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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.

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.

Background A methodical approach to health services called "quality of care" places an emphasis on both interpersonal and technical competence in the delivery of medical care. One of the key elements of high-quality care is the client's or patient's satisfaction, which includes treating them with respect, being aware of their needs, and meeting those needs. Dermatologists are forced to expand service availability and respond to patients' needs and desires as required through satisfaction surveys as a result of an increase in the number of insured patients and demand for services. Methods A cross-sectional study was conducted in Saudi Arabia to measure patient satisfaction with the medical care provided to patients in dermatology clinics affiliated with the government and private hospitals by recording the responses received from a questionnaire assessing the doctor's attitude, such as whether the dermatologist was punctual and had the patient's medical records. The modified Arabic language digitally administered questionnaire with 17 closed-ended items was used to collect data from respondents. Results In total, 1002 patients, including 70.76% females and 29.24% males, participated in the study; 83.33% of patients visited a dermatology clinic of which 74.61% visited private clinics, and the disease had already developed in 64.55% of patients. A 5-point Likert scale with six statements was used to measure patient satisfaction with the visiting doctor. Overall, the mean score was very high (4.41 ± 0.92). Conclusion According to the results of this study, respect for patients' wishes, emotional support, and physical comfort appear to be the most crucial factors in determining patient happiness. Healthcare systems should strive to achieve a balance in services that not only offer clinically effective care but are also perceived by the patients as acceptable and beneficial. This is true regardless of demographic status.

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.

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

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 (

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 β-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.

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. Keywords: Liraglutide, Cardiotoxicity, Gefitinib, Antioxidant, MAPK, Cardioprotection

Estimates from epidemiological studies indicate the high global prevalence of seizures in children. They can be associated with different complications that might even be life-threatening. Different risk factors have been reported to increase the risk and severity of seizures, like metabolic disorders, infections, and reduced access to needed care. Therefore, providing appropriate management is essential to enhance the prognosis of these cases. In the present article, we conducted a literature review to shed more light on identifying, diagnosing, and managing seizures in children. The identification process depends on different factors, including obtaining an adequate history from the patient or their caregivers, performing a thorough general and neurological examination, and conducting appropriate investigations whenever needed. It should be noted that in severe cases, these approaches should be made promptly not to delay the management approaches, which can be life-saving. Reassuring family attendants is also recommended. Besides, increasing awareness among these families about the diagnosis, identification, prognosis, reporting, and responding to seizures might reduce the risk of recurrence and enhance the prognosis of seizures. Choosing a treatment strategy is usually based on different factors, including the child's age, epilepsy type, family preferences, the presence of comorbidities, and ability to administer medications. For recurrent seizures, home-based medications, like rectal diazepam or buccal midazolam, might also be used to lower the risk of recurrence and reduce the intensity of seizures.

Bacterial cystitis accounts for the majority of urinary tract infection (UTI). It is frequently found in young, otherwise healthy females showing no signs of anatomical or physiological urinary tract defects. Among young women who have experienced an episode of acute bacterial cystitis, 25% to 50% develop recurrent episodes. Individuals with recurrent cystitis episodes have a greater susceptibility to urogenital colonization with uropathogens that thrive by adhering to uroepithelial cells. Further, there is an increased likelihood of infection with an antibiotic resistant uropathogen due to previous antimicrobial therapy for recurring infections. At each step of the pathogenesis, different host genetic, biologic, and behavioral factors, and bacterial factors interact and influence susceptibility to recurrent cystitis. Behavioral factors like sexual intercourse, use of spermicidal contraceptives and history of recurrent cystitis are major independent risk factors for recurrent cystitis infections. In post-menopausal women without comorbidities, estrogen depletion is mainly responsible for increased susceptibility to recurrent cystitis. Certain strain-specific bacterial virulence determinants may also contribute to recurrent cystitis by providing a selective advantage. Phenotypically, recurrent cystitis is categorized as reinfection or bacterial persistence. Majority of recurrent cystitis cases seen in men occur due to structural or functional abnormalities of the urinary bladder which allows same pathogens from the same site in the bladder to cause recurrences due to bacterial persistence. The concept of ‘uncomplicated’ and ‘complicated’ recurrent cystitis is used for classification of recurrent cystitis cases, similar to UTIs. Uncomplicated recurrent cystitis comprises cases occurring in young, healthy, nonpregnant women, mainly due to uropathogenic Escherichia coli. Due to the unique spectrum of host-bacterial interactions in the urinary tract, the distinction between complicated and uncomplicated recurrent cystitis is not straightforward. ‘Complicating’ factors such as structural, obstructive, neoplastic, functional, and neurological abnormalities of the urinary tract, systemic conditions including pregnancy, and certain demographic factors are attributed in the development of complicated recurrent bacterial cystitis.

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.

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 IC

Autism is a neurodevelopmental disorder characterized by deficits and qualitative impairments in communication and implicit skill learning. Its prevalence is higher than previous estimates, and treatments have limited efficacy and are costly. Here, we assessed the therapeutic potential of JNJ77777120 (JNJ), a histamine-4 receptor (H4R) antagonist, using BTBR T+ Itpr3tf/J (BTBR) mice, a confirmed model of autism, and C57BL/6J (C57) mice, a commonly chosen reference strain. We first examined the effects of JNJ treatment on BTBR mice exposed to gamma-rays (irradiation-exposed) using a three-chambered apparatus. We further investigated the possible molecular mechanisms through which JNJ administration modulates IL-17A-, RORγT-, IL-22-, T-bet-, STAT3-, ICOS-, and Foxp3-producing CD8+ T cells in the spleens of irradiation-exposed BTBR mice. The effects of JNJ administration on the mRNA and protein expression of IL-17A, RORγT, IL-22, T-bet, STAT-3, pSTAT3, IL-10, and Foxp3 in brain tissue were also explored. Results showed that JNJ treatment with irradiation exposure increased social interactions in BTBR mice compared to that in irradiation-exposed BTBR mice. Additionally, JNJ-treated and irradiation-exposed BTBR mice exhibited decreases in IL-17A-, RORγT-, IL-22-, T-bet-, and STAT3-producing CD8+ T cells and increases in ICOS- and Foxp3-producing CD8+ T cells. Moreover, JNJ treatment and irradiation exposure in BTBR mice regulated the mRNA and protein expression levels of IL-17A, RORγT, IL-22, T-bet, STAT3, pSTAT-3, IL-10, and Foxp3 in the brain tissue. These results suggest that JNJ is useful for the treatment of autism, as this H4R antagonist could block inflammatory cytokine production and transcription factor signaling.

The rate of obesity is on rise worldwide and almost 13% of the global population is obese leading to development of various other diseases and complications. Lack of effective outcome from conventional approach for weight control and loss is causing a transition among people to approach for bariatric surgeries. Sleeve gastrectomy is one of the surgical techniques of bariatric surgery aimed to achieve weight loss. Like any other surgical procedure, it also has certain post-operative complications associated with it. The complications of sleeve gastrectomy are further divided into early and late phase. The purpose of this research is to review the available information about early and late complication of sleeve gastrectomy. In the surgical treatment of morbid obesity, sleeve gastrectomy is the most widely performed bariatric procedure. It is a minimally invasive and risk-free surgery with a low risk of complications and death. The complication rates for early and late complication range from 5.4% to 7.3%, with incidence of serious complications ranging from 1.2% to 2.2%. Early complications include bleeding such as intraluminal or extraluminal, a leak in the staple line, and the formation of an abscess. While gastric stenosis, nutritional shortages, mediastinal pouch migration, and the development or worsening of gastroesophageal reflux disease are all late consequences. Older age, male sex, increased body mass index, smoking, and comorbidities are considered the risk factors for the development of complications of sleeve gastrectomy. Overall, sleeve gastrectomy is considered a safe and effective surgical weight loss technique.

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-β-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.

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.

Background: Cardiovascular disease is a leading cause of death in diabetic patients. Hyperglycemia and iatrogenic hypoglycemia 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. In the present study, we aimed to find the role of carnitine in the regulation of hypoglycemia-induced hypertension and cardiac hypertrophy. Methods: Albino Wistar male rats were divided into six groups. The, first three groups received saline (n= 5), D-carnitine (n= 5) at dose of 500mg/kg/day, intraperitoneal for carnitine depletion, or acetyl-L-carnitine (n= 5) at a dose of 300mg/kg/day, intraperitoneal for carnitine supplementation for 15 days. In the last three groups, rats had pretreatment conditions for 5 days with saline, D-carnitine or acetyl-L-carnitine. Then, they were treated with insulin glargine (InG) for 10 days with saline (n= 6), D-carnitine (n= 5) or acetyl-L-carnitine (n= 6), respectively. Results: Our results showed that carnitine deficiency provoked hypoglycemia-induced hypertension. Mean arterial pressure was elevated from 78.16 ± 4.67 to 100 ± 2.09 mmHg in InG treated group, and from 78.2 ± 3.8 to 123.4 ± 12.6 mmHg in InG+D-carnitine treated group. Acetyl-L-carnitine resisted the elevation in blood pressure in all hypoglycemic animals and kept it within the normal values (68.33 ± 6.7 mmHg). In heart, acetyl-L-carnitine increased myocardial carnitine content leading to the attenuation of hypoglycemia-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 transferase. Moreover, acetyl-L-carnitine prevented induction of cardiac hypertrophy during hypoglycemic conditions, which was assessed via the evaluation of mRNA expression of the cardiac hypertrophy biomarkers, α-myosin heavy chain and β-myosin heavy chain. Conclusions: These findings demonstrate that carnitine plays an essential role in providing energy and antioxidants to the cardiovascular system leading to the prevention of hypoglycemia-induced hypertension and cardiac hypertrophy.

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.

Neuroinflammation has been observed in association with neurodegenerative diseases including Alzheimer’s disease (AD). In particular, a positive correlation has been documented between neuroinflammatory cytokine release and the progression of the AD, which suggests these cytokines are involved in AD pathophysiology. A histological hallmark of the AD is the presence of beta-amyloid (Aβ) plaques and tau neurofibrillary tangles. Beta-amyloid is generated by the sequential cleavage of beta (β) and gamma (γ) sites in the amyloid precursor protein (APP) by β- and γ-secretase enzymes and its accumulation can result from either a decreased Aβ clearance or increased metabolism of APP. Previous studies reported that neuroinflammatory cytokines reduce the efflux transport of Aβ, leading to elevated Aβ concentrations in the brain. However, less is known about the effects of neuroinflammatory mediators on APP expression and metabolism. In this article, we review the modulatory role of neuroinflammatory cytokines on APP expression and metabolism, including their effects on β- and γ-secretase enzymes.

Autism is a neurodevelopmental disorder characterized by qualitative impairment in communication, social interaction, and repetitive stereotypic behavior. Resveratrol plays a role in several disorders such as neuroimmune, autoimmune, and allergic disorders. BTBR T+ Itpr3tf/J (BTBR) mice, a model for autism, show several behavioral deficits that are physiological characteristics similar to those observed in patients with autism. Previous studies have shown that JAK-STAT signaling pathway is associated with many neurodevelopmental disorders. We investigated the possible role of resveratrol on IL-6+, TNF-α+, IFN-γ+, and STAT3+ in CD4+ T spleen cells in BTBR mice as compared to C57BL/6J mice. We also assessed the effect of resveratrol treatment on IL-6, TNF-α, IFN-γ, JAK1, and STAT3 mRNA expression levels in the brain tissue. We further assessed IL-6, IFN-γ, TNF-α, phosphorylated (p) JAK1, and pSTAT3 (Tyr705) protein expression levels in the brain tissue. Resveratrol (20 and 40 mg/kg)-treated mice had significantly decreased in IL-6+, TNF-α+, IFN-γ+, and STAT3+ in CD4+ spleen cells as compared with BTBR control mice. Resveratrol treatment also decreased IL-6, TNF-α, IFN-γ, JAK1, and STAT3 mRNA expression levels as compared with BTBR control mice in the brain tissue. Moreover, resveratrol treatment resulted in decreased protein expression levels of IL-6, IFN-γ, TNF-α, pJAK1, and pSTAT3 (Tyr705) as compared with BTBR control mice in the brain tissues. Taken together, these results indicate the efficacy of resveratrol in reducing cytokines and JAK-1/STAT3 signaling in BTBR mice, which is a novel and important finding and might be important for future therapies in neuroimmune dysfunction.

Feeding animals glucose, fructose, sucrose, and fat-enriched diets can lead to diet-induced hyperglycemia, severity of which largely depends on type and concentration of nutrients used and length of dietary intervention. As a strategy of dietary intervention, we adopted glucose-enriched diet, drinking water, and intraperitoneal (i.p.) glucose injection at the dose previously determined to be effective to establish a sustained hyperglycemia over a period of 2 weeks. In our current study, we used 4 groups of Sprague Dawley rats: control, glucose-treated, glucose+tempol, and glucose+captopril-treated groups. Our study demonstrated that glucose levels gradually started to increase from day 3, and reached to the highest levels (321 mg dl−1) at day 12 and maintained similar levels until the end of the study on day 14 in glucose treated-group compared to control. However, tempol- and captopril-treated groups showed significantly high glucose levels in only second week. Plasma insulin level has been significantly increased in glucose-treated animals but not in tempol- and captopril-treated groups when compared to control. We also observed elevated blood pressure (BP) in glucose-treated group compared to control, which can be attributed to increased Ang II production from 46.67 pg.ml−1 to 99 pg.ml−1 (control vs. glucose), increased oxidative stress in cortical proximal tubule (PT), decreased urine flow, and increased expression and activity of PT-specific α1-subunit of Na+-K+-ATPase in renal cortex, the latter is responsible for increased sodium reabsorption from epithelial cells of PT into peritubular capillaries, leading to increased blood volume and eventual blood pressure. All these events are reversed in captopril- and tempol-treated animals. This article is protected by copyright. All rights reserved

Four new phosphanegold(I) complexes; [Au{(o-MeO-Ph)3P}Cl] (1), [Au{(o-MeO-Ph)3P}{(Me-Et-Ph)P}]Cl (2), [Au{(o-MeO-Ph)3P}(Ph3P)]Cl (3) and [Au{(o-MeO-Ph)3P}2]Cl (4) (where o-MeO-Ph)3P = tris(o-methoxyphenyl)phosphane and (Me-Et-Ph)P = methylethylphenylphosphane) were prepared and characterized by elemental analysis, FTIR and NMR spectroscopy. The structure of one of the complexes was determined by X-ray crystallography, which showed that the gold(I) atom is linearly coordinated to the phosphorus and Cl atoms. The in vitro cytotoxicity of the complexes was investigated against four human cancer cell lines; A549, HeLa, MDA-MB-231 and MCF7. In all cases, the tested complexes showed excellent cytotoxicity for the selected cells, with IC50 values much less than cisplatin. In order to know the possible mode of cell death, complex 1 was further evaluated for induction of apoptosis towards the A549 cells. The results indicated that the apoptosis induction increases with the complex concentration.

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).

Gallstones are still one of the most common cause with epidemiological patterns indicating an increasing incidence. The surgical approaches of acute gallstone pancreatitis were discussed in this review. PubMed, Embase, and Google scholar databases were searched up to April, 2019 for published studies with English language and human subjects discussing the management of Acute pancreatitis and surgical approaches. Surgical procedure has a really limited role in the medical diagnosis of acute pancreatitis. One of the most typical signs for treatment in acute pancreatitis is for the therapy of issues and most significantly the therapy of infected walled off necrosis. Other indicators for surgical procedure in acute pancreatitis are for the therapy of acute area disorder, non-occlusive intestinal ischaemia and necrosis, enterocutaneous fistulae, vascular complications and pseudocyst. Surgical procedure also has a role in the avoidance of recurrent acute pancreatitis by cholecystectomy. Despite the more restricted role, doctors have an important contribution to make in the multidisciplinary care of patients with complicated acute pancreatitis.

Background Placenta previa is defined the growth of the placenta at the lower uterine segment near or over internal cervical os. A lot of literature. In the recent a lot of articles were done in order to provide the patients with better outcomes. Objective This study aims to evaluate the recent updates regarding placenta previa risk factors, clinical presentation, diagnosis and management. Methods PubMed database was used for articles selection, and the following keys used in the mesh {Placenta previa, Management, risk factors and diagnosis}. A total of 6 articles were enrolled according to our inclusion and exclusion criteria. Conclusion Placenta previa start to appear at the second and third trimester, physicians should be able to identify the condition during the routine ultrasound scan or at sudden presentation in order to provide the best outcomes for the patients. In addition, Placenta previa patients should be educated well about their condition. As a general idea caesarean section is method of choose for delivery.

COVID-19 causes a wide range of clinical symptoms. COVID-19 hematologic and cardiovascular involvement induces thromboembolic symptoms in various organs, most notably venous thromboembolism (VTE); peripheral arterial involvement is uncommon. Acute limb ischemia (ALI) is a vascular emergency known as a dramatic drop in arterial perfusion of a limb that poses a challenge to the limb's viability. Given routine need for thromboprophylaxis, hospitalised COVID-19 patients are at an elevated risk of ALI, limb loss, or even mortality. Understanding the various specific symptoms of COVID-19 patients, especially extrapulmonary manifests, is crucial for both better patient care and the development of adequate infection prevention methods. Although ALI is a complication of COVID-19 in hospitalized patients, it is now being understood that it can arise in patients with mild COVID-19 symptoms, and that ALI can be the first presenting sign of COVID-19 even in the absence of respiratory symptoms. It is recommended that acutely admitted COVID-19 cases should be given pharmacologic thromboprophylaxis with low molecular weight heparin (LMWH) or fondaparinux unless there is a chance of bleeding or contraindicated. Anticoagulant treatment, primarily with LMWH, correlates strongly with an improved prognosis in serious COVID-19 patients who follow sepsis-induced coagulopathy requirements or have significantly elevated D-dimer levels.

Acute lung injury (ALI) is one of the most serious complications in critically ill patients which often leads to morbidity and mortality. ALI characterized by severe inflammation of lungs occurs due to uncontrolled inflammatory immune response. However, the immunological mechanism(s) are far from being understood. The spleen tyrosine kinase (SYK), a key component of immune receptor signaling, plays a critical role in the modulation of inflammatory signaling in different immune cells. However, its role in ALI remains to be explored. Therefore, in this study, we investigated the effect of R406, a SYK inhibitor in lipopolysaccharide (LPS)-induced ALI mouse model. LPS led to increased SYK expression in neutrophils and gamma delta (γδ) T cells. This was associated with increased neutrophilic airway inflammation, vascular permeability, myeloperoxidase activity in the lung with upregulated expression of NADPH oxidase (NOX2)/MCP-1/TNF-α in neutrophils and IL-17A in γδ T cells/lung. Pulmonary inflammation was associated with higher mortality in mice with ALI. Inhibition of SYK signaling using R406 in the lung led to blockade of neutrophilic airway inflammation, vascular permeability, pro-inflammatory cytokine release and oxidative stress in innate immune cells, i.e. γδ T cells and neutrophils and the lung. R406 administered LPS group had better survival rate than LPS group. This suggests that SYK upregulation in γδ T cells and neutrophils plays an important role in inflammatory process during ALI. In conclusion, R406 exhibited a great potential to block the LPS-induced airway inflammation and mortality which could be developed as a potential future therapy in ALI.

Background: Breast cancer is affected by the immune system in that different cytokines play roles in its initiation and progression. Interleukin-10 (IL-10), an anti-inflammatory cytokine, is an immunosuppressive factor involved in tumorigenesis. The present study was conducted to investigate the gene silencing effect of a small interference RNA (siRNA) targeting IL-10 on the apoptotic pathway in breast cancer cell line. Methods: The siRNA targeting IL-10 and a glyceraldehyde 3-phosphate dehydrogenase (GAPDH) clone were introduced into MDA-MB-231 cells. Real-time PCR assays were used to determine IL-10 and GAPDH gene expression levels, in addition to those for protein kinase B (AKT), phosphoinositide 3-kinase (PI3K), B-cell lymphoma 2 (Bcl2), caspase-3 and caspase-9 genes related to apoptosis. Results: Inhibition of IL-10 by the siRNA accelerated apoptosis and was accompanied by significant increase in caspase-3 and caspase-9 and a significant decrease in PI3K, AKT and Bcl2 expression levels compared to the non-transfected case. Conclusions: In conclusion, the production of IL-10 may represent a new escape mechanism by breast cancer cells to evade destruction by the immune system. IL-10 gene silencing causes down regulation of both PI3K/AKT and Bcl2 gene expression and also increases the Bbc3, BAX caspase3, and caspase 3 cleavage expression levels. IL–10 might represent a promising new target for therapeutic strategies.