A novel disposable ultrasensitive sensor based on nanosized ceria uniformly loaded carbon nanofiber nanoceramic film wrapped on pencil graphite rods for electrocatalytic monitoring of a tyrosine kinase inhibitor capmatinib.

For the first time, we introduce a novel disposable and ultrasensitive sensing electrode made up of nanosized ceria uniformly loaded carbon nanofibers (CeNPs@CNF) sol-gel nanoceramic film (CF) wrapped on eco-friendly and inexpensive pencil graphite rods (PGRs) to explore their electro-catalytic detection of the anticancer drug capmatinib (CMB). The as-prepared CeNPs@CNF hybrid nanocomposite was described by XRD, SEM, TEM, HRTEM, and EDX analysis. The CV study clearly demonstrated that, the disposable CeNPs@CNF-CF/PGRE sensor exhibited excellent redox activities in the ideal probe [Fe(CN)6]3-/4-. Due to the outstanding electrochemical properties, larger electrochemically active surface area, and tremendous electro-catalytic activity of CeNPs@CNF, the reduction current of CMB on the CeNPs@CNF-CF/PGRE sensor is considerably higher than that of bare PGRE. The detection conditions, such as supporting electrolyte, pH of the buffer solution, amount of modifier, adsorption potential, and time, were studied and optimized. The sensing platform demonstrated high sensitivity (1.2 µA nM-1 cm-2), an ultralow detection limit (0.6 nM), and a wide linear range of 2.0 nM-400 nM of CMB compared to the bare PGRE. Additionally, the CeNPs@CNF-CF/PGRE sensor showed high selectivity, stability, and simple operation, which provided a promising alternative tool for fast detection of CMB in human body fluids with good recoveries.

Exploring the Enigmatic Link: Unraveling the Relationship Between Obesity and Cigarette Smoking Among Diverse College Students at Imam Mohammed Ibn Saud Islamic University in Riyadh, Saudi Arabia.

BACKGROUND: Obesity is defined as an excess of body fat. This medical condition frequently results in a high BMI and an increased risk of a variety of health problems, including diabetes, cardiovascular disease, and certain types of cancer. Cigarette smoking includes inhaling smoke created by the combustion of tobacco. It is linked to a variety of health issues, including lung cancer, heart disease, and respiratory ailments, and is a primary cause of preventable disease and premature death worldwide. The association between obesity and cigarette smoking is complex and incompletely understood. This study aims to investigate the intriguing association between obesity and cigarette smoking among diverse college students at Imam Mohammed Ibn Saud Islamic University in Riyadh, Saudi Arabia. METHODOLOGY: The study was conducted as an observational study, specifically an analytical cross-sectional study, to measure the prevalence of cigarette smoking and obesity and their association. This type of study is chosen because of its advantages including targeting a large sample in a short time and inexpensive way, with no loss to follow-up, unlike some other study designs. RESULTS: In this study, we were able to collect data from 603 participants, of which 57.4% were male and 67.8% of them aged between 20 and 24 years old. Moreover, we found that 39.6% had normal weight; however, the prevalence of obesity, overweight, and underweight were 24%, 28.1%, and 8.3%, respectively. Considering the prevalence of smoking, we found that 22.6% of the participants reported being current smokers, while 5.3% were former smokers. There is a significant difference between participants with different BMIs (P=0.001). The prevalence of smoking was significantly higher in obese and overweighted participants (35.1% and 31.3%, respectively) compared with 28.4% in normal-weighted participants. CONCLUSION: The prevalence of smoking and obesity in this study was significantly higher than reported in different studies. Moreover, we found a significant relationship between smoking and obesity; however, further investigation should be conducted to determine the cause of this relationship.

Genetic variants associated with dengue hemorrhagic fever. A systematic review and meta-analysis.

Dengue hemorrhagic fever (DHF) is a severe condition resulting from the dengue virus, with four serotypes known as DEN-1, DEN-2, DEN-3, and DEN-4. Genetic variations play a crucial role in influencing susceptibility to DHF. Therefore, this investigation conducted a meta-analysis to uncover genetic changes that might have remained undetected in individual studies due to small sample sizes or methodological differences. Among 2212 initially identified studies, 23 were deemed suitable for analysis based on PRISMA guidelines. Toll-like receptors (TLR) and CD209 showed significant association with DHF (odds ratios: TLR=0.56, CD209 =0.55), indicating protective effects. However, tumor necrosis factor (TNF) and human leukocyte antigen (HLA) did not exhibit a statistically significant relationship with DHF. This study emphasizes the relevance of TLR and CD209 in DHF susceptibility and resistance across diverse geographical locations.

Selective fluorescence turn-on detection of combination cisplatin-etoposide chemotherapy based on N-CDs/GSH-CuNCs nanoprobe.

Cisplatin (CIS) and etoposide (ETP) combination therapy is highly effective for treating various cancers. However, the potential for pharmacokinetic interactions between these drugs necessitates selective sensing methods to quantitate both CIS and ETP levels in patient's plasma. This work develops a dual fluorescence probe strategy using glutathione-capped copper nanoclusters (GSH-CuNCs) and nitrogen-doped carbon dots (N-CDs) for the simultaneous analysis of CIS and ETP. The fluorescence signal of GSH-CuNCs at 615 nm increased linearly with CIS concentration while the N-CD emission at 480 nm remained unaffected. Conversely, the N-CD fluorescence was selectively enhanced by ETP with no interference with the CuNC fluorescence. Extensive materials characterization including UV-vis, fluorescence spectroscopy, XRD, and TEM confirmed the synthesis of the nanoprobes. The sensor showed high sensitivity with limits of detection of 6.95 ng mL-1 for CIS and 7.63 ng mL-1 for ETP along with excellent selectivity against potential interferences in rabbit plasma. Method feasibility was demonstrated with application to real rabbit plasma samples. The method was further applied to estimate the pharmacokinetic parameters of CIS before and after ETP coadministration. The dual nanoprobe sensing strategy enables rapid and selective quantitation of CIS and ETP levels to facilitate therapeutic drug monitoring and optimization of combination chemotherapy regimens.

Worsening of imiquimod-induced psoriasiform inflammation in mice by environmental pollutant, di-(2-ethylhexyl) phthalate through dysregulation in IL-17A and Nrf2/iNOS signaling in peripheral myeloid and CD4 + T cells.

Psoriasis is a devastating autoimmune illness resulting from excessive keratinocyte growth and leukocyte infiltration into the dermis/epidermis. In the pathogenesis of psoriasis, different immune cells such as myeloid cells and CD4 + T cells play a key role. Th17/Th1 immune responses and oxidant-antioxidant responses are critical in regulation of psoriatic inflammation. Di-2-ethylhexyl phthalate (DEHP) is one of the well-known plasticizers and has widespread use worldwide. DEHP exposure through ingestion may produce harmful effects on the skin through systemic inflammation and oxidative stress, which may modify psoriatic inflammation. However, the effect of oral DEHP exposure on inflammatory cytokines and Nrf2/iNOS signaling in myeloid cells and CD4 + T cells in the context of psoriatic inflammation has not been investigated earlier. Therefore, this study explored the effect of DEHP on systemic inflammation in myeloid cells (IL-6, IL-17A, IL-23), Th17 (p-STAT3, IL-17A, IL-23R, TNF-α), Th1 (IFN-γ), Treg (Foxp3, IL-10), and Nrf2/iNOS signaling in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our study showed increased Th17 signaling in imiquimod model which was further aggravated by DEHP exposure. Further, Nrf2 and iNOS signaling were also elevated in IMQ model where DEHP exposure further increased iNOS expression but did not modify the Nrf2 expression. Most importantly, IL-17A levels were also elevated in myeloid cells along with IL-6 which were further elevated by DEHP exposure. Overall, this study shows that IL-17A signaling is upregulated, whereas there is deficiency of Nrf2/HO-1 signaling by DEHP exposure in mice with psoriasiform inflammation. These observations suggest that DEHP aggravates IL-17A-mediated signaling both in CD4 + T cells as well as myeloid cells which is linked to exacerbation of IMQ-induced psoriatic inflammation in mice. Strategies that counteract the effect of DEHP exposure in the context of psoriatic inflammation through downregulation of IL-17A may be fruitful.

A novel microextraction technique aided by air agitation using a natural hydrophobic deep eutectic solvent for the extraction of fluvastatin and empagliflozin from plasma samples: application to pharmacokinetic and drug-drug interaction study.

This study focuses on the interaction between the antihyperlipidemic drug fluvastatin (FLV) and the antidiabetic drug empagliflozin (EMP), which are commonly co-administered medications. EMP's impact on FLV levels is attributed to its inhibition of organic anion transporting polypeptide 1B1 (OATP1B1), responsible for FLV liver uptake, consequently elevating FLV concentrations in blood. Traditional extraction methods for FLV faced difficulties due to its high hydrophobicity. In this study, a hydrophobic natural deep eutectic solvent (NDES) using air assisted dispersive liquid-liquid microextraction (AA-DLLME) was utilized as an excellent choice for achieving the highest extraction recovery, reaching 96% for FLV and 92% for EMP. The NDES was created through the combination of menthol and hippuric acid in a 4 : 1 ratio, making it a green and cost-effective pathway. Liquid phase microextraction followed by spectrofluorometric measurements of FLV at λem = 395 nm and EMP at λem = 303 nm, with excitation at a single wavelength of 275 nm was carried out. Response surface methodology (RSM) relying on central composite design (CCD) was used to optimize the variables affecting the AA-NDES-DLLME. The optimized conditions for extraction are: NDES volume of 200 µL, centrifugation time of 15 minutes, air-agitation cycle of 6 cycles, and sample pH of 4.0. Under these optimized conditions, the developed method exhibited good linearity and precision. The method showed good recoveries from rabbit plasma samples spiked at varying concentrations of the analyzed compounds. To assess the applicability and effectiveness of the hydrophobic DES, the validated method was applied to extract the studied drugs from rabbit plasma samples after oral administration of FLV alone and in combination with EMP. The pharmacokinetic parameters of FLV were calculated in both cases to investigate any changes and determine the need for dose adjustment.

Examining the Effects of Dasatinib, Sorafenib, and Nilotinib on Vascular Smooth Muscle Cells: Insights into Proliferation, Migration, and Gene Expression Dynamics.

BACKGROUND: Dasatinib, nilotinib, and sorafenib are clinically proven tyrosine kinase inhibitors (TKIs) used for the treatment of leukemia and hepatocellular carcinoma. However, there is a growing concern regarding cardiotoxicity associated with their use. The impact of these TKIs on vascular smooth muscle cells (VSMCs) remains unexplored. This study aims to investigate the effects of TKIs on VSMC proliferation and migration, as well as to elucidate the underlying mechanisms involving inflammatory and apoptotic pathways. METHODS: VSMCs were extracted from albino rats and cultured in vitro. The cells were divided into four experimental groups: control, dasatinib, sorafenib, and nilotinib. The MTT assay was employed to assess the cytotoxic effects of TKIs on VSMCs. A scratch assay was conducted to evaluate the inhibitory potential of TKIs on VSMC migration. Flow cytometry analysis was used to detect apoptotic cells. Real-Time PCR expression was utilized to determine the differential gene expression of apoptotic and inflammatory markers. RESULTS: Dasatinib, nilotinib, and sorafenib demonstrated significant inhibitory effects on VSMC viability and migration at low concentrations (<1 µmol/L, p < 0.05). Furthermore, gene expression analysis revealed up-regulation of inflammatory biomarkers (TNF-α, IL-6, and IL-1ß) and apoptotic markers (P53, BAX), along with down-regulation of the anti-apoptotic biomarker BCL-2 in response to all TKIs. CONCLUSIONS: This study demonstrates that dasatinib, nilotinib, and sorafenib inhibit VSMC proliferation and migration, suggesting their potential to induce vascular injury and remodeling by activating inflammation and apoptosis pathways. These findings highlight the need for further investigation into the cardiotoxic effects of these TKIs and the development of strategies to mitigate their adverse vascular effects.

Augmented antitumor effects of erlotinib and cabozantinib on A549 non-small cell lung cancer: In vitro and in vivo studies.

Non-small cell lung carcinoma is a challenging disease worldwide. This study aims to determine whether combining erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, with cabozantinib, a mesenchymal-epithelial transition factor (c-Met) inhibitor, would have an augmented therapeutic benefit on A549 cells. The combination of erlotinib and cabozantinib (5 µM) inhibited A549 cell viability compared to each monotherapy at ≥ 10 µM as confirmed by the MTT assay. Combination therapy also has a more potent inhibition of cellular migration than monotherapy using the wound-healing assay. Furthermore, mRNA expression analyses for assessing apoptosis, metastasis, and cell cycle-related genes, the results showed that combination therapy significantly inhibits levels of BCL-2, MMP-9, VEGF, and TGF-ß while inducing p53, p21, and BAX expression. In terms of oncogenic markers, western blotting analysis showed a significant reduction of BCl-2 expression and elevation in caspase3, p53, and p21 proteins as indicators of cell death via apoptosis. The antitumor in vivo effect of the combination therapy showed significant tumor inhibition compared to monotherapy. In conclusion, combination therapy could be a potential promising strategy to treat non-small cell lung carcinoma.

Protective role of Dodonaea viscosa extract against streptozotocin-induced hepatotoxicity and nephrotoxicity in rats.

Previous investigations have shown that D. viscosa herbal extract is often used to treat a variety of diseases. Therefore, the purpose of this study was to investigate any additional potential impacts on rat liver and kidney damage induced by diabetes. Streptozotocin (STZ) (60 mg/kg/day) was given as a single dosage to cause type 1 diabetes. After then, diabetic rats received oral doses of D. viscosa for four weeks at 150 and 300 mg/kg/day. Blood, liver, and kidney tissues were collected at the end of the treatment and examined. Analysis was made of the serum lipid profile, liver, and kidney functions, as well as blood biochemistry. Moreover, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), prostaglandin E-2 (PGE-2), and nitric oxide (NO) were estimated in serum. In liver and kidney samples, thiobarbituric acid reactive substances (TBARs) and reduced glutathione (GSH), as well as the pro-inflammatory cytokines and enzymatic activities of glutathione peroxidase (GPx), glutathione reeducates (GR), glutathione-S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) were analyzed. Histological changes in liver and kidney cross-sections were also observed. Our findings demonstrated that D. viscosa dramatically decreased pro-inflammatory indicators in blood, kidney, and liver tissues as well as blood glucose, and restored insulin levels, and lipid profiles. Additionally, it significantly raises the antioxidant enzyme activity SOD, CAT, GPx, and GST, while significantly lowering TBARs levels. The above-mentioned biochemical changes that took place in tissues were further supported by histological alterations. These findings imply that D. viscosa protects against STZ-induced hyperglycemia, aberrant lipid synthesis, and oxidative stress and that these benefits may be mediated by interacting with various targets to increase the levels of antioxidant enzymes in the liver and kidneys. Its mode of action and safety for use as medicine against various metabolic problems caused by diabetes require more research.

Hydroxychloroquine ameliorates dasatinib-induced liver injury via decrease in hepatic lymphocytes infiltration.

Dasatinib is an effective treatment for chronic myeloid leukemia. However, cases of idiosyncratic hepatotoxicity were reported. This study was conducted to investigate the chemopreventive effects of hydroxychloroquine against dasatinib-induced hepatotoxicity. Balb/c mice were randomly assigned into four groups; vehicle control (5% DMSO, i.p., n = 6), dasatinib (50 mg/kg; i.p., n = 6), hydroxychloroquine (10 mg/kg, i.p., n = 6), and hydroxychloroquine + dasatinib (10 mg/kg + 50 mg/kg; i.p., n = 6). Treatments were given once every 2 days for 14 days. Serum and histopathological assessments of liver architecture and fibrosis were performed using H&E, Masson's trichrome, and reticulin staining. The infiltration of lymphocytes was assessed using immunohistochemistry. The gene expression of antioxidant enzymes (CAT, SOD-2, GPX-1) was assessed using real-time quantitative PCR. Dasatinib showed a significant increase in liver injury biomarkers (AST and ALT) with higher lymphocytes infiltration (as indicated by CD3+, CD4+, CD8+, and CD20+ immunohistochemistry). Hepatic tissue of Dasatinib group exhibited significant downregulation in the gene expression of antioxidant enzymes (CAT, SOD-2, and GPX-1) compared to the control group. However, the combination of hydroxychloroquine with dasatinib showed a slight increase in AST and ALT. Also, hydroxychloroquine + dasatinib treated mice showed a significant reduction in lymphocytes infiltration as compared to dasatinib. The results showed that dasatinib induces an immune response leading to an increase in lymphocytes infiltration which promotes hepatocyte destruction and persistent liver injury. The results also suggest that hydroxychloroquine ameliorates dasatinib-induced hepatotoxicity via reduction in hepatic infiltration of T and B immune cells.

The Potential Protective Role of Naringenin against Dasatinib-Induced Hepatotoxicity.

Dasatinib (DASA) is a novel tyrosine kinase inhibitor, approved for leukemia treatment. However, the long-term use of DASA induces several complications, especially liver damage. On the other hand, Naringenin (NGN) is a potent antioxidant and anti-inflammatory agent which is known to exert protective effects in several liver disease animal models. Yet, the effect of NGN on DASA-induced hepatotoxicity has not been examined. This study investigated the hepatoprotective effects of NGN against DASA-induced acute liver injury, using a mouse model. The mice were given NGN (50, 100, and 200 mg/kg po) or saline for 7 days, followed by DASA on the eighth day (25 mg/kg p.o.). DASA treatment alone was found to cause overexpression of proinflammatory cytokines, such as interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and malonyl aldehyde (MDA), whereas attenuation of antioxidant genes including superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GPx). Interestingly, a pretreatment with NGN + DASA resulted in minimizing the proinflammatory mediators and restoring the levels of antioxidant genes. In addition, there was evidence of necro-inflammatory changes in histopathological findings in the liver samples after DASA administration which remarkably reduced with NGN + DASA. Thus, this study revealed that NGN could minimize the hepatotoxicity induced by DASA by providing anti-inflammatory and antioxidant protection.

The Progress of Speech Recognition in Health Care: Surgery as an Example.

Artificial Intelligence (AI) is a computer system that simulates intelligent human behavior. The use of AI is rapidly shifting Healthcare. Speech recognition (SR) is a type of AI physicians use to operate Electronic Health records (EHR). This paper aims to demonstrate the technological advancements made thus far concerning speech recognition in health care and explore multiple scholarly studies to generate a wide-ranging and detailed assessment of its current progress. The effectiveness of speech recognition is the heart of this analysis. This review investigates published papers on the progress and effectiveness of speech recognition in Healthcare. Eight research papers exploring the progress and effectiveness of speech recognition in Healthcare were thoroughly reviewed. Articles were identified from Google Scholar, PubMed, and the World Wide Web. The five relevant papers generally discussed the progress and current effectiveness of SR in Healthcare, implementing SR in the EHR, adapting healthcare workers to SR and the problems they face, developing an intelligent healthcare system based on SR and using SR systems in other languages. Conclusion: This report demonstrates the technological improvements realized concerning SR in Healthcare. It proved that SR could be a tremendous help to providers if every medical and health institution continued to progress in using this technology.

Targeting Store-Operated Calcium Entry Regulates the Inflammation-Induced Proliferation and Migration of Breast Cancer Cells.

Persistent challenges complicating the treatment of breast cancer remain, despite some recent undeniable successes. Sufficient evidence currently exists demonstrating the crucial role of inflammation, characterized by the enhanced activation of Toll-like receptor 4 (TLR4) and the COX-2/PGE2 pathway, in the migration and proliferation of breast cancer cells. Interestingly, the store-operated calcium entry (SOCE) pathway was shown to be essential for the TLR4 activity and COX-2 expression in immune cells such as macrophages and microglia. However, whether SOCE influences inflammatory signaling and the inflammation-induced proliferation and migration of breast cancer cells is still unknown. Thus, the current study intended to delineate the role of SOCE in the TLR4-induced inflammation, migration, and proliferation of breast cancer cells. To this end, MDA-MB-231 breast cancer cells were treated with lipopolysaccharide (LPS) to activate TLR4, BTP2 to inhibit SOCE, and Thapsigargin to induce SOCE. Following these treatments, several experiments were conducted to evaluate the proliferation and migration rates of the MDA-MB-231 cells and the expression of several inflammatory and oncogenic genes, including COX-2, PGE2, IL-6, IL-8, and VEGF. Different techniques were used to achieve the aims of this study, including qRT-PCR, Western blotting, ELISA, MTT, and wound healing assays. This study shows that SOCE inhibition using BTP2 suppressed the LPS-induced migration and proliferation of breast cancer cells. Additionally, treatment with LPS caused approximately six- and three-fold increases in COX-2 mRNA and protein expression, respectively, compared to the controls. The LPS-induced elevations in the COX-2 mRNA and protein levels were suppressed by BTP2 to the control levels. In addition to its effect on COX-2, BTP2 also suppressed the LPS-induced productions of PGE2, IL-6, IL-8, and VEGF. Conversely, SOCE induction using Thapsigargin enhanced the LPS-induced inflammation, migration, and proliferation of breast cancer cells. Collectively, these results provide evidence for the potentially important role of SOCE in inflammation-induced breast cancer progression processes. Thus, we argue that the current study may provide novel targets for designing new therapeutic approaches for the treatment of breast cancer.

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.

Neuroprotective Effects of Phytochemicals against Aluminum Chloride-Induced Alzheimer's Disease through ApoE4/LRP1, Wnt3/ß-Catenin/GSK3ß, and TLR4/NLRP3 Pathways with Physical and Mental Activities in a Rat Model.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that is associated with abnormal cognition. AD is aided in its initiation and progression by hereditary and environmental factors. Aluminum (Al) is a neurotoxic agent that causes oxidative stress, which is linked to AD progression. Additionally, Nrf2/HO-1, APOE4/LRP1, Wnt3/ß-catenin, and TLR4/NLRP3 are the main signaling pathways involved in AD pathogenesis. Several phytochemicals are promising options in delaying AD evolution. OBJECTIVES: This study aimed at studying the neuroprotective effects of some phytochemicals as morin (MOR), thymol (TML), and thymoquinone (TMQ) on physical and mental activities (PhM) in Al chloride (AlCl3)-induced AD rat model. Another objective was to determine the specificity of phytochemicals to AD signaling pathways using molecular docking. METHODS: Eighty male Dawley rats were divided into eight groups. Each group received: saline (control group), AlCl3, (ALAD), PhM, either alone or with a combination of MOR, TML, and/or TMQ for five weeks. Animals were then subjected to behavioral evaluation. Brain tissues were used for histopathological and biochemical analyses to determine the extent of neurodegeneration. The effect of phytochemicals on AlCl3-induced oxidative stress and the main signaling pathways involved in AD progression were also investigated. RESULTS: AlCl3 caused a decline in spatial learning and memory, as well as histopathological changes in the brains of rats. Phytochemicals combined with PhM restored antioxidant activities, increased HO-1 and Nrf2 levels, blocked inflammasome activation, apoptosis, TLR4 expression, amyloide-ß generation, and tau hyperphophorylation. They also brought ApoE4 and LRP1 levels back to normal and regulated Wnt3/ß-catenin/GSK3ß signaling pathway. CONCLUSIONS: The use of phytochemicals with PhM is a promising strategy for reducing AD by modulating Nrf2/HO-1, TLR4/NLRP3, APOE4/LRP1, and Wnt3/ß-catenin/GSK-3ß signaling pathways.

Lck signaling inhibition causes improvement in clinical features of psoriatic inflammation through reduction in inflammatory cytokines in CD4+ T cells in imiquimod mouse model.

Psoriasis is a chronic dermal inflammatory disease with a world-wide prevalence in which different immune/non-immune cells, e.g. T cells, macrophages, neutrophils, and keratinocytes play a decisive role. These immune cells interact among themselves by releasing multiple mediators which eventually cause characteristic psoriatic plaques in the skin. T cells are reported to be significant contributors to psoriatic inflammation through release of multiple cytokines which are controlled by several kinases, one of them being Lymphocyte-specific protein tyrosine kinase (Lck). Lck has been reported to be crucial for expression/production of several key inflammatory cytokines though modulation of several other kinases/transcription factors in T cells. Therefore, in this investigation, effect of Lck inhibitor, A-770041 was examined on PLCγ, p38MAPK, NFATc1, NFkB and STAT3, TNF-α, IFN-γ, Foxp3, IL-17A, in CD4+ T cells in imiquimod (IMQ)-induced psoriatic inflammation in mice. Results from the present study exhibit that p-Lck expression is enhanced in CD4+ T cells of IMQ-treated mice which is concomitant with enhanced clinical features of psoriatic inflammation (ear/back skin thickness, MPO activity, acanthosis/leukocytic infiltration) and molecular parameters (enhanced expression of p-Lck, p-PLCγ, p-p38-MAPK, NFATc1, p-NFkB, TNF-α, IFN-γ, p-STAT3, and IL-17A in CD4+ T cells). Inhibition of Lck signaling led to amelioration of clinical features of psoriasis through attenuation of Th1/Th17 immune responses and upregulation of Treg cells in IMQ-treated mice. In summary, current investigations reveal that Lck signaling is a crucial executor of inflammatory signaling in CD4+ T cells in the context of psoriatic inflammation. Therefore, Lck inhibition may be pursued as an effective strategy to counteract psoriatic inflammation.

Long term predictors of breathlessness, exercise intolerance, chronic fatigue and well-being in hospitalized patients with COVID-19: A cohort study with 4 months median follow-up.

BACKGROUND: Post-acute COVID-19 syndrome (PACS) is an emerging healthcare burden. We therefore aimed to determine predictors of different functional outcomes after hospital discharge in patients with COVID-19. METHODS: An ambidirectional cohort study was conducted between May and July 2020, in which PCR-confirmed COVID-19 patients underwent a standardized telephone assessment between 6 weeks and 6 months post discharge. We excluded patients who died, had a mental illness or failed to respond to two follow-up phone calls. The medical research council (MRC) dyspnea scale, metabolic equivalent of task (MET) score for exercise tolerance, chronic fatigability syndrome (CFS) scale and World Health Organization-five well-being index (WHO-5) for mental health were used to evaluate symptoms at follow-up. RESULTS: 375 patients were contacted and 153 failed to respond. The median timing for the follow-up assessment was 122 days (IQR, 109-158). On multivariate analyses, female gender, pre-existing lung disease, headache at presentation, intensive care unit (ICU) admission, critical COVID-19 and post-discharge ER visit were predictors of higher MRC scores at follow-up. Female gender, older age >67 years, arterial hypertension and emergency room (ER) visit were associated with lower MET exercise tolerance scores. Female gender, pre-existing lung disease, and ER visit were associated with higher risk of CFS. Age, dyslipidemia, hypertension, pre-existing lung disease and duration of symptoms were negatively associated with WHO-5 score. CONCLUSIONS: Several risk factors were associated with an increased risk of PACS. Hospitalized patients with COVID-19 who are at risk for PACS may benefit from a targeted pre-emptive follow-up and rehabilitation programs.

Ischiorectal fossa metastasis from colon cancer: Case report of a rare entity and review of literature.

INTRODUCTION AND IMPORTANCE: Colorectal cancer is one of the most common cancers both nationally and internationally. It commonly metastases to local lymph nodes, liver and lungs, with few reported cases of rare sites of metastasis such as adrenal glands, breast and skin. CASE PRESENTATION: We report a 55-year-old-female admitted as case of large bowel obstruction and unintentional weight loss. Computed tomography scan of chest, abdomen and pelvis (CT CAP) showed sigmoid colon circumferential thickening with three lesions in the right hemi-liver. A laparoscopic diverting ileostomy followed by a colonoscopy showed a sigmoidal mass consistent with adenocarcinoma on histopathology. Hence, she received neoadjuvant chemotherapy followed by hepatectomy for the liver metastasis. Post-operatively CT CAP showed a newly developed right ischiorectal fossa (IRF) nodule along with newly developed porta hepatis lymph node. PET scan showed uptake in these two new lesions. Therefore, the patient underwent resection of the primary tumor, porta hepatis lymph node and right ischiorectal fossa nodule excision. The histopathology of the primary tumor came as moderately differentiated adenocarcinoma with both ischiorectal lesion and the porta hepatis nodule being positive for metastatic disease. CLINICAL DISCUSSION & CONCLUSION: Ischiorectal fossa tumors are extremely rare with the majority being benign in origin. Nevertheless, the possibility of metastasis is there with no clear explanation regarding the pathway of how the metastatic cells can reach the IRF. Pre-operative diagnosis is important to determine the appropriate approach particularly if the mass is thought to be malignant. Further larger studies are needed to understand the pathway of metastasis to IRF.

A Computer Modeling Study of Water Radiolysis at High Dose Rates. Relevance to FLASH Radiotherapy.

"FLASH radiotherapy" is a new method of radiation treatment by which large doses of radiation are delivered at high dose rates to tumors almost instantaneously (a few milliseconds), paradoxically sparing healthy tissue while preserving anti-tumor activity. To date, no definitive mechanism has been proposed to explain the different responses of the tumor and normal tissue to radiation. As a first step, and given that living cells and tissues consist mainly of water, we studied the effects of high dose rates on the transient yields (G values) of the radical and molecular species formed in the radiolysis of deaerated/aerated water by irradiating protons, using Monte Carlo simulations. Our simulation model consisted of two steps: 1. The random irradiation of a right circular cylindrical volume of water, embedded in nonirradiated bulk water, with single and instantaneous pulses of N 300-MeV incident protons ("linear energy transfer" or LET ∼ 0.3 keV/µm) traveling along the axis of the cylinder; and 2. The development of these N proton tracks, which were initially contained in the irradiated cylinder, throughout the solution over time. The effect of dose rate was studied by varying N, which was calibrated in terms of dose rate. For this, experimental data on the yield G(Fe3+) of the super-Fricke dosimeter as a function of dose rate up to ∼1010 Gy/s were used. Confirming previous experimental and theoretical studies, significant changes in product yields were found to occur with increasing dose rate, with lower radical and higher molecular yields, which result from an increase in the radical density in the bulk of the solution. Using the kinetics of the decay of hydrated electrons, a critical time (τc), which corresponds to the "onset" of dose-rate effects, was determined for each value of N. For the cylindrical irradiation model, τc was inversely proportional to the dose rate. Moreover, the comparison with experiments with pulsed electrons underlined the importance of the geometry of the irradiation volume for the estimation of τc. Finally, in the case of aerated water radiolysis, we calculated the yield of oxygen consumption and estimated the corresponding concentration of consumed (depleted) oxygen as a function of time and dose rate. It was shown that this concentration increases substantially with increasing dose rate in the time window ∼1 ns-10 µs, with a very pronounced maximum around 0.2 µs. For high-dose-rate irradiations (>109 Gy/s), a large part of the available oxygen (∼0.25 mM for an air-saturated solution) was found to be consumed. This result, which was obtained on a purely water radiation chemistry basis, strongly supports the hypothesis that the normal tissue-sparing effect of FLASH stems from temporary hypoxia due to oxygen depletion induced by high-dose-rate irradiation.

Coadministration of Ketamine and Perampanel Improves Behavioral Function and Reduces Inflammation in Acute Traumatic Brain Injury Mouse Model.

Traumatic brain injury (TBI) is among the most debilitating neurological disorders with inadequate therapeutic options. It affects all age groups globally leading to post-TBI behavioral challenges and life-long disabilities requiring interventions for these health issues. In the current study, C57BL/6J mice were induced with TBI through the weight-drop method, and outcomes of acutely administered ketamine alone and in combination with perampanel were observed. The impact of test drugs was evaluated for post-TBI behavioral changes by employing the open field test (OFT), Y-maze test, and novel object recognition test (NOR). After that, isolated plasma and brain homogenates were analyzed for inflammatory modulators, i.e., NF-κB and iNOS, through ELISA. Moreover, metabolomic studies were carried out to further authenticate the TBI rescuing potential of drugs. The animals treated with ketamine-perampanel combination demonstrated improved exploratory behavior in OFT (P < 0.05), while ketamine alone as well as in combination yielded anxiolytic effect (P < 0.05-0.001) in posttraumatic mice. Similarly, the % spontaneous alternation and % discrimination index were increased after the administration of ketamine alone (P < 0.05) and ketamine-perampanel combination (P < 0.01-0.001) in the Y-maze test and NOR test, respectively. ELISA demonstrated the reduced central and peripheral expression of NF-κB (P < 0.05) and iNOS (P < 0.01-0.0001) after ketamine-perampanel polypharmacy. The TBI-imparted alteration in plasma metabolites was restored by drug combination as evidenced by metabolomic studies. The outcomes were fruitful with ketamine, but the combination therapy proved more significant in improving all studied parameters. The benefits of this new investigated polypharmacy might be due to their antiglutamatergic, antioxidant, and neuroprotective capacity.