Anti-Parkinson potential of hesperetin nanoparticles: in vivo and in silico investigations.

Parkinson's disease (PD) is characterised by the gradual demise of dopaminergic neurons. In recent years, there has been significant interest in herbal treatments. In this study, hesperetin nanoparticles (HTN) were developed and compared their anti-PD potential with hesperetin (HT) on rotenone induced PD rats. Molecular docking was also performed to evaluate the binding affinity of hesperetin on pathological protein, i.e. D2 dopamine receptors (DR2), using Auto Dock Vina tools. The results showed a higher binding relationship of HTN on dopamine receptors (-7.2 kcal/mol) compared to L-dopa (-6.4 kcal/mol), supporting their potential as drug candidates for PD therapy. HTN was effectively synthesised using the fabrication technique and characterised by zeta potential and SEM analysis. HTN had favourable characteristics, including a size of 249.8 ± 14.9 nm and a Z-potential of -32.9 mV. After being administered orally, HTN demonstrated a notable anti-Parkinsonian effects, indicated by the significant improvement in motor function as assessed by the rota rod test (p < .001***), pole test (p < .001***), stair test (p < .01**), wood walk test (p < .01**) and an increase in substantia nigra (SN) antioxidant levels, CAT (p < .001***), SOD (p < .001***), GSH (p < .01**). Additionally, HTN led to increased dopamine levels (p < .01**) and a decrease in the oxidant system, MDA levels (p < .01**). Furthermore, histopathological examination revealed decreased SN neuronal necrosis in diseased animals treated with HTN compared to those treated with HT in a rat model of Parkinson's disease. Therefore, HTN can be regarded as a viable platform for efficient therapy of PD.

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.

Cadmium exposure exacerbates immunological abnormalities in a BTBR T+ Itpr3tf/J autistic mouse model by upregulating inflammatory mediators in CD45R-expressing cells.

Autism spectrum disorder (ASD) is a neurodevelopmental illness characterized by behavior, learning, communication, and social interaction abnormalities in various situations. Individuals with impairments usually exhibit restricted and repetitive actions. The actual cause of ASD is yet unknown. It is believed, however, that a mix of genetic and environmental factors may play a role in its development. Certain metals have been linked to the development of neurological diseases, and the prevalence of ASD has shown a positive association with industrialization. Cadmium chloride (Cd) is a neurotoxic chemical linked to cognitive impairment, tremors, and neurodegenerative diseases. The BTBR T+ Itpr3tf/J (BTBR) inbred mice are generally used as a model for ASD and display a range of autistic phenotypes. We looked at how Cd exposure affected the signaling of inflammatory mediators in CD45R-expressing cells in the BTBR mouse model of ASD. In this study, we looked at how Cd affected the expression of numerous markers in the spleen, including IFN-γ, IL-6, NF-κB p65, GM-CSF, iNOS, MCP-1, and Notch1. Furthermore, we investigated the effect of Cd exposure on the expression levels of numerous mRNA molecules in brain tissue, including IFN-γ, IL-6, NF-κB p65, GM-CSF, iNOS, MCP-1, and Notch1. The RT-PCR technique was used for this analysis. Cd exposure increased the number of CD45R+IFN-γ+, CD45R+IL-6+, CD45R+NF-κB p65+, CD45R+GM-CSF+, CD45R+GM-CSF+, CD45R+iNOS+, and CD45R+Notch1+ cells in the spleen of BTBR mice. Cd treatment also enhanced mRNA expression in brain tissue for IFN-γ, IL-6, NF-κB, GM-CSF, iNOS, MCP-1, and Notch1. In general, Cd increases the signaling of inflammatory mediators in BTBR mice. This study is the first to show that Cd exposure causes immune function dysregulation in the BTBR ASD mouse model. As a result, our study supports the role of Cd exposure in the development of ASD.

Pharmacoscreening, molecular dynamics, and quantum mechanics of inermin from Panax ginseng: a crucial molecule inhibiting exosomal protein target associated with coronary artery disease progression.

Background: Exosomes, microvesicles, carry and release several vital molecules across cells, tissues, and organs. Epicardial adipose tissue exosomes are critical in the development and progression of coronary artery disease (CAD). It is hypothesized that exosomes may transport causative molecules from inflamed tissue and deliver to the target tissue and progress CAD. Thus, identifying and inhibiting the CAD-associated proteins that are being transported to other cells via exosomes will help slow the progression of CAD. Methods: This study uses a systems biological approach that integrates differential gene expression in the CAD, exosomal cargo assessment, protein network construction, and functional enrichment to identify the crucial exosomal cargo protein target. Meanwhile, absorption, distribution, metabolism, and excretion (ADME) screening of Panax ginseng-derived compounds was conducted and then docked against the protein target to identify potential inhibitors and then subjected to molecular dynamics simulation (MDS) to understand the behavior of the protein-ligand complex till 100 nanoseconds. Finally, density functional theory (DFT) calculation was performed on the ligand with the highest affinity with the target. Results: Through the systems biological approach, Mothers against decapentaplegic homolog 2 protein (SMAD2) was determined as a potential target that linked with PI3K-Akt signaling, Ubiquitin mediated proteolysis, and the focal adhesion pathway. Further, screening of 190 Panax ginseng compounds, 27 showed drug-likeness properties. Inermin, a phytochemical showed good docking with -5.02 kcal/mol and achieved stability confirmation with SMAD2 based on MDS when compared to the known CAD drugs. Additionally, DFT analysis of inermin showed high chemical activity that significantly contributes to effective target binding. Overall, our computational study suggests that inermin could act against SMAD2 and may aid in the management of CAD.

Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study.

Background and Objectives: PON1 is a multi-functional antioxidant protein that hydrolyzes a variety of endogenous and exogenous substrates in the human system. Growing evidence suggests that the Leu55Met and Gln192Arg substitutions alter PON1 activity and are linked with a variety of oxidative-stress-related diseases. Materials and Methods: We implemented structural modeling and molecular dynamics (MD) simulation along with essential dynamics of PON1 and molecular docking with their endogenous (n = 4) and exogenous (n = 6) substrates to gain insights into conformational changes and binding affinity in order to characterize the specific functional ramifications of PON1 variants. Results: The Leu55Met variation had a higher root mean square deviation (0.249 nm) than the wild type (0.216 nm) and Gln192Arg (0.202 nm), implying increased protein flexibility. Furthermore, the essential dynamics analysis confirms the structural change in PON1 with Leu55Met vs. Gln192Arg and wild type. Additionally, PON1 with Leu55Met causes local conformational alterations at the substrate binding site, leading to changes in binding affinity with their substrates. Conclusions: Our findings highlight the structural consequences of the variants, which would increase understanding of the role of PON1 in the pathogenesis of oxidative-stress-related diseases, as well as the management of endogenous and exogenous chemicals in the treatment of diseases.

Ameliorative anticancer effect of dendrimeric peptide modified liposomes of letrozole: In vitro and in vivo performance evaluations.

Letrozole (LTZ) loaded dendrimeric nano-liposomes were prepared for targeted delivery to breast cancer cells. Surface modification with cationic peptide dendrimers (PDs) and a cancer specific ligand, transferrin (Tf), was attempted. Arginine-terminated PD (D-1) and Arginine-terminated, lipidated PD (D-2) were synthesized using Solid Phase Peptide Synthesis, purified by preparative HPLC and characterized using 1HNMR, MS and DSC analyses. Surface modification of drug loaded liposomes with Tf and/or PD was carried out. Formulations were characterized using FTIR, DSC, 1HNMR, XRD and TEM. Tf-conjugated LTZ liposomes (LTf) and Tf/D-2-conjugated LTZ liposomes (LTfD-2) showed greater cytotoxic potential (IC50 = 95.03 µg/mL and 23.75 µg/mL respectively) with enhanced cellular uptake in MCF7 cells compared to plain LTZ. Blocking studies of Tf (Tf-receptor mediated internalization) revealed decreased uptake of LTf and LTfD-2 confirming the role of Tf in uptake of Tf-conjugated liposomes. Intravenous treatment with LTfD-2 caused highest reduction in tumor volumes of female BALB/c-nude mice (145 mm3) compared to plain LTZ (605 mm3) and unconjugated LTZ liposomes (LP) (300 mm3). In vivo biodistribution studies revealed higher fluorescence in tumor tissue and liver of LTfD-2 treated mice than LTf or LP treatment. Immunohistochemical studies revealed greater apoptotic potential of LTfD-2 as indicated by TUNEL assay and ROS detection assay. The study reveals the superior therapeutic efficacy of the developed LTZ liposomal nanocarriers using PDs to enhance the transfection efficiency in addition to modifying the surface characteristics by attaching a targeting ligand for active drug targeting to breast cancer cells.

Effect of Smartphone Use on Sleep in Undergraduate Medical Students: A Cross-Sectional Study.

Smartphone use, particularly at night, has been shown to provoke various circadian sleep-wake rhythm disorders such as insomnia and excessive daytime tiredness. This relationship has been mainly scrutinized among patient groups with higher rates of smartphone usage, particularly adolescents and children. However, it remains obscure how smartphone usage impacts sleep parameters in adults, especially undergraduate college students. This study sought to (1) investigate the association between smartphone use (actual screen time) and four sleep parameters: Pittsburgh sleep quality score (PSQI), self-reported screen time, bedtime, and rise time; (2) compare the seven PSQI components between good and poor sleep quality subjects. In total, 264 undergraduate medical students (aged 17 to 25 years) were recruited from the Government Doon Medical College, Dehradun, India. All participants completed a sleep questionnaire, which was electronically shared via a WhatsApp invitation link. Hierarchical and multinomial regression analyses were performed in relation to (1) and (2). The average PSQI score was 5.03 ± 0.86, with approximately one in two respondents (48.3%) having a poor sleep index. Smartphone use significantly predicted respondents' PSQI score (ß = 0.142, p = 0.040, R2 = 0.027), perceived screen time (ß = 0.113, p = 0.043, R2 = 343), bedtime (ß = 0.106, p = 0.042, R2 = 045), and rise time (ß = 0.174, p = 0.015, R2 = 0.028). When comparing poor-quality sleep (PSQI ≥ 5) to good-quality sleep (PSQI < 5), with good-quality sleep as the reference, except sleep efficiency and sleep medications (p > 0.05), five PSQI components declined significantly: subjective sleep quality (ß = -0.096, p < 0.001); sleep latency (ß = -0.034, p < 0.001); sleep duration (ß = -0.038, p < 0.001); sleep disturbances (ß = 1.234, p < 0.001); and sleep dysfunction (ß = -0.077, p < 0.001). Consequently, public health policymakers should take this evidence into account when developing guidelines around smartphone use-i.e., the when, where, and how much smartphone use-to promote improved sleep behaviour and reduce the rate of sleep-wake rhythm disorders.

Unveiling the Cardioprotective Power: Liquid Chromatography-Mass Spectrometry (LC-MS)-Analyzed Neolamarckia cadamba (Roxb.) Bosser Leaf Ethanolic Extract against Myocardial Infarction in Rats and In Silico Support Analysis.

Neolamarckia cadamba (Roxb.) Bosser, a member of the Rubiaceae family, is a botanical species with recognized therapeutic properties. It is commonly used in traditional medicine to treat cardiac ailments and other disorders. However, the precise active constituents and the potential mechanisms by which they manage cardiovascular disorders remain unclear. Therefore, this study aimed to ascertain the bioactive components and investigate their underlying mechanisms of action. N. cadamba is used to treat cardiovascular disorders using the integrated metabolomic methodology. An HPLC-QTOF-MS/MS analysis determined the potential chemicals in the N. cadamba leaf ethanol extract (NCEE). A thorough investigation of the NCEE samples used in this study led to the identification of 32 phytoconstituents. Of the 32 compounds, 19 obeyed Lipinski's rule of five (RO5). A molecular docking study directed towards HMG-CoA reductase used 19 molecules. The reference drug atorvastatin indicated a binding energy of -3.9 kcal/mol, while the other substances, Cinchonain Ib and Dukunolide B, revealed binding energies of -5.7 and -5.3 kcal/mol, respectively. Both phytocompounds showed no toxicity and exhibited favorable pharmacokinetic properties. In vivo study results concluded that treatment with NCEE significantly reduced the cardiac myocardial infarction (MI) marker CK-MB and atherogenic risk indices, such as the atherogenic index plasma (AIP), cardiac risk ratio (CRR), and atherogenic coefficient (AC) in isoproterenol-induced MI rats. In MI rats, NCEE therapy significantly improved the antioxidant system of the heart tissue, as evidenced by the increased levels of GSH and SOD, lower levels of the oxidative stress marker MDA, and significantly decreased HMG-CoA activity. Additionally, electrocardiogram (ECG) signals from rats treated with NCEE resembled those treated with traditional atorvastatin to treat myocardial infarction. This study used H&E staining to show that administering NCEE before treatment reduced cardiac myocyte degeneration in rats with myocardial infarction, increased the presence of intact nuclei, and increased myocardial fiber strength. The potential cardioprotective effect observed in myocardial infarction (MI) rats treated with NCEE can be extrapolated from computational data to be caused by Cinchonain Ib.

Saxagliptin, a selective dipeptidyl peptidase-4 inhibitor, alleviates somatic cell aneugenicity and clastogenicity in diabetic mice.

Diabetes-related complications are becoming increasingly common as the global prevalence of diabetes increases. Diabetes is also linked to a high risk of developing cancer. This raises the question of whether cancer vulnerability is caused by diabetes itself or the use of antidiabetic drugs. Chromosomal instability, a source of genetic modification involving either an altered chromosomal number or structure, is a hallmark of cancer. Saxagliptin has been approved by the FDA for diabetes treatment. However, the detailed in vivo effects of prolonged saxagliptin treatment on chromosomal instability have not yet been reported. In this study, streptozotocin was used to induce diabetes in mice, and both diabetic and non-diabetic mice received saxagliptin for five weeks. Fluorescence in situ hybridization was conducted in combination with a bone marrow micronucleus test for measuring chromosomal instability. Our results indicated that saxagliptin is neither mutagenic nor cytotoxic, under the given treatment regimen. Diabetic mice had a much higher incidence of micronuclei formation, and a centromeric DNA probe was present inside the majority of the induced micronuclei, indicating that most of these were caused by chromosome nondisjunction. Conversely, diabetic mice treated with saxagliptin exhibited a significant decrease in micronuclei induction, which were centromeric-positive and centromeric-negative. Diabetes also causes significant biochemical changes indicative of oxidative stress, such as increased lipid peroxidation and decreased reduced/oxidized glutathione ratio, which was reversed by saxagliptin administration. Overall, saxagliptin, the non-mutagenic antidiabetic drug, maintains chromosomal integrity in diabetes and reduces micronuclei formation by restoring redox imbalance, further indicating its usefulness in diabetic patients.

Comparative Efficacy of Metformin and Glimepiride in Modulating Pharmacological Network to Increase BDNF Levels and Benefit Type 2 Diabetes-Related Cognitive Impairment.

Cognitive impairment is anotable complication of type 2 diabetes (T2DM), accompanied by reduced brain-derived neurotrophic factor (BDNF) in the brain and blood. Anti-diabetic drugs reduce hyperglycemia, yet their effect on cognitive improvement is unknown. We aimed to investigate the effect of anti-diabetic drugs regulating BDNF in T2DM through computational and case-control study design. We obtained T2DMproteins viatext-mining to construct a T2DMprotein network. From the T2DMnetwork, the metformin and glimepiride interactomes and their crucial shortest-path-stimulating BDNF were identified. Using qRTPCR, the genes encoding the shortest-path proteins were assessed in four groups (untreated-T2DM, metformin-treated, glimepiride-treated, and healthy controls). Finally, ELISA was used to assess serum BDNF levels to validate drug efficacy. As a result of this investigation, aT2DMnetwork was constructed with 3683 text-mined proteins. Then, the T2DMnetwork was explored to generate a metformin and glimepiride interactome that establishes the critical shortest-path for BDNF stimulation. Metformin stimulates BDNF via APP binding to the PRKAB1 receptor. Whereas, glimepiride increases BDNF by binding to KCNJ11 via AP2M1 and ESR1 proteins. Both drug shortest-path encoding genes differed significantly between the groups. Unlike metformin, BDNF gene and protein expression rise significantly with glimepiride. Overall, glimepiride can effectively increase BDNF, which could benefit T2DM patients with cognitive deterioration.

Elucidating the Histone Deacetylase Gene Expression Signatures in Peripheral Blood Mononuclear Cells That Correlate Essential Cardiac Function and Aid in Classifying Coronary Artery Disease through a Logistic Regression Model.

A proinflammatory role of HDACs has been implicated in the pathogenesis of atherosclerosis as an emerging novel epigenetic diagnostic biomarker. However, its association with the clinical and cardiovascular function in coronary artery disease is largely unknown. The study aimed to profile the gene expression of HDAC1-11 in human peripheral blood mononuclear cells and to evaluate their influence on hematological, biochemical, and two-dimensional echocardiographic indices in CAD. The HDAC gene expression profiles were assessed in 62 angioproven CAD patients and compared with 62 healthy controls. Among the HDACs, upregulated HDACs 1,2, 4, 6, 8, 9, and 11 were upregulated, and HDAC3 was downregulated, which was significantly (p ≤ 0.05) linked with the hematological (basophils, lymphocytes, monocytes, and neutrophils), biochemical (LDL, HDL, and TGL), and echocardiographic parameters (cardiac function: biplane LVEF, GLS, MV E/A, IVRT, and PV S/D) in CAD. Furthermore, our constructed diagnostic model with the crucial HDACs establishes the most crucial HDACs in the classification of CAD from control with an excellent accuracy of 88.6%. Conclusively, our study has provided a novel perspective on the HDAC gene expression underlying cardiac function that is useful in developing molecular methods for CAD diagnosis.

Dapagliflozin Mitigated Elevated Disomic and Diploid Sperm in a Mouse Model of Diabetes and Recover the Disrupted Ogg1, Parp1, and P53 Gene Expression.

Increases in numerical chromosomal syndromes were observed in children of diabetic mothers. However, the effects of diabetes on male reproduction, specifically numerical chromosomal aberrations (aneuploidy), have not been studied. Furthermore, despite the increasing use of dapagliflozin for diabetes treatment, no data exists on its ability to affect aneuploidy levels in germ cells. Thus, our investigation aimed to evaluate the effects of diabetes on spontaneous sperm aneuploidy and whether treatment with dapagliflozin influences the frequency of aneuploidy in the sperm of an experimental diabetic animal model. Our findings show that dapagliflozin has no aneugenic effects on the meiotic stages of spermatogenesis. In contrast, diabetes raised the frequency of aneuploidy, and dapagliflozin administration decreased the elevated levels of disomic and diploid sperm. The level of oxidative stress was markedly increased in diabetic mice, but were reduced by dapagliflozin treatment. Furthermore, the expression of some of DNA repair genes was disrupted in diabetic animals, whereas dapagliflozin therapy restored these disruptions and significantly enhanced DNA repair. Thus, dapagliflozin may effectively ameliorate diabetes-induced aneugenic effects on male meiosis and treating diabetic patients with dapagliflozin may effectively mitigate the transmission of diabetes-induced chromosomal defects to offspring.

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

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

Bacillus Calmette-Guérin Vaccine Attenuates Haloperidol-Induced TD-like Behavioral and Neurochemical Alteration in Experimental Rats.

Tardive dyskinesia (TD) is a hyperkinetic movement disorder that displays unusual involuntary movement along with orofacial dysfunction. It is predominantly associated with the long-term use of antipsychotic medications, particularly typical or first-generation antipsychotic drugs such as haloperidol. Oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis are major pathophysiological mechanisms of TD. The BCG vaccine has been reported to suppress inflammation, oxidative stress, and apoptosis and exert neuroprotection via several mechanisms. Our study aimed to confirm the neuroprotective effect of the BCG vaccine against haloperidol-induced TD-like symptoms in rats. The rats were given haloperidol (1 mg/kg, i.p.) for 21 days after 1 h single administration of the BCG vaccine (2 × 107 cfu). Various behavioral parameters for orofacial dyskinesia and locomotor activity were assessed on the 14th and 21st days after haloperidol injection. On the 22nd day, all rats were euthanized, and the striatum was isolated to estimate the biochemical, apoptotic, inflammatory, and neurotransmitter levels. The administration of the BCG vaccine reversed orofacial dyskinesia and improved motor function in regard to haloperidol-induced TD-like symptoms in rats. The BCG vaccine also enhanced the levels of antioxidant enzymes (SOD, GSH) and reduced prooxidants (MDA, nitrite) and pro-apoptotic markers (Cas-3, Cas-6, Cas-9) in rat brains. Besides this, BCG treatment also restored the neurotransmitter (DA, NE, 5-HT) levels and decreased the levels of HVA in the striatum. The study findings suggest that the BCG vaccine has antioxidant, antiapoptotic, and neuromodulatory properties that could be relevant in the management of TD.

Aflatoxin B1 Exposure Aggravates Neurobehavioral Deficits and Immune Dysfunctions of Th1, Th9, Th17, Th22, and T Regulatory Cell-Related Transcription Factor Signaling in the BTBR T+Itpr3tf/J Mouse Model of Autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by impaired communication, reciprocal social interactions, restricted sociability deficits, and stereotyped behavioral patterns. Environmental factors and genetic susceptibility have been implicated in an increased risk of ASD. Aflatoxin B1 (AFB1) is a typical contaminant of food and feed that causes severe immune dysfunction in humans and animals. Nevertheless, the impact of ASD on behavioral and immunological responses has not been thoroughly examined. To investigate this phenomenon, we subjected BTBR T+Itpr3tf/J (BTBR) mice to AFB1 and evaluated their marble-burying and self-grooming behaviors and their sociability. The exposure to AFB1 resulted in a notable escalation in marble-burying and self-grooming activities while concurrently leading to a decline in social contacts. In addition, we investigated the potential molecular mechanisms that underlie the impact of AFB1 on the production of Th1 (IFN-γ, STAT1, and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A, IL-21, RORγT, and STAT3), Th22 (IL-22, AhR, and TNF-α), and T regulatory (Treg) (IL-10, TGF-ß1, and FoxP3) cells in the spleen. This was achieved using RT-PCR and Western blot analyses to assess mRNA and protein expression in brain tissue. The exposure to AFB1 resulted in a significant upregulation of various immune-related factors, including IFN-γ, STAT1, T-bet, IL-9, IRF4, IL-17A, IL-21, RORγ, STAT3, IL-22, AhR, and TNF-α in BTBR mice. Conversely, the production of IL-10, TGF-ß1, and FoxP3 by CD4+ T cells was observed to be downregulated. Exposure to AFB1 demonstrated a notable rise in Th1/Th9/Th22/Th17 levels and a decrease in mRNA and protein expression of Treg. The results above underscore the significance of AFB1 exposure in intensifying neurobehavioral and immunological abnormalities in BTBR mice, hence indicating the necessity for a more comprehensive investigation into the contribution of AFB1 to the development of ASD.

Screening of Crucial Cytosolicproteins Interconnecting the Endoplasmic Reticulum and Mitochondria in Parkinson's Disease and the Impact of Anti-Parkinson Drugs in the Preservation of Organelle Connectivity.

Mitochondrial dysfunction is well-established in Parkinson's disease (PD); however, its dysfunctions associating with cell organelle connectivity remain unknown. We aimed to establish the crucial cytosolic protein involved in organelle connectivity between mitochondria and the endopalmic reticulum (ER) through a computational approach by constructing an organelle protein network to extract functional clusters presenting the crucial PD protein connecting organelles. Then, we assessed the influence of anti-parkinsonism drugs (n = 35) on the crucial protein through molecular docking and molecular dynamic simulation and further validated its gene expression in PD participants under, istradefylline (n = 25) and amantadine (n = 25) treatment. Based on our investigation, D-aspartate oxidase (DDO )protein was found to be the critical that connects both mitochondria and the ER. Further, molecular docking showed that istradefylline has a high affinity (-9.073 kcal/mol) against DDO protein, which may disrupt mitochondrial-ER connectivity. While amantadine (-4.53 kcal/mol) shows negligible effects against DDO that contribute to conformational changes in drug binding, Successively, DDO gene expression was downregulated in istradefylline-treated PD participants, which elucidated the likelihood of an istradefylline off-target mechanism. Overall, our findings illuminate the off-target effects of anti-parkinsonism medications on DDO protein, enabling the recommendation of off-target-free PD treatments.

Citronellal as a Promising Candidate for Alzheimer's Disease Treatment: A Comprehensive Study on In Silico and In Vivo Anti-Acetylcholine Esterase Activity.

One of the primary therapeutic approaches for managing Alzheimer's disease (AD) involves the modulation of Acetylcholine esterase (AChE) activity to elevate acetylcholine (ACh) levels inside the brain. The current study employed computational chemistry approaches to evaluate the inhibitory effects of CTN on AChE. The docking results showed that Citronellal (CTN) and standard Donepezil (DON) have a binding affinity of -6.5 and -9.2 Kcal/mol, respectively, towards AChE. Further studies using molecular dynamics (MD) simulations were carried out on these two compounds. Binding free energy calculations and ligand-protein binding patterns suggested that CTN has a binding affinity of -12.2078. In contrast, DON has a much stronger binding relationship of -47.9969, indicating that the standard DON has a much higher binding affinity than CTN for AChE. In an in vivo study, Alzheimer-type dementia was induced in mice by scopolamine (1.5 mg/kg/day i.p) for 14 days. CTN was administered (25 and 50 mg/kg. i.p) along with scopolamine (SCO) administration. DON (0.5 mg/kg orally) was used as a reference drug. CTN administration significantly improved the mice's behavior as evaluated by the Morris water maze test, evident from decreased escape latency to 65.4%, and in the CPS test, apparent from reduced escape latency to 69.8% compared to the positive control mice. Moreover, CTN significantly increased the activities of antioxidant enzymes such as catalase and superoxide dismutase (SOD) compared to SCO. Furthermore, CTN administration significantly decreased SCO-induced elevated AChE levels in mice. These results were supported by histopathological and in silico molecular docking studies. CTN may be a potential antioxidant and neuroprotective supplement.

The Exposure to Lead (Pb) Exacerbates Immunological Abnormalities in BTBR T+ Itpr3tf/J Mice through the Regulation of Signaling Pathways Relevant to T Cells.

Autism spectrum disorder (ASD) is a common neurodevelopmental illness characterized by abnormal social interactions, communication difficulties, and repetitive and limited behaviors or interests. The BTBR T+ Itpr3tf/J (BTBR) mice have been used extensively to research the ASD-like phenotype. Lead (Pb) is a hazardous chemical linked to organ damage in the human body. It is regarded as one of the most common metal exposure sources and has been connected to the development of neurological abnormalities. We used flow cytometry to investigate the molecular mechanism behind the effect of Pb exposure on subsets of CD4+ T cells in the spleen expressing IFN-γ, T-bet, STAT1, STAT4, IL-9, IRF4, IL-22, AhR, IL-10, and Foxp3. Furthermore, using RT-PCR, we studied the effect of Pb on the expression of numerous genes in brain tissue, including IFN-γ, T-bet, STAT1, STAT4, IL-9, IRF4, IL-22, AhR, IL-10, and Foxp3. Pb exposure increased the population of CD4+IFN-γ+, CD4+T-bet+, CD4+STAT1+, CD4+STAT4+, CD4+IL-9+, CD4+IRF4+, CD4+IL-22+, and CD4+AhR+ cells in BTBR mice. In contrast, CD4+IL-10+ and CD4+Foxp3+ cells were downregulated in the spleen cells of Pb-exposed BTBR mice compared to those treated with vehicle. Furthermore, Pb exposure led to a significant increase in IFN-γ, T-bet, STAT1, STAT4, IL-9, IRF4, IL-22, and AhR mRNA expression in BTBR mice. In contrast, IL-10 and Foxp3 mRNA expression was significantly lower in those treated with the vehicle. Our data suggest that Pb exposure exacerbates immunological dysfunctions associated with ASD. These data imply that Pb exposure may increase the risk of ASD.

Targeted Delivery of 5-Fluorouracil and Sonidegib via Surface-Modified ZIF-8 MOFs for Effective Basal Cell Carcinoma Therapy.

The therapeutic effectiveness of the most widely used anticancer drug 5-fluorouracil (5-FU) is constrained by its high metabolism, short half-life, and rapid drug resistance after chemotherapy. Although various nanodrug delivery systems have been reported for skin cancer therapy, their retention, penetration and targeting are still a matter of concern. Hence, in the current study, a topical gel formulation that contains a metal-organic framework (zeolitic imidazole framework; ZIF-8) loaded with 5-FU and a surface modified with sonidegib (SDG; acting as a therapeutic agent as well as a targeting ligand) (5-FU@ZIF-8 MOFs) is developed against DMBA-UV-induced BCC skin cancer in rats. The MOFs were prepared using one-pot synthesis followed by post drug loading and SDG conjugation. The optimized MOFs were incorporated into hyaluronic acid-hydroxypropyl methyl cellulose gel and further subjected to characterization. Enhanced skin deposition of the 5-FU@ZIF-8-SDG MOFs was observed using ex vivo skin permeation studies. Confocal laser microscopy studies showed that 5-FU@ZIF-8-SDG MOFs permeated the skin via the transfollicular pathway. The 5-FU@ZIF-8-SDG MOFs showed stronger cell growth inhibition in A431 cells and good biocompatibility with HaCaT cells. Histopathological studies showed that the efficacy of the optimized MOF gels improved as the epithelial cells manifested modest hyperplasia, nuclear pleomorphism, and dyskeratosis. Additionally, immunohistochemistry and protein expression studies demonstrated the improved effectiveness of the 5-FU@ZIF-8-SDG MOFs, which displayed a considerable reduction in the expression of Bcl-2 protein. Overall, the developed MOF gels showed good potential for the targeted delivery of multifunctional MOFs in topical formulations for treating BCC cancer.

Comparative Antibacterial and Efflux Pump Inhibitory Activity of Isolated Nerolidol, Farnesol, and α-Bisabolol Sesquiterpenes and Their Liposomal Nanoformulations.

The efflux systems are considered important mechanisms of bacterial resistance due to their ability to extrude various antibiotics. Several naturally occurring compounds, such as sesquiterpenes, have demonstrated antibacterial activity and the ability to inhibit efflux pumps in resistant strains. Therefore, the objective of this research was to analyze the antibacterial and inhibitory activity of the efflux systems NorA, Tet(K), MsrA, and MepA by sesquiterpenes nerolidol, farnesol, and α-bisabolol, used either individually or in liposomal nanoformulation, against multi-resistant Staphylococcus aureus strains. The methodology consisted of in vitro testing of the ability of sesquiterpenes to reduce the Minimum Inhibitory Concentration (MIC) and enhance the action of antibiotics and ethidium bromide (EtBr) in broth microdilution assays. The following strains were used: S. aureus 1199B carrying the NorA efflux pump, resistant to norfloxacin; IS-58 strain carrying Tet(K), resistant to tetracyclines; RN4220 carrying MsrA, conferring resistance to erythromycin. For the EtBr fluorescence measurement test, K2068 carrying MepA was used. It was observed the individual sesquiterpenes exhibited better antibacterial activity as well as efflux pump inhibition. Farnesol showed the lowest MIC of 16.5 µg/mL against the S. aureus RN4220 strain. Isolated nerolidol stood out for reducing the MIC of EtBr to 5 µg/mL in the 1199B strain, yielding better results than the positive control CCCP, indicating strong evidence of NorA inhibition. The liposome formulations did not show promising results, except for liposome/farnesol, which reduced the MIC of EtBr against 1199B and RN4220. Further research is needed to evaluate the mechanisms of action involved in the inhibition of resistance mechanisms by the tested compounds.