Association between COVID-19 severity and tobacco smoking status: a retrospective cohort study using propensity score matching weights analysis.

INTRODUCTION: The COVID-19 pandemic continues to be a global threat to public health, with over 766 million confirmed cases and more than 6 million reported deaths. Patients with a smoking history are at a greater risk of severe respiratory complications and death due to COVID-19. This study investigated the association between smoking history and adverse clinical outcomes among COVID-19 patients admitted to a designated medical centre in Saudi Arabia. METHODS: A retrospective observational cohort study was conducted using patient chart review data from a large tertiary medical centre in the eastern region of the country. Patients admitted between January and December 2020 were screened. The inclusion criteria were ≥18 years of age and confirmed COVID-19 infection via reverse-transcription-PCR. The exclusion criteria were unconfirmed COVID-19 infection, non-COVID-19 admissions, unconfirmed smoking status, vaccinated individuals, essential chart information missing or refusal to consent. Statistical analyses comprised crude estimates, matching weights (as the main analysis) and directed acyclic graphs (DAGs) causal pathway analysis using an ordinal regression model. RESULTS: The sample comprised 447 patients (never-smoker=321; ever-smoker=126). The median age (IQR) was 50 years (39-58), and 73.4% of the sample were males. A matching weights procedure was employed to ensure covariate balance. The analysis revealed that the odds of developing severe COVID-19 were higher in the ever-smoker group with an OR of 1.44 (95% CI 0.90 to 2.32, p=0.130). This was primarily due to an increase in non-invasive oxygen therapy with an OR of 1.05 (95% CI 0.99 to 1.10, p=0.101). The findings were consistent across the different analytical methods employed, including crude estimates and DAGs causal pathway analysis. CONCLUSION: Our findings suggest that smoking may increase the risk of adverse COVID-19 outcomes. However, the study was limited by its retrospective design and small sample size. Further research is therefore needed to confirm the findings.

Therapeutic benefits of quercetin in traumatic brain injury model exposed to cigarette smoke.

Scientific evidences reported the deleterious effect of cigarette smoking or passive smoking on brain health particularly cognitive functions, blood-brain barrier (BBB) permeability, up-regulation of inflammatory cascades, and depletion of the antioxidant system. These combined effects become more progressive in the events of stroke, traumatic brain injury (TBI), and many other neurodegenerative diseases. In the current study, we investigated the long-term administered therapeutic potential of quercetin in ameliorating the deleterious neurobiological consequences of chronic tobacco smoke exposure in TBI mice. After exposure to 21 days of cigarette smoke and treatment with 50 mg/kg of quercetin, C57BL/6 mice were challenged for the induction of TBI by the weight drop method. Subsequently, a battery of behavioral tests and immunohistochemical analyses revealed the beneficial effect of quercetin on the locomotive and cognitive function of TBI + smoked group mice (p < 0.05 vs control sham). Immunohistochemistry analysis (Nrf2, HO-1, NFkB, caspase 3) demonstrated a marked protection after 21 days of quercetin treatment in the chronic tobacco smoking group possibly by up-regulation of antioxidant pathways, and decreased apoptosis. In conclusion, our findings support the therapeutic effectiveness of quercetin in partly protecting the central neurological functions that become aberrantly impaired in combined habitual cigarette-smoking individuals impacted with TBI.

Investigating Behavioral and Neuronal Changes in Adolescent Mice Following Prenatal Exposure to Electronic Cigarette (E-Cigarette) Vapor Containing Nicotine.

A substantial percentage of pregnant smokers stop using traditional cigarettes and switch to alternative nicotine-related products such as e-cigarettes. Prenatal exposure to tobacco increases the risk of psychiatric disorders in children. Adolescence is a complex phase in which higher cognitive and emotional processes undergo maturation and refinement. In this study, we examined the behavioral and molecular effects of first-trimester prenatal exposure to e-cigarettes. Adult female mice were divided into normal air, vehicle, and 2.5%-nicotine-exposed groups. Our analyses indicated that the adolescents in the 2.5%-nicotine-exposed group exhibited a significant lack of normal digging behavior, elevated initial sucrose intake, and reduced recognition memory. Importantly, we identified a substantial level of nicotine self-administration in the 2.5%-nicotine-exposed group. At a molecular level, the mRNAs of metabotropic glutamate receptors and transporters in the nucleus accumbens were not altered. This previously undescribed work indicates that prenatal exposure to e-cigarettes might increase the risk of nicotine addiction during adolescence, reduce cognitive capacity, and alter normal adolescent behavior. The outcome will aid in translating research and assist healthcare practitioners in tackling addiction and mental issues caused by toxicological exposure. Further, it will inform relevant policymaking, such as recommended taxation, labeling e-cigarette devices with more detailed neurotoxic effects, and preventing their sale to pregnant women and adolescents.

Nicotine and cotinine quantification after a 4-week inhalation of electronic cigarette vapors in male and female mice using UPLC-MS/MS.

OBJECTIVES: To detect the cotinine and nicotine serum concentrations of female and male C57BL/6J mice after a 4-week exposure to electronic (e)-cigarette vapors using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). METHODS: This experimental study was carried out at an animal facility and laboratories, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, between January and August 2020. A 4-week exposure to e-cigarettes was carried out using male and female mice and serum samples were obtained for cotinine and nicotine quantification using UPLC-MS/MS. The chromatographic procedures involved the use of a BEH HSS T3 C18 column (100 mm x 2.1 mm, 1.7 µm) with acetonitrile as a mobile phase and 0.1% formic acid (2:98 v/v). RESULTS: The applied methodology has highly efficient properties of detection, estimation, and extraction, where the limit of quantification (LOQ) for nicotine was 0.57 ng/mL and limit of detection (LOD) for nicotine was 0.19 ng/mL, while the LOQ for cotinine was 1.11 ng/mL and LOD for cotinine was 0.38 ng/mL. The correlation coefficient was r2>0.99 for both compounds. The average recovery rate was 101.6±1.33 for nicotine and 100.4±0.54 for cotinine, while the precision and accuracy for cotinine and nicotine were less than 6.1. The serum cotinine level was higher in males (433.7±19.55) than females (362.3±16.27). CONCLUSION: This study showed that the gender factor might play a crucial role in nicotine metabolism.

Effects of Chronic Inhalation of Electronic Cigarette Vapor Containing Nicotine on Neurobehaviors and Pre/Postsynaptic Neuron Markers.

Nicotine-exposed animal models exhibit neurobehavioral changes linked to impaired synaptic plasticity. Previous studies highlighted alterations in neurotransmitter levels following nicotine exposure. Vesicular glutamate transporter (VGLUT1) and vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) are essential for the transport and release of glutamate and GABA, respectively, from presynaptic neurons into synapses. In our work, an e-cigarette device was used to deliver vapor containing nicotine to C57BL/6J mice for four weeks. Novel object recognition, locomotion, and Y-maze tests were performed to investigate the behavioral parameters. Protein studies were conducted to study the hippocampal expression of VGLUT1, VGAT, and postsynaptic density protein 95 (PSD95) as well as brain cytokine markers. Long-term memory and locomotion tests revealed that e-cigarette aerosols containing nicotine modulated recognition memory and motor behaviors. We found that vapor exposure increased VGLUT1 expression and decreased VGAT expression in the hippocampus. No alterations were found in PSD95 expression. We observed that vapor-containing nicotine exposure altered certain brain cytokines such as IFNß-1 and MCP-5. Our work provides evidence of an association between neurobehavioral changes and altered hippocampal VGLUT1 and VGAT expression in mice exposed to e-cigarette vapors containing nicotine. Such exposure was also associated with altered neurobehaviors, which might affect neurodegenerative diseases.

Metformin attenuates V-domain Ig suppressor of T-cell activation through the aryl hydrocarbon receptor pathway in Melanoma: In Vivo and In Vitro Studies.

Melanoma is an aggressive skin cancer with a high rate of metastasis to other organs. Recent studies specified the overexpression of V-domain Ig suppressor of T-cell activation (VISTA) and Aryl Hydrocarbon Receptor (AHR) in melanoma. Metformin shows anti-tumor activities in several cancer types. However, the mechanism is unclear. This study aims to investigate the inhibitory effect of metformin on VISTA via AHR in melanoma cells (CHL-1, B16) and animal models. VISTA and AHR levels were assessed by qPCR, Western blot, immunofluorescence microscope, flow cytometry, and immunohistochemistry. Here, metformin significantly decreased VISTA and AHR levels in vitro and in vivo. Furthermore, metformin inhibited all AHR-regulated genes. VISTA levels were dramatically inhibited by AHR modulations using shRNA and αNF, confirming the central role of AHR in VISTA. Finally, melanoma cells were xenografted in C57BL/6 and nude mice. Metformin significantly reduced the tumor volume and growth rate. Likewise, VISTA and AHR-regulated protein levels were suppressed in both models. These findings demonstrate for the first time that VISTA is suppressed by metformin and identified a new regulatory mechanism through AHR. The data suggest that metformin could be a new potential therapeutic strategy to treat melanoma patients combined with targeted immune checkpoint inhibitors.

Examining Anxiety, Sleep Quality, and Physical Activity as Predictors of Depression among University Students from Saudi Arabia during the Second Wave of the COVID-19 Pandemic.

Conducted during the second wave of the pandemic, this cross-sectional study examined the link between sleep quality, physical activity, exposure, and the impact of COVID-19 as predictors of mental health in Saudi undergraduate students. A convenience sample of 207 participants were recruited, 89% of whom were females and 94% were single. The measures included questionnaires on the level of exposure and the perceived impact of COVID-19, a physical activity measure, GAD-7, PHQ-9, and PSQI. The results indicated that approximately 43% of participants exhibited moderate anxiety, and 50% were at risk of depression. Overall, 63.93% of students exposed to strict quarantine for at least 14 days (n = 39) exhibited a high risk of developing depression (χ2(1) = 6.49, p < 0.05, ϕ = 0.18). A higher risk of depression was also found in students whose loved ones lost their jobs (χ2(1) = 4.24, p < 0.05, ϕ = 0.14). Moreover, there was also a strong association between depression and anxiety (ß = 0.33, p < 0.01), sleep quality (ß = 0.32, p < 0.01), and the perceived negative impact of COVID-19 on socio-economic status (ß = 0.26, p < 0.05), explaining 66.67% of depression variance. Our study highlights the socio-economic impact of this pandemic and the overwhelming prevalence of depression.

COVID-19 Vaccination-Related Sentiments Analysis: A Case Study Using Worldwide Twitter Dataset.

COVID-19 pandemic has caused a global health crisis, resulting in endless efforts to reduce infections, fatalities, and therapies to mitigate its after-effects. Currently, large and fast-paced vaccination campaigns are in the process to reduce COVID-19 infection and fatality risks. Despite recommendations from governments and medical experts, people show conceptions and perceptions regarding vaccination risks and share their views on social media platforms. Such opinions can be analyzed to determine social trends and devise policies to increase vaccination acceptance. In this regard, this study proposes a methodology for analyzing the global perceptions and perspectives towards COVID-19 vaccination using a worldwide Twitter dataset. The study relies on two techniques to analyze the sentiments: natural language processing and machine learning. To evaluate the performance of the different lexicon-based methods, different machine and deep learning models are studied. In addition, for sentiment classification, the proposed ensemble model named long short-term memory-gated recurrent neural network (LSTM-GRNN) is a combination of LSTM, gated recurrent unit, and recurrent neural networks. Results suggest that the TextBlob shows better results as compared to VADER and AFINN. The proposed LSTM-GRNN shows superior performance with a 95% accuracy and outperforms both machine and deep learning models. Performance analysis with state-of-the-art models proves the significance of the LSTM-GRNN for sentiment analysis.

Cathepsin B inhibitor alleviates Th1, Th17, and Th22 transcription factor signaling dysregulation in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory infiltration in association with demyelination in the central nervous system. Among the factors involved in the immunological mechanisms of MS, Th1, Th17, and Th22 cells play a critical role. In the present study, we investigated the role of CA-074, a potent Cathepsin B inhibitor, in MS progression, using the SJL/J mouse model of experimental autoimmune encephalomyelitis (EAE). Following induction of EAE, mice were administered CA-074 (10 mg/kg) intraperitoneally each day, beginning on day 14 and continuing until day 28, and were evaluated for clinical signs. We further investigated the effect of CA-074 on Th1 (T-bet/STAT4), Th17 (IL-17A/RORγT), Th22 (TNF-α/IL-22), and regulatory T (Treg/Foxp3) cells in the spleen, using flow cytometry. We also analyzed the effect of CA-074 on T-bet, IL-17A, RORγT, IL-22, and mRNA and protein levels using RT-PCR and western blot analysis for brain tissues. Cathepsin B expression were also assessed by western blot in the brain tissues. The severity of clinical scores decreased significantly in CA-074-treated mice compared with that in EAE control mice. Moreover, the percentage of CD4+T-bet+, CXCR5+T-bet+, CD4+STAT4+, CD4+IL-17A+, CXCR5+IL-17A+, CD4+RORγT+, CCR6+RORγT+, CD4+TNF-α+, CD4+IL-22+, and CCR6+IL-22+ cells decreased while CD25+Foxp3+ increased in CA-074-treated EAE mice as compared to vehicle-treated EAE mice. Further, CA-074-treated EAE mice had downregulated Cathepsin B protein expression which was associated with decreased T-bet, IL-17A, RORγT, and IL-22 mRNA/protein expression. These results suggest that Cathepsin B could be a novel therapeutic candidate against for the treatment of MS.

Examining bedtime procrastination, study engagement, and studyholism in undergraduate students, and their association with insomnia.

Introduction: Compulsive overstudying, known as studyholism, is an emerging behavioral addiction. In this study, we examine the prevalence of, and the relationships between, insomnia, study engagement, studyholism, bedtime procrastination among undergraduate students. Methods: The Studyholism (SI-10), Athens Insomnia (AIS), and bedtime procrastination scales were administered to a convenience sample of 495 university students. Results: Our findings indicate that the prevalence of insomnia was 75.31%, high studyholism was found in 15.31% of the sample, and increased study engagement was detected in 16.94%. Gender differences analysis revealed that females reported higher studyholism and bedtime procrastination than males. Fifth-year students had higher levels of studyholism than internship (p < 0.001), first-year (p < 0.01), and sixth-year students (p < 0.05). Insomnia was positively related to studyholism and bedtime procrastination. Furthermore, insomnia can be positively predicted by studyholism and bedtime procrastination. Participants with a medium level of studyholism were twice as likely to experience insomnia as those with a low level. Studyholics were six times more susceptible to insomnia than students with low studyholism levels. Compared to individuals with low bedtime procrastination levels, those with medium and high bedtime procrastination were twice as likely to report insomnia. Conclusion: Our study highlights the interplay between insomnia, studyholism, and bedtime procrastination. Further, the findings indicate the need to increase awareness of insomnia.

Mechanistic Insights into Luteolin-Loaded Elastic Liposomes for Transdermal Delivery: HSPiP Predictive Parameters and Instrument-Based Evidence.

We evaluated mechanistic insights into luteolin (LUT)-loaded elastic liposomes (OLEL1) permeated across rat skin. HSPiP software-based parameters, thermal analysis, infrared analysis, and morphological evaluations were employed to understand mechanistic observations of drug permeation and deposition. HSPiP provided HSP values (δd, δp, and δh) of OLEL1 (based on composition), LUT, excipients, and rat skin (literature value and by-default value). Rat skin was studied via Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), fluorescence microscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM) studies. The δd and δh estimation of the skin and phosphatidylcholine showed close relation in terms of δd and δh. Similarly, OLEL1 and the skin might interact with each other mainly through δd and δp forces as evidenced by the predicted values. The untreated skin showed characteristic stretching and vibrations as compared to lower frequencies caused by OLEL1. DSC showed changes in the thermal behavior of the skin after OLEL1 treatment as compared to the untreated skin. Visualization of these changes was evident under fluorescence microscopy and SEM for confirmed substantial reversible surface perturbation of the skin protein layer for improved vesicle permeation and subsequent internalization with the inner skin matrix. The AFM study confirmed the nanoscale surface roughness variation caused substantially by OLEL1 and OLEL1 placebo as compared to the untreated control and drug solution. Thus, the study clearly demonstrated mechanistic insights into LUT-loaded vesicles across rat skin for enhanced permeation and drug deposition.

COVID-19: A new challenge for mental health and policymaking recommendations.

The coronavirus disease 2019 (COVID-19) infection has emerged lately, leading to a serious public health threat. The clinical features associated with COVID-19 are yet to be conclusively documented. Caution is needed when interpreting the severity of the symptoms as most of the diagnosed patients are those attending clinical assessments. Features of COVID-19 are far from understood. There is a suggested increased risk of COVID-19 infection among people with mental health disorders, which is primarily attributable to the challenges associated with limited resources. There are a variety of reasons why individuals with mental health disorders are more susceptible to infectious diseases. There is currently no specific recommended antiviral treatment. The interventions now used are supportive treatments to alleviate the symptoms and invasive mechanical ventilation. In this review, we discuss the adverse events associated with COVID-19 vaccinations. We further highlight the need to develop guidelines and recommendations for managing patients with mental health. It is evident from this review, there is a need to provide training programs with interprofessional, multidisciplinary communication channels.

Isolation and Establishment of a Highly Proliferative, Cancer Stem Cell-Like, and Naturally Immortalized Triple-Negative Breast Cancer Cell Line, KAIMRC2.

In vitro studies of a disease are key to any in vivo investigation in understanding the disease and developing new therapy regimens. Immortalized cancer cell lines are the best and easiest model for studying cancer in vitro. Here, we report the establishment of a naturally immortalized highly tumorigenic and triple-negative breast cancer cell line, KAIMRC2. This cell line is derived from a Saudi Arabian female breast cancer patient with invasive ductal carcinoma. Immunocytochemistry showed a significant ratio of the KAIMRC2 cells' expressing key breast epithelial and cancer stem cells (CSCs) markers, including CD47, CD133, CD49f, CD44, and ALDH-1A1. Gene and protein expression analysis showed overexpression of ABC transporter and AKT-PI3Kinase as well as JAK/STAT signaling pathways. In contrast, the absence of the tumor suppressor genes p53 and p73 may explain their high proliferative index. The mice model also confirmed the tumorigenic potential of the KAIMRC2 cell line, and drug tolerance studies revealed few very potent candidates. Our results confirmed an aggressive phenotype with metastatic potential and cancer stem cell-like characteristics of the KAIMR2 cell line. Furthermore, we have also presented potent small molecule inhibitors, especially Ryuvidine, that can be further developed, alone or in synergy with other potent inhibitors, to target multiple cancer-related pathways.

Demographics, comorbidities, and outcomes among young and middle-aged COVID-19 patients in Saudi Arabia.

The impact of different sociodemographic and clinical characteristics on the COVID-19-related morbidity and mortality rates have been studied extensively around the world; however, there is a dearth of data on the impact of different clinical and sociodemographic variables on the COVID-19-related outcomes in Saudi Arabia. This study aimed to identify those at high risk of worse clinical outcomes, such as hospitalization and longer length of stay (LOS) among young and middle-aged adults (18 to 55 years). In this questionnaire-based cross-sectional study, 706 patients with real-time polymerase chain reaction (RT-PCR) confirmed COVID-19 infection were interviewed. Patients' demographic characteristics, dietary habits, medical history, and lifestyle choices were collected through phone interviews. Patients with chronic health conditions, such as diabetes and hypertension, reported a higher rate of hospitalization, ICU admission, oxygen-support needs, and a longer period of recovery and LOS. Multiple logistic regression showed that diabetes, hypertension, and pulmonary disease (e.g., asthma and chronic obstructive pulmonary disease (COPD)) were associated with a higher risk of hospitalization and longer LOS. Multiple logistic regression showed that symptoms of breathlessness, loss of smell and/or taste, diarrhea, and cough were associated with a longer recovery period. Similarly, breathlessness, vomiting, and diarrhea were associated with higher rates of hospitalization. The findings of this study confirm the similarity of the factors associated with worse clinical outcomes across the world. Future studies should use more robust designs to investigate the impact of different therapies on the COVID-19-related morbidity and mortality in Saudi Arabia.

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.

Examining the central effects of chronic stressful social isolation on rats.

Stress-related disorders are extremely complex and current treatment strategies have limitations. The present study investigated alternative pathological mechanisms using a combination of multiple environmental approaches with biochemical and molecular tools. The aim of the present study was to evaluate blood-brain-barrier (BBB) integrity in socially manipulated animal housing conditions. Multiple environmentally-related models were employed in the current study. The main model proposed (chronically isolated rats) was biochemically validated using the level of peripheral corticosterone. The current study examined and compared the mRNA levels of certain inflammatory and BBB markers in the hippocampal tissue of chronically isolated rats, including claudin-5 (cldn5) and tight junction protein (tjp). Animals were divided into four groups: i) Standard housed rats (controls); ii) chronically isolated rats; iii) control rats treated with fluoxetine, which is a standard selective serotonin reuptake inhibitor; and iv) isolated rats treated with fluoxetine. To further examine the effect of environmental conditions on BBB markers, the current study assessed BBB markers in enriched environmental (EE) housing and short-term isolation conditions. The results demonstrated a significant increase in cldn5 and tjp levels in the chronically isolated group. Despite some anomalous results, alterations in mRNA levels were further confirmed in EE housing conditions compared with chronically isolated rats. This trend was also observed in rats subjected to short-term isolation compared with paired controls. Additionally, levels of IL-6, an inflammatory marker associated with neuroinflammation, were markedly increased in the isolated group. However, treatment with fluoxetine treatment reversed these effects. The results indicated that BBB integrity may be compromised in stress-related disorders, highlighting a need for further functional studies on the kinetics of BBB in stress-related models.

The Role of Nicotinic Receptors in the Attenuation of Autism-Related Behaviors in a Murine BTBR T + tf/J Autistic Model.

Nicotinic receptors are distributed throughout the central and peripheral nervous system. Postmortem studies have reported that some nicotinic receptor subtypes are altered in the brains of autistic people. Recent studies have demonstrated the importance of nicotinic acetylcholine receptors (nAChRs) in the autistic behavior of BTBR T + tf/J mouse model of autism. This study was undertaken to examine the behavioral effects of targeted nAChRs using pharmacological ligands, including nicotine and mecamylamine in BTBR T + tf/J and C57BL/6J mice in a panel of behavioral tests relating to autism. These behavioral tests included the three-chamber social interaction, self-grooming, marble burying, locomotor activity, and rotarod test. We examined the effect of various oral doses of nicotine (50, 100, and 400 mcg/mL; po) over a period of 2 weeks in BTBR T + tf/J mouse model. The results indicated that the chronic administration of nicotine modulated sociability and repetitive behavior in BTBR T + tf/J mice while no effects observed in C57BL/6J mice. Furthermore, the nonselective nAChR antagonist, mecamylamine, reversed nicotine effects on sociability and increased repetitive behaviors in BTBR T + tf/J mice. Overall, the findings indicate that the pharmacological modulation of nicotinic receptors is involved in modulating core behavioral phenotypes in the BTBR T + tf/J mouse model. LAY SUMMARY: The involvement of brain nicotinic neurotransmission system plays a crucial role in regulating autism-related behavioral features. In addition, the brain of the autistic-like mouse model has a low acetylcholine level. Here, we report that nicotine, at certain doses, improved sociability and reduced repetitive behaviors in a mouse model of autism, implicating the potential therapeutic values of a pharmacological intervention targeting nicotinic receptors for autism therapy. Autism Res 2020, 13: 1311-1334. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Serum proteomic profiling of patients with amphetamine use disorder.

BACKGROUND: Amphetamine use disorder has been recently classified as an epidemic condition. Amphetamine use/abuse has been associated with several neurological and inflammatory effects. However, the exact mechanism involved in these effects warrants further investigation. The aim of this study was to determine any alterations in the serum proteome of individuals classified as patients with amphetamine use disorder compared to that of control subjects. METHODS: An untargeted proteomic approach employing two-dimensional difference in gel electrophoresis coupled with mass spectrometry was used to identify the patterns of differentially expressed proteins. Serum samples were collected from 20 individuals (males) including 10 subjects with amphetamine use disorder and 10 healthy controls for the present study. RESULTS: The analysis revealed 78 proteins with a significant difference in protein abundance between the amphetamine-addicted subjects and controls. Among them, 71 proteins were upregulated while 7 proteins remained downregulated in the amphetamine-addicted group. These proteins were further analyzed by ingenuity pathway analysis (IPA) to investigate their correlation with other biomarkers. IPA revealed the correlation of altered proteins with mitogen-activated protein kinase (MAP2K1/K2), p38MAPK, protein kinase-B (PKB; Akt), extracellular signal-regulated kinase (ERK1/2), and nuclear factor-κB signaling pathways. Importantly, these pathways are highly involved in neurological diseases, inflammatory responses, and cellular compromise. CONCLUSIONS: Our data suggest that the changes in the levels of serum proteins between amphetamine and control groups might affect cellular compromise, inflammatory response, and neurological diseases.

Systemic TNF-α blockade attenuates anxiety and depressive-like behaviors in db/db mice through downregulation of inflammatory signaling in peripheral immune cells.

Research studies have indicated that the comorbidity burden of mood disorders and obesity is reasonably high. Insulin signaling has been shown to modulate multiple physiological functions in the brain, indicating its association with neuropsychiatric diseases, including mood disorders. Leptin is a hormone responsible for regulating body weight and insulin homeostasis. Previous studies on db/db mice (a mouse model that carries a spontaneous genetic mutation in leptin receptor Leprdb ) have shown that they exhibit inflammation as well as neurobehavioral traits associated with mood. Therefore, targeting inflammatory pathways such as TNF-α may be an effective strategy in the treatment of obesity-linked mood disorders. The objective of this study was to investigate the effect of long-term administration of etanercept (a TNF-α blocker) on anxiety and depressive-like behaviors in db/db mice. This was performed using light/dark box, forced swim, and open field tests with lean littermate wild type (WT) mice serving as a control group. Using flow cytometry in peripheral blood, we further examined the molecular effects of etanercept on NF-κB p65, TNF-α, IL-17A, and TLR-4 expressing CD4+, CD8+, and CD14+ cells in the peripheral blood. Our data show that peripheral administration of etanercept decreased these cells in db/db mice. Furthermore, our results indicated that peripheral administration of etanercept reduced anxiety and depressive-like behaviors. Therefore, targeting TNF-α signaling might be an effective strategy for modulating obesity-associated depression and anxiety.

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.