The effect of inhibiting hindbrain A2 noradrenergic neurons by 6-Hydroxydopamine on lipopolysaccharide-treated male rats autistic animal model.

Autism spectrum disorder (ASD) is a complex neurodevelopmental illness that often emerges in early childhood. The incidence of ASD has shown a notable rise in recent years. ASD is defined by deficits in social communication, and presence of rigid and repetitive behaviors and interests. The underlying mechanisms of ASD remain elusive. Multiple studies have documented the presence of neuroinflammation and increased levels of inflammatory cytokines, specifically, IL-6, TNF, and NF-κB, in various brain regions, including the prefrontal cortex (PFC) and hippocampus in individuals with ASD. Noradrenergic neurons play a crucial role in brain development and the regulation of motor, behavioral, and memory functions. This study sought to examine the impact of intracerebroventricular (icv.) injection of the neurotoxin, 6-hydroxydopamine (6-OHDA), in the caudal dorsal vagal complex A2 neurons on various neuroinflammatory pathways at the hippocampus and PFC in valproic acid (VPA) autistic animal model. This was done in conjunction with an intraperitoneal (i.p.) injection of Lipopolysaccharides (LPS) in animal models with VPA-induced autism. We specifically examined the impact of the caudal fourth ventricle 6-OHDA icv. injection and LPS (i.p.) injection on self-grooming behavior. We measured the mRNA expression of IL-6, TNF-a, and NF-κB using qRT-PCR, and the protein expression of COX-2, GPX-1, p-AMPK, and AMPK using western blot analysis. The self-grooming activity was considerably higher in the combined treatment group (6-OHDA icv. + LPS i.p.) compared to the control group. A substantial increase observed in the expression of IL-6, TNF-α, and NF-κB genes in the PFC of the treatment group that received icv. Administration of 6-OHDA, compared to the control group. The VPA-autism rats that received the combo treatment exhibited a slight increase in the expression level of NF-κB gene in the hippocampus, compared to the control group. At the PFC, we noticed a substantial drop in the expression of the antioxidant protein GPX-1 in the group that received the combo treatment compared to the control group. Our data investigates a novel aspect that the 6-OHDA-induced inhibition of hindbrain A2 neurons could be influencing the neuroinflammatory pathways in the PFC and hippocampus of autistic animal models.

Awareness of Carpal Tunnel Syndrome Among the Adult Population in Northern Saudi Arabia.

Background Carpal tunnel syndrome (CTS) is the most prevalent entrapment neuropathy affecting the upper limb. It is recognized as a complex condition that is attributed to both non-medical and medical risk factors. Lack of awareness leads to delays in seeking advice, diagnosis, and treatment.  Objective To determine the awareness of CTS, its associated symptoms, signs, and risk factors among the adult population. Subjects and methods A cross-sectional study design was carried out among the adult population in Arar city, Northern Saudi Arabia.  Results In total, 338 respondents participated in this study. More than one-third (40.8%) mentioned that median nerve entrapment is a cause of CTS. The most commonly cited risk factor by the respondents was engaging in physical tasks such as using a computer (53%). Additionally, 60% of participants agreed that symptoms of CTS include tingling and numbness in the thumb, index, and middle fingers. Conclusion The findings of the study indicated a lack of adequate community awareness about CTS among the studied population.

Carfilzomib Mitigates Lipopolysaccharide/D-Galactosamine/Dimethylsulfoxide-Induced Acute Liver Failure in Mice.

Acute liver failure (ALF) is a disease accompanied by severe liver inflammation. No effective therapy is available yet apart from liver transplantation; therefore, developing novel treatments for ALF is urgently required. Inflammatory mediators released by NF-кB activation play an essential role in ALF. Proteasome inhibitors have many medical uses, such as reducing inflammation and NF-кB inhibition, which are believed to account for most of their repurposing effects. This study was undertaken to explore the possible protective effects and the underlying mechanisms of carfilzomib, a proteasome inhibitor, in a mouse model of ALF induced by lipopolysaccharide/D-galactosamine/dimethylsulfoxide (LPS/GalN/DMSO). Carfilzomib dose-dependently protected mice from LPS/GalN/DMSO-induced liver injury, as indicated by the decrease in serum alanine aminotransferase and aspartate aminotransferase levels. LPS/GalN/DMSO increased TNF-α, NF-кB, lipid peroxidation, NO, iNOS, cyclooxygenase-II, myeloperoxidase, and caspase-3 levels. Carfilzomib administration mitigated LPS/GalN/DMSO-induced liver damage by decreasing the elevated levels of TNF-α, NF-кB, lipid peroxidation, nitric oxide, iNOS, cyclooxygenase-II, myeloperoxidase, caspase-3, and histopathological changes. A restored glutathione level was also observed in the carfilzomib-treated LPS/GalN/DMSO mice. Our results demonstrate that carfilzomib protects against LPS/GalN/DMSO-induced ALF by inhibiting NF-кB, decreasing inflammatory mediators, oxidative/nitrosative stress, neutrophil recruitment, and apoptosis, suggesting that carfilzomib may be a potential therapeutic agent for ALF.

Impacts of the DPP-4 Inhibitor Saxagliptin and SGLT-2 Inhibitor Dapagliflozin on the Gonads of Diabetic Mice.

Diabetes mellitus is a metabolic disease that can cause systemic problems, including testicular dysfunction. Several diabetes medications have demonstrated potential adverse effects on the male reproductive system; however, the effects of saxagliptin and dapagliflozin have not been sufficiently examined. This investigation studied the impacts of saxagliptin and dapagliflozin treatments on the gonads in a male mouse model of diabetes. Testicular disturbances were assessed by sperm DNA damage, diakinesis-metaphase I chromosome examination, and spermiogram analysis. Our results showed more sperm DNA damage, more spermatocyte chromosome aberrations, lower sperm motility/count, and more sperm morphological anomalies in diabetic mice than in the control mice. Dapagliflozin significantly restored all examined measures to the control values in diabetic mice, unlike saxagliptin, which exacerbated the reduction in sperm count and motility. Both drugs significantly restored the gonadal redox imbalances in diabetic mice by decreasing reactive oxygen species accumulation and increasing glutathione levels. In conclusion, our study presents preliminary evidence for the safety and efficacy of dapagliflozin in alleviating testicular abnormalities induced by diabetes, making it a promising candidate drug for patients with diabetes in their reproductive age. As saxagliptin may have negative effects on fertility, its prescription should be avoided in young male diabetic patients.

Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model.

Tivozanib is a triple vascular endothelial growth factor receptor inhibitor, recently approved for the treatment of refractory advanced renal cell carcinoma. Clinical studies showed that around 46% of patients who received tivozanib suffer from hypertension in all grades. Thus, the present study was conducted to identify the role of angiotensin-II (AngII) in the mechanism underlying tivozanib-induced vascular toxicity and hypertension. C57BL/6 male mice received tivozanib (1 mg/kg) with or without losartan (10 or 30 mg/kg) for 3 weeks. Blood pressure was recorded every 3 days, and proteinuria was measured every week. On day 21, all mice were euthanized, and samples were harvested for further analysis. Tivozanib elevated blood pressure until systolic blood pressure reached 163 ± 6.6 mmHg on day 21 of treatment with low urination and high proteinuria. AngII and its receptors, endothelin-1, and oxidative stress markers were significantly increased. While nitric oxide (NO) levels were reduced in plasma and aortic tissues. AngII type 1 receptor blockade by losartan prevented these consequences caused by tivozanib and kept blood pressure within normal range. The results showed that AngII and ET-1 might be potential targets in the clinical studies and management of hypertension induced by tivozanib.

Dapagliflozin Mitigates Hypotension in Lipopolysaccharide-Induced Acute Inflammation Independent of Glycemia Level.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been suggested to have anti-inflammatory properties in diabetes. The goal of this study was to evaluate the role of the SGLT2 inhibitor dapagliflozin (DAPA) in the attenuation of lipopolysaccharide (LPS)-induced hypotension. Male Wistar albino rats were divided into normal and diabetic groups and received DAPA (1 mg/kg/day) for two weeks followed by a single dose of 10 mg/kg LPS. Blood pressure was recorded throughout the study and the circulatory levels of cytokines were assessed using a multiplex array, while the aortas were harvested for analysis. DAPA attenuated the vasodilation and hypotension caused by LPS. Mean arterial pressure (MAP) was preserved in the normal and diabetic DAPA-treated septic groups (MAP = 83.17 ± 5.27, 98.43 ± 5.57 mmHg) compared to the vehicle-treated septic groups (MAP = 65.60 ± 3.31, 68.21 ± 5.88 mmHg). Most of the cytokines induced by LPS were decreased in the DAPA-treated septic groups. In the aorta, the inducible nitric oxide synthase-derived nitric oxide had lower expression in the DAPA-treated rats. In contrast, the expression of α-smooth muscle actin, a marker of the vessel's contractile state, was higher in the DAPA-treated rats in comparison with non-treated septic rats. These findings revealed that the protective role of DAPA against LPS-induced hypotension is likely to be glucose-lowering independent, as was observed in the non-diabetic septic group. Taken together, the results show that DAPA has a potential effect in the prevention of the hemodynamic disturbances of sepsis regardless of glycemia levels.

Exposure to Methylmercury at Juvenile Stage Worsens Autism-like Symptoms in Adult BTBR T+tf/J Mice Due to Lack of Nuclear Factor Erythroid 2-Related Factor 2 Signaling Upregulation in Periphery and Brain.

Autism spectrum disorder (ASD) is a multifaceted developmental condition that first appears in infancy. The condition is characterized by recurrent patterns in behavior and impairments in social and vocalization abilities. Methylmercury is a toxic environmental pollutant, and its derivatives are the major source of organic mercury to human beings. Inorganic mercury, which is released from a variety of pollutants into oceans, rivers, and streams, is transformed into methylmercury by bacteria and plankton in the water, which later builds up in fish and shellfish, and then enters humans through the consumption of fish and shellfish and increases the risk of developing ASD by disturbing the oxidant-antioxidant balance. However, there has been no prior research to determine the effect of juvenile exposure of methylmercury chloride on adult BTBR mice. Therefore, the current study evaluated the effect of methylmercury chloride administered during the juvenile stage on autism-like behavior (three-chambered sociability, marble burying, self-grooming tests) and oxidant-antioxidant balance (specifically Nrf2, HO-1, SOD-1, NF-kB, iNOS, MPO, and 3-nitrotyrosine) in the peripheral neutrophils and cortex of adult BTBR and C57BL/6 (B6) mice. Our results show that exposure to methylmercury chloride at a juvenile stage results in autism-like symptoms in adult BTBR mice which are related to a lack of upregulation of the Nrf2 signaling pathway as demonstrated by no significant changes in the expression of Nrf2, HO-1, and SOD-1 in the periphery and cortex. On the other hand, methylmercury chloride administration at a juvenile stage increased oxidative inflammation as depicted by a significant increase in the levels of NF-kB, iNOS, MPO, and 3-nitrotyrosine in the periphery and cortex of adult BTBR mice. This study suggests that juvenile exposure to methylmercury chloride contributes to the worsening of autism-like behavior in adult BTBR mice through the disruption of the oxidant-antioxidant balance in the peripheral compartment and CNS. Strategies that elevate Nrf2 signaling may be useful to counteract toxicant-mediated worsening of ASD and may improve quality of life.

Valsartan prevents gefitinib-induced lung inflammation, oxidative stress, and alteration of plasma metabolites in rats.

Gefitinib (GEF) is an inhibitor of the epidermal growth factor receptor, linked to higher risk of severe/fatal interstitial lung disease (ILD). This study was performed to determine the protective roles of an angiotensin-II type-1 receptor (AT1R) "valsartan (VAL)" in prevention of lung inflammation, oxidative stress and metabolites alteration induced by GEF. Four groups of male Wistar albino rats were received vehicle, VAL (30 mg/kg), GEF (30 mg/kg), or both for four weeks. Blood samples and lungs were harvested for plasma metabolites and histological analysis, respectively, and evaluation of inflammation and oxidative stress. GEF monotherapy showed a dense inflammation in lungs, and significantly increased tumor necrosis factor-α (P = 0.0349), interleukin-6 (P < 0.0001), chemokine ligand-3 (P = 0.0420), and interleukin-1ß (P = 0.0377). GEF increased oxidative stress markers including glutathione, malondialdehyde, and catalase levels. Also, several plasma metabolites including butanoic acid, N-methylphenylethanolamine, oxalic acid, l-alanine, phosphoric acid, l-theorinine, pyroglutamic acid, and 2-bromosebacic acid were changed by GEF. The combination of VAL plus GEF reduced the inflammation and oxidative stress mediated by GEF monotherapy. In addition, the combination treatment returned plasma metabolites to the normal levels compared to GEF monotherapy. These findings revealed that VAL has a possible pulmonary protective role against pulmonary toxicity of GEF, which may lead to novel approaches for management of GEF-induced ILD.

Effect of Natural Adenylcyclase/cAMP/CREB Signalling Activator Forskolin against Intra-Striatal 6-OHDA-Lesioned Parkinson's Rats: Preventing Mitochondrial, Motor and Histopathological Defects.

Parkinson's disease (PD) is characterised by dopaminergic neuronal loss in the brain area. PD is a complex disease that deteriorates patients' motor and non-motor functions. In experimental animals, the neurotoxin 6-OHDA induces neuropathological, behavioural, neurochemical and mitochondrial abnormalities and the formation of free radicals, which is related to Parkinson-like symptoms after inter-striatal 6-OHDA injection. Pathological manifestations of PD disrupt the cAMP/ATP-mediated activity of the transcription factor CREB, resulting in Parkinson's-like symptoms. Forskolin (FSK) is a direct AC/cAMP/CREB activator isolated from Coleus forskohlii with various neuroprotective properties. FSK has already been proven in our laboratory to directly activate the enzyme adenylcyclase (AC) and reverse the neurodegeneration associated with the progression of Autism, Multiple Sclerosis, ALS, and Huntington's disease. Several behavioural paradigms were used to confirm the post-lesion effects, including the rotarod, open field, grip strength, narrow beam walk (NBW) and Morris water maze (MWM) tasks. Our results were supported by examining brain cellular, molecular, mitochondrial and histopathological alterations. The FSK treatment (15, 30 and 45 mg/kg, orally) was found to be effective in restoring behavioural and neurochemical defects in a 6-OHDA-induced experimental rat model of PD. As a result, the current study successfully contributes to the investigation of FSK's neuroprotective role in PD prevention via the activation of the AC/cAMP/PKA-driven CREB pathway and the restoration of mitochondrial ETC-complex enzymes.

Angiotensin II type 1 receptor blockade attenuates gefitinib-induced cardiac hypertrophy via adjusting angiotensin II-mediated oxidative stress and JNK/P38 MAPK pathway in a rat model.

Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR), used for the treatment of advanced or metastatic non-small cell lung cancer. Recently, studies proved that Gefitinib-induced cardiotoxicity through induction of oxidative stress leads to cardiac hypertrophy. The current study was conducted to understand the mechanisms underlying gefitinib-induced cardiac hypertrophy through studying the roles of angiotensin II (AngII), oxidative stress, and mitogen-activated protein kinase (MAPK) pathway. Male Wistar albino rats were treated with valsartan, gefitinib, or both for four weeks. Blood samples were collected for AngII and cardiac markers measurement, and hearts were harvested for histological study and biochemical analysis. Gefitinib caused histological changes in the cardiac tissues and increased levels of cardiac hypertrophy markers, AngII and its receptors. Blocking of AngII type 1 receptor (AT1R) via valsartan protected hearts and normalized cardiac markers, AngII levels, and the expression of its receptors during gefitinib treatment. valsartan attenuated gefitinib-induced NADPH oxidase and oxidative stress leading to down-regulation of JNK/p38-MAPK pathway. Collectively, AT1R blockade adjusted AngII-induced NADPH oxidase and JNK/p38-MAPK leading to attenuation of gefitinib-induced cardiac hypertrophy. This study found a pivotal role of AngII/AT1R signaling in gefitinib-induced cardiac hypertrophy, which may provide novel approaches in the management of EGFRIs-induced cardiotoxicity.

Acetyl-11-keto-ß-boswellic acid improves clinical symptoms through modulation of Nrf2 and NF-κB pathways in SJL/J mouse model of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is characterized by chronic autoimmune inflammation of central nervous system (CNS), i.e. brain and spinal cord. Autoimmune inflammation of the CNS and periphery causes demyelination of axons ultimately leading to clinical symptoms such as gait imbalance, lack of coordination and paraplegia. Innate immune cells such as dendritic cells and neutrophils play a critical role in the initiation and progression of MS through upregulation of oxidants. Two prominent pathways that play important role in regulation of oxidant-antioxidant balance are nuclear factor-erythroid factor 2-related factor 2(Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Nrf2-mediated upregulation of antioxidants counteracts NF-κB-mediated oxidant generation. Therefore, this study evaluated the effects of nutraceutical drug, acetyl-11-keto-ß-boswellic acid (AKBA) in relapsing remitting model of experimental autoimmune encephelomyelitis (EAE). Efficacy of AKBA was explored on clinical symptoms, Nrf2, hemeoxygenase-1 (HO-1), NF-κB, inducible nitric oxide synthase (iNOS) in CNS and periphery of SJL/J mice. Our results show that expression of p-NF-κB and iNOS is elevated, whereas expression of Nrf2 and HO-1 is decreased in CD11c + DCs and CNS, which is linked with appearance of clinical symptoms in immunized SJL/J mice. Treatment of immunized SJL/J mice with AKBA causes improvement of clinical symptoms and downregulation of inflammatory markers in CD11c + DCs (p-NF-κB, iNOS, and nitrotyrosine), and CNS (p-NF-κB, iNOS, nitrotyrosine,lipid peroxides, and total antioxidant capacity). Treatment of immunized SJL/J mice with AKBA also causes rectification of Nrf2 signaling in CD11c + DCs, and CNS. These results propose AKBA ameliorates EAE disease progression through rectification of Nrf2 signaling and attenuation of NF-κB pathway in RR model of EAE. Therefore, nutraceutical compound, AKBA may be therapeutically useful in RRMS.

Design, synthesis and molecular docking of new [1,2,4] triazolo[4,3-a]quinoxaline derivatives as anticancer agents targeting VEGFR-2 kinase.

Vascular endothelial growth factor receptor-2 (VEGFR-2) is critically involved in cancer angiogenesis. Blocking of VEGFR-2 signaling pathway proved effective suppression of tumor growth. Accordingly, two series of new triazoloquinoxaline-based derivatives were designed and synthesized as VEGFR-2 inhibitors. All in vitro cytotoxic activities of the synthesized compounds were evaluated against two human cancer cell lines (MCF-7 and HepG2). To confirm the potential mechanism of cytotoxicity, enzymatic assays against VEGFR-2 were estimated for all the target compounds. The results of VEGFR-2 inhibitory activity and cytotoxicity were in high correlation. Compound 22a exhibited the highest cytotoxic effect with IC50 values of 6.2 and 4.9 µM against MCF-7 and HepG2, respectively, comparing to sorafenib (IC50 = 3.53 and 2.18 µM). Such derivative showed the best VEGFR-2 inhibitory activity with an IC50 value of 3.9 nM, which is very close to that of sorafenib (IC50 = 3.13 nM). Moreover, compounds 22b, 23b, and 23e exhibited strong cytotoxic activity with IC50 values ranging from 11.7 to 15.3 µM. Also, these compounds showed promising VEGFR-2 inhibition with IC50 values of 4.2, 5.7, and 4.7 nM, respectively. In silico docking, ADMET, and toxicity studies were carried out for the synthesized compounds. The results revealed that some compounds have a good binding mode against VEGFR-2 and a high level of drug-likeness.

Identification of new [1,2,4]triazolo[4,3-a]quinoxalines as potent VEGFR-2 tyrosine kinase inhibitors: Design, synthesis, anticancer evaluation, and in silico studies.

Tumor angiogenesis is mainly regulated by VEGFR-2. In this study, a new series of [1,2,4]triazolo[4,3-a]quinoxaline based-derivatives has been designed and synthesized to develop new anti-proliferative and anti-VEGFR-2 members. Anti-proliferative activities of the synthesized compounds were tested against MCF-7 and HepG2 cell lines. Compound 19a exhibited the highest activity towards both MCF-7 and HepG2 cell lines (IC50 = 8.2 and 5.4 µM, respectively), compared to sorafenib (IC50 = 3.51 and 2.17 µM, respectively). Additionally, all compounds were screened to evaluate their effect as VEGFR-2 inhibitors. Compound 19a (IC50 = 3.4 nM) exhibited good activity compared to sorafenib (IC50 = 3.12 nM). Furthermore, compound 19a disrupted the HepG2 cell cycle by arresting the G2/M phase. Also, marked increase in the percentage apoptotic cells was achieved by compound 19a. The induced apoptotic effect of compound 19a in HepG2 cells was assured by increased pro-apoptotic marker (Bax) expression by 2.33-fold and decreased anti-apoptotic (Bcl-2) expression by 1.88-fold, resulting in an elevation of the Bax/Bcl-2 ratio in HepG2 cells. Comparing to the control cells, compound 19a induced an increase in expression of cleaved caspase-3 and caspase-9 by 2.44- and 2.69-fold, respectively. Finally, the binding modes of the target derivatives were investigated through docking studies against the proposed molecular target (VEGFR-2, PDB ID: 2OH4).

Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression of tumour propagation. Accordingly, two series of new 3-methylquinoxaline derivatives have been designed and synthesised as VEGFR-2 inhibitors. The synthesised derivatives were evaluated in vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the VEGFR-2 inhibitory activities of the target compounds were estimated to indicate the potential mechanism of their cytotoxicity. To a great extent, the results of VEGFR-2 inhibition were highly correlated with that of cytotoxicity. Compound 27a was the most potent VEGFR-2 inhibitor with IC50 of 3.2 nM very close to positive control sorafenib (IC50 = 3.12 nM). Such compound exhibited a strong cytotoxic effect against MCF-7 and HepG2, respectively with IC50 of 7.7 and 4.5 µM in comparison to sorafenib (IC50 = 3.51 and 2.17 µM). In addition, compounds 28, 30f, 30i, and 31b exhibited excellent VEGFR-2 inhibition activities (IC50 range from 4.2 to 6.1 nM) with promising cytotoxic activity. Cell cycle progression and apoptosis induction were investigated for the most active member 27a. Also, the effect of 27a on the level of caspase-3, caspase-9, and BAX/Bcl-2 ratio was determined. Molecular docking studies were implemented to interpret the binding mode of the target compounds with the VEGFR-2 pocket. Furthermore, toxicity and ADMET calculations were performed for the synthesised compounds to study their pharmacokinetic profiles.

Protective effect of valsartan against doxorubicin-induced cardiotoxicity: Histopathology and metabolomics in vivo study.

Doxorubicin (DOX) treatment has been associated with cardiotoxicity. Therefore, it is crucial to search for a therapeutic that can effectively mitigate DOX-induced cardiotoxicity. This study was conducted to investigate the protective effects of valsartan (VAL) against DOX-induced cardiotoxicity. Sprague-Dawley rats were divided into four treatment groups: Group I: Control, Group II: VAL (30 mg/kg, ip), Group III: DOX (15 mg/kg, ip), and Group IV: VAL + DOX (30 + 15 mg/kg, ip). All groups were treated every other day for 14 days. Blood was isolated for biochemical and metabolomics studies, and sections of the heart were also analyzed for histopathological and immunohistochemical alterations to detect changes in P53, BAX, BCL-2, and P62 expression. The combination of VAL + DOX resulted in a marked decrease in cardiac biomarker enzymes (aminotransferase and creatine phosphokinase) compared to DOX monotherapy. In addition, the histopathological examination of the VAL + DOX combination revealed a low percentage of fibrosis and inflammation. Immunohistochemical expression of p53 and BAX was significantly reduced, whereas BCL-2 expression was significantly increased in the VAL + DOX treatment group compared to DOX monotherapy. Also, the combination of VAL + DOX reverses the negative effect of DOX on nuclear p62 expression. Analysis of serum metabolites showed that DOX monotherapy reduced the number of several amino acids, whereas the combination of VAL + DOX restored these metabolic pathways. This study revealed the potential cardioprotective effect of VAL, which may provide novel and promising approaches for managing cardiotoxicity induced by DOX.

Role of carnitine in regulation of blood pressure (MAP/SBP) and gene expression of cardiac hypertrophy markers (α/ß-MHC) during insulin-induced hypoglycaemia: Role of oxidative stress.

Cardiovascular disease is a leading cause of death in diabetic patients. Hyperglycaemia and iatrogenic hypoglycaemia exacerbate several pathogenic mechanisms underlying hypertension and heart diseases. Carnitine is a potent endogenous antioxidant and cellular fatty acid transporter for antioxidative stress and energy production in the cardiovascular system. The current study aimed to find the role of carnitine in the regulation of hypoglycaemia-induced hypertension and cardiac hypertrophy. Male rats received insulin glargine (InG) to induce hypoglycaemia followed by D-carnitine or acetyl-L-carnitine for carnitine depletion or carnitine supplementation, respectively. The obtained results showed that carnitine deficiency provoked hypoglycaemia-induced hypertension. Mean arterial pressure was elevated from 78.16 ± 11.4 to 100 ± 5.11 mm Hg in InG treated group, and from 78.2 ± 8.5 to 123.4 ± 28.2 mm Hg in InG + D-carnitine treated group. Acetyl-L-carnitine resisted the elevation in blood pressure in all hypoglycaemic animals and kept it within the normal values (68.33 ± 6.7 mm Hg). Acetyl-L-carnitine increased myocardial carnitine content leading to the attenuation of hypoglycaemia-induced oxidative stress, which was evaluated through measurement of the oxidative stress biomarkers such as inducible nitric oxide synthase, NAD(P)H quinone dehydrogenase-1, heme oxygenase-I, and glutathione S-transferase. Moreover, acetyl-L-carnitine prevented induction of gene expression of cardiac hypertrophy markers during hypoglycaemic conditions, which was assessed via the evaluation of mRNA expression of α-myosin heavy chain and ß-myosin heavy chain. These findings demonstrate that carnitine might play an essential role in prevention of hypoglycaemia-induced hypertension and cardiac hypertrophy through providing energy and antioxidants to the cardiovascular system.

Bruton's tyrosine kinase inhibition attenuates oxidative stress in systemic immune cells and renal compartment during sepsis-induced acute kidney injury in mice.

Sepsis is a life-threatening condition which affects multiple organs including the kidney. Sepsis-induced acute kidney injury (AKI) is a major health burden throughout the globe. Pathogenesis of sepsis-induced AKI is complex; however, it involves both innate and adaptive immune cells such as B cells, T cells, dendritic cells (DCs), macrophages, and neutrophils. Bruton's tyrosine kinase (BTK) is reportedly involved in inflammatory and oxidative signaling in different immune cells, however its contribution with respect to sepsis-induced AKI has not been delineated. This study attempted to investigate the role of BTK and its inhibition on oxidizing enzymes NADPH oxidase (NOX-2) and inducible nitric oxide synthase (iNOS) in DCs, neutrophils, and B cells during AKI. Our data reveal that BTK is activated in DCs, neutrophils, and B cells which causes an increase in AKI associated biochemical markers such as serum creatinine/blood urea nitrogen, renal myeloperoxidase activity, and histopathological disturbances in renal tubular structures. Activation of BTK causes upregulation of NOX-2/iNOS/nitrotyrosine in these immune cells and kidney. Treatment with BTK inhibitor, Ibrutinib causes attenuation in AKI associated dysfunction in biochemical parameters (serum creatinine/blood urea nitrogen, renal myeloperoxidase activity) and oxidative stress in immune cells and kidney (iNOS/NOX2/lipid peroxides/nitrotyrosine/protein carbonyls). In summary, the current investigation reveals a compelling role of BTK signaling in sepsis-induced AKI which is evident from amelioration of AKI associated renal dysfunction after its inhibition.

Elucidation of the Molecular Mechanisms Underlying Sorafenib-Induced Hepatotoxicity.

Sorafenib is a small, orally-active multikinase inhibitor that is most frequently used for the management of renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine-resistant thyroid carcinoma. However, recent reports have associated sorafenib with hepatotoxicity that can limit its clinical application, although the mechanism of hepatotoxicity is still to be elucidated. Thus, our study was designed to explore the molecular mechanisms underlying sorafenib-induced hepatotoxicity in an in vivo model. Twenty male adult Wistar rats were randomly placed into two groups; the first group received an oral dose of normal saline (vehicle), and the second received sorafenib (30 mg/kg) once daily for twenty-one consecutive days. After twenty-one days, liver tissues and blood samples were used for gene expression, protein expression, and biochemical analysis. Sorafenib treatment resulted in markedly increased levels of alanine aminotransferase and alkaline phosphatase, which indicate the presence of liver damage. Additionally, sorafenib administration induced the inflammatory and oxidative stress marker NF-κB-p65, while antioxidant enzymes were attenuated. Moreover, sorafenib caused upregulation of both gene and protein for the apoptotic markers cleaved Caspase-3, Bax, and Bid, and downregulation of the antiapoptotic protein Bcl-2. In conclusion, our findings suggest that sorafenib administration is associated with hepatotoxicity, which might be due to the activation of oxidative stress and apoptotic pathways.

Liraglutide attenuates gefitinib-induced cardiotoxicity and promotes cardioprotection through the regulation of MAPK/NF-κB signaling pathways.

Gefitinib is an effective treatment for patients with locally advanced non-small cell lung cancer. However, it is associated with cardiotoxicity that can limit its clinical use. Liraglutide, a glucagon-like peptide 1 receptor agonist, showed potent cardioprotective effects with the mechanism is yet to be elucidated. Therefore, this study aimed to determine the efficiency of liraglutide in protecting the heart from damage induced by gefitinib. Adult male Wistar rats were randomly divided into control group, liraglutide group (200 µg/kg by i.p. injection), gefitinib group (30 mg/kg orally) and liraglutide plus gefitinib group. After 28 days, blood and tissue samples were collected for histopathological, biochemical, gene and protein analysis. We demonstrated that gefitinib treatment (30 mg/kg) resulted in cardiac damage as evidenced by histopathological studies. Furthermore, serum Creatine kinase-MB (CK-MB), N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac Troponin-I (cTnI) were markedly elevated in gefitinib group. Pretreatment with liraglutide (200 µg/kg), however, restored the elevation in serum markers and diminished gefitinib-induced cardiac damage. Moreover, liraglutide improved the gene and protein levels of anti-oxidant (superoxide dismutase) and decreased the oxidative stress marker (NF-κB). Mechanistically, liraglutide offered protection through upregulation of the survival kinases (ERK1/2 and Akt) and downregulation of stress-activated kinases (JNK and P38). In this study, we provide evidence that liraglutide protects the heart from gefitinib-induced cardiac damage through its anti-oxidant property and through the activation of survival kinases.

Bruton's tyrosine kinase inhibitor suppresses imiquimod-induced psoriasis-like inflammation in mice through regulation of IL-23/IL-17A in innate immune cells.

Psoriasis is an unchecked chronic inflammation characterized by thick, erythematous, and scaly plaques on the skin. The role of innate immune cells in the pathogenesis of psoriasis is well documented. Bruton's tyrosine kinase (BTK) has been reported to execute important signaling functions in innate immune cells such as dendritic cells (DCs) and gamma delta T cells. However, whether inhibition of BTK would lead to modulation of innate immune function in the context of psoriatic inflammation remains largely unexplored. In the present study, we investigated the effect of selective BTK inhibitor, PCI-32765 on inflammatory signaling in CD11c + DCs and gamma delta T cells in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our results show that IMQ treatment led to induction of p-BTK expression along with concomitant increase in inflammatory cytokines (IL-23, TNF-α) in CD11c + DCs in the skin. Preventive treatment with BTK inhibitor led to significant reversal in IMQ-induced inflammatory changes in CD11c + DCs of skin. Further, there was a significant decrease in dermal IL-17A levels and IL-17A + Î³Î´ + T cells after treatment with BTK inhibitor. Furthermore, short treatment of back skin with IMQ led to upregulated expression of p-BTK along with inflammatory cytokines in CD11c + DCs (IL-23, TNF-α) and IL-17A in γδ + T cells which were reversed by BTK inhibitor. Overall, our study proposes that BTK signaling serves a crucial signaling function in innate immune cells in the context of psoriatic inflammation in mice. Therefore, BTK might be a promising therapeutic target to treat psoriatic inflammation.