and potential roles of both autophagy and necroptosis in CP-induced AKI. We also explore the potential of targeting these pathways to overcome CP-induced AKI according to recent advances.

Protective effects of cardamom aqueous extract against tamoxifen-induced pancreatic injury in female rats.

Tamoxifen (TAM) is a commonly used drug for breast cancer treatment. Although effective, TAM has deleterious effects on many organs. The toxic effects of TAM on the pancreas and the underlying mechanisms however, have not fully investigated. In the present study, we investigated the effects of TAM on the pancreatic tissue in female rats. We also examined whether cardamom aqueous extract (CAE) protects against TAM-induced pancreatic injury. TAM-intoxicated rats were injected with 45 mg/kg of TAM for 10 days, whereas rats in the CAE-treated group were administered 10 mL/kg of CAE for 20 days, starting 10 days prior to TAM administration. Treatment with TAM resulted in severe degeneration of the pancreatic acini and marked increases in the serum levels of pancreatic lipase, α-amylase, glucose, fatty acids and triglycerides along with decreased insulin serum levels. TAM led to oxidative stress as evident from a significant increase in the pancreatic levels of lipid peroxides and nitric oxide along with the depletion of reduced glutathione, glutathione peroxidase, and superoxide dismutase. Moreover, inflammation was indicated by a significant increase in tumor necrosis factor-α and interleukin-6 levels, enhanced expression of the macrophage recruitment marker; CD68 as well as up-regulated protein levels of toll-like receptor 4 and nuclear factor kappa B and increased p-p38/MAPK ratio; which are important signals in the production of inflammatory cytokines. TAM also markedly increased the pancreatic levels of caspase-3 and BAX reflecting its apoptotic effects. The CAE treatment ameliorated all the biochemical and histological changes induced by TAM. The present study revealed, for the first time, that TAM has toxic effects on the pancreatic tissue through oxidative stress, inflammation and apoptotic effects. The present study also provides evidence that CAE exerts cytoprotective effects against these deleterious effects induced by TAM in the pancreatic tissue. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00198-w.

TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity.

BACKGROUND: Cisplatin (Cp) is an antineoplastic agent with a dose-limiting nephrotoxicity. Cp-induced nephrotoxicity is characterized by the interplay of oxidative stress, inflammation, and apoptosis. Toll-4 receptors (TLR4) and NLPR3 inflammasome are pattern-recognition receptors responsible for activating inflammatory responses and are assigned to play a significant role with gasdermin (GSDMD) in acute kidney injuries. N-acetylcysteine (NAC) and chlorogenic acid (CGA) have documented nephroprotective effects by suppressing oxidative and inflammatory pathways. Therefore, the current study aimed to investigate the contribution of the upregulation of TLR4/inflammasomes/gasdermin signaling to Cp-induced nephrotoxicity and their modulation by NAC or CGA. METHODS: A single injection of Cp (7 mg/kg, i.p.) was given to Wistar rats. Rats received either NAC (250 mg/kg, p.o.) and/or CGA (20 mg/kg, p.o.) one week before and after the Cp injection. RESULTS: Cp-induced acute nephrotoxicity was evident by the increased blood urea nitrogen and serum creatinine and histopathological insults. Additionally, nephrotoxicity was associated with increased lipid peroxidation, reduced antioxidants, and elevated levels of inflammatory markers (NF-κB and TNF-α) in the kidney tissues. Moreover, Cp upregulated both TLR4/NLPR3/interleukin-1beta (IL-1ß) and caspase-1/GSDMD-signaling pathways, accompanied by an increased Bax/BCL-2 ratio, indicating an inflammatory-mediated apoptosis. Both NAC and/or CGA significantly corrected these changes. CONCLUSIONS: This study emphasizes that inhibition of TLR4/NLPR3/IL-1ß/GSDMD might be a novel mechanism of the nephroprotective effects of NAC or CGA against Cp-induced nephrotoxicity in rats.

Chrysin Attenuates Fructose-Induced Nonalcoholic Fatty Liver in Rats via Antioxidant and Anti-Inflammatory Effects: The Role of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor Axis.

Aim: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and if untreated, it may propagate into end-stage liver disease. The classical arm of the renin-angiotensin system (RAS) has a fundamental role in triggering oxidative stress and inflammation, which play potential roles in the pathogenesis of NAFLD. However, the nonclassical alternative axis of RAS, angiotensin- (Ang-) converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor, opposes the actions of the classical arm, mitigates the metabolic dysfunction, and improves hepatic lipid metabolism rendering it a promising protective target against NAFLD. The current study is aimed at investigating the impact of chrysin, a well-known antioxidant flavonoid, on this defensive RAS axis in NAFLD. Methods: Rats were randomly distributed and treated daily for eight weeks as follows: the normal control, chrysin control (50 mg/kg, p.o), NAFLD group (received 20% fructose in drinking water), and treated groups (25 and 50 mg/kg chrysin given orally and concomitantly with fructose). Diminazene aceturate (DIZE) (15 mg/kg, s.c.) was used as a reference ACE2 activator. Key Findings. High fructose induced significant weight gain, hepatocyte degeneration with fat accumulation, and inflammatory cell infiltration (as examined by H&E staining). This was accompanied by a substantial increase in liver enzymes, glucose, circulating and hepatic triglycerides, lipid peroxides, inflammatory cytokines, and Ang II (the main component of classical RAS). At the same time, protein levels of ACE2, Ang (1-7), and Mas receptors were markedly reduced. Chrysin (25 and 50 mg/kg) significantly ameliorated these abnormalities, with a prominent effect of the dose of 50 mg/kg over DIZE and the lower dose in improving ACE2, Ang (1-7), and Mas. Significance. Chrysin is a promising efficient protective remedy against NAFLD; mechanisms include the activation of ACE2/Ang (1-7)/Mas axis.

Case Report: Central retinal artery occlusion following sildenafil intake.

Purpose: To report a case of central retinal artery occlusion associated with sildenafil intake and briefly discuss its causative pathogenesis. Methods: A 50-year-old man with no premorbidities presented with symptoms of sudden severe visual field constriction in the left eye (LE). Best-corrected visual acuity in the LE was 20/25. Fundus examination and fluorescein angiography of the LE were suggestive of central retinal artery occlusion (CRAO) with cilioretinal artery sparing. Further investigation revealed that 100 mg of sildenafil had been taken for the first time three hours before the onset of symptoms. Results: The patient was treated promptly with intravenous acetazolamide, sublingual isosorbide dinitrate and ocular massage, but without visual recovery. No other associated systemic or local risk factors were found, and the case was classified as a potential complication of sildenafil. Conclusion: Although no direct link could be established, the aim of this report is to highlight the incidence and to consider this issue when evaluating any case of central retinal artery occlusion.

Assessment of commitment to healthy daily habits and diets, preventive measures, and beliefs about natural products utilization during COVID-19 pandemic in certain population in Egypt and Saudi Arabia.

Objective: The purpose of this research is to assess the commitment of participants in Saudi Arabia and Egypt towards healthy daily habits, preventive measures, healthy food habits, and beliefs about natural products as an immunostimulants during COVID-19 pandemic. Method: A cross-sectional questionnaire-based study was conducted in Saudi Arabia (mainly Riyadh and Jeddah) and Egypt (mainly Cairo). The questionnaire instrument was created based on an extensive literature review on the COVID-19 pandemic, including its spreading and transmission methods, preventive measures, healthy lifestyle, and diets that increase human immunity against viral infections and the use of natural products and drinks. The questionnaire was created by Microsoft 365® office forms, participants were invited through emails and other social media. The questionnaire includes a demographic section (gender, nationality, residency country, city, age, marital status, educational level, employment status, chronic disease history, under anxiety or stress, have a temper or irritable person, were infected/currently infected and in contact to COVID-19 patient) and (23) questions arranged under five domains; Domain I daily habits (4), Domain II keeping preventive measures (4), Domain III healthy eating habits (9), Domain IV for participants currently or previously infected, or in contact with a patient (4) Domain V for assessment of participants' beliefs towards the use of natural products to elevate immunity during COVID-19 pandemic (2), beside 4 choice questions (stimulant drinks, natural drinks, natural products, and zinc-rich food). SPSS® was used to analyze the results using Student' t-test, ANOVA, and Tukey's HSD tests. Result: 510 individuals with various demographic characteristics participated in the study. This study revealed that the participants belief in healthy foods, natural drinks (mainly ginger, lemon, and cinnamon), natural products (mainly honey, olive oil, and black seed), healthy habits, and preventive measures as sanitizers, social distance, and exercise. Only 13% of all participants were infected with COVID-19, although 31% of them were in contact with COVID -19 patients, about 93% were under stress, and 22% were with chronic diseases. Participants who are married, not in contact with patients and not previously infected by COVID-19 are more adhered to preventive measures while those previously or currently infected are more committed to healthy lifestyle and diet habits. Qualification level seems to make no significant difference in any domain. 78.6% of the participants beliefs in the benefits of utilizing natural products in preventing infection with corona virus or reducing the period of treatment in case of infection. About 95.7% of the infected persons had no need of hospitalization and about 50% are cured within two weeks of infection. The questionnaire revealed that Nescafe and black tea were the most used stimulant drinks among the participants, particularly the students and who were always under stress. Most of the participants agreed with the utilization of Zn-rich food, particularly Egyptians, which may help in boosting their immunity. Conclusion: Natural products selected in the present study can be used in combination with the existing clinical standards of care that have the potential to serve as prophylactic agents in populations that are at risk to develop COVID-19 infection.