Effect of dexmedetomidine on ncRNA and mRNA profiles of cerebral ischemia-reperfusion injury in transient middle cerebral artery occlusion rats model.

Ischemic stroke poses a significant global health burden, with rapid revascularization treatments being crucial but often insufficient to mitigate ischemia-reperfusion (I/R) injury. Dexmedetomidine (DEX) has shown promise in reducing cerebral I/R injury, but its potential molecular mechanism, particularly its interaction with non-coding RNAs (ncRNAs), remains unclear. This study investigates DEX's therapeutic effect and potential molecular mechanisms in reducing cerebral I/R injury. A transient middle cerebral artery obstruction (tMACO) model was established to simulate cerebral I/R injury in adult rats. DEX was administered pre-ischemia and post-reperfusion. RNA sequencing and bioinformatic analyses were performed on the ischemic cerebral cortex to identify differentially expressed non-coding RNAs (ncRNAs) and mRNAs. The sequencing results showed 6,494 differentially expressed (DE) mRNA and 2698 DE circRNA between the sham and tMCAO (I/R) groups. Additionally, 1809 DE lncRNA, 763 DE mRNA, and 2795 DE circRNA were identified between the I/R group and tMCAO + DEX (I/R + DEX) groups. Gene ontology (GO) analysis indicated significant enrichment in multicellular biogenesis, plasma membrane components, and protein binding. KEGG analysis further highlighted the potential mechanism of DEX action in reducing cerebral I/R injury, with hub genes involved in inflammatory pathways. This study demonstrates DEX's efficacy in reducing cerebral I/R injury and offers insights into its brain-protective effects, especially in ischemic stroke. Further research is warranted to fully understand DEX's neuroprotective mechanisms and its clinical applications.

Vitamin B6 Via p-JNK/Nrf-2/NF-κB Signaling Ameliorates Cadmium Chloride-Induced Oxidative Stress Mediated Memory Deficits in Mice Hippocampus.

BACKGROUND: Cadmium chloride (Cd) is a pervasive environmental heavy metal pollutant linked to mitochondrial dysfunction, memory loss, and genetic disorders, particularly in the context of neurodegenerative diseases like Alzheimer's disease (AD). METHODS: This study investigated the neurotherapeutic potential of vitamin B6 (Vit. B6) in mitigating Cd-induced oxidative stress and neuroinflammation-mediated synaptic and memory dysfunction. Adult albino mice were divided into four groups: Control (saline-treated), Cd-treated, Cd+Vit. B6- treated, and Vit. B6 alone-treated. Cd and Vit. B6 were administered intraperitoneally, and behavioral tests (Morris Water Maze, Y-Maze) were conducted. Subsequently, western blotting, antioxidant assays, blood glucose, and hyperlipidemia assessments were performed. RESULTS: Cd-treated mice exhibited impaired cognitive function, while Cd+Vit. B6-treated mice showed significant improvement. Cd-induced neurotoxic effects, including oxidative stress and neuroinflammation, were observed, along with disruptions in synaptic proteins (SYP and PSD95) and activation of p-JNK. Vit. B6 administration mitigated these effects, restoring synaptic and memory deficits. Molecular docking and MD simulation studies confirmed Vit. B6's inhibitory effect on IL-1ß, NRF2, and p-JNK proteins. CONCLUSION: These results highlight Vit. B6 as a safe therapeutic supplement to mitigate neurodegenerative disorders, emphasizing the importance of assessing nutritional interventions for combating environmental neurotoxicity in the interest of public health.

Identification of novel and potential inhibitors against the dengue virus NS2B/NS3 protease using virtual screening and biomolecular simulations.

Approximately 3.9 billion individuals are vulnerable to dengue infection, a prevalent cause of tropical diseases worldwide. Currently, no drugs are available for preventing or treating Flavivirus diseases, including Dengue, West Nile, and the more recent Zika virus. The highly conserved Flavivirus NS2B-NS3 protease, crucial for viral replication, is a promising therapeutic target. This study employed in-silico methodologies to identify novel and potentially effective anti-dengue small molecules. A pharmacophore model was constructed using an experimentally validated NS2B-NS3 inhibitor, with the Gunner Henry score confirming the model's validity. The Natural Product Activity and Species Source (NPASS) database was screened using the validated pharmacophore model, yielding a total of 60 hits against the NS2B-NS3 protease. Furthermore, the docking finding reveals that our newly identified compounds from the NPASS database have enhanced binding affinities and established significant interactions with allosteric residues of the target protein. MD simulation and post-MD analysis further validated this finding. The free binding energy was computed in terms of MM-GBSA analysis, with the total binding energy for compound 1 (-57.3 ± 2.8 and - 52.9 ± 1.9 replica 1 and 2) indicating a stronger binding affinity for the target protein. Overall, this computational study identified these compounds as potential hit molecules, and these findings can open up a new avenue to explore and develop inhibitors against Dengue virus infection.

Implementing Formative Assessment in Human Anatomy Practical Sessions: Medical Students' Perception and Effect on Final Exam Performance.

Background: Formative assessment with feedback is part of the assessment program in medical education to improve students' learning. Limited research has focused on its application and impact on practical anatomy education. Methods: This study aimed to examine medical students' perceptions of formative assessment in practical anatomy sessions of body systems-based educational units and explore its influence on final practical exam performance. A descriptive, cross-sectional study was conducted. Data was collected from 173 Year 2 medical students through a survey that addressed their perception of process and importance of formative assessment and feedback. The survey employed a 5-point Likert scale. Two open-ended questions were appended at the end of the survey. Students' performance in Unit 3 (where formative assessment was conducted) was compared to their performance in Unit 2 (where no formative assessment was conducted) and with the performance of the previous academic year's students in Unit 3 (where no formative assessment was conducted). Descriptive statistics were used. The level of statistical significance was set at p-value < 0.05. Responses to open-ended questions (qualitative data) were counted, categorized as themes, and presented as frequencies and percentages. Results: The survey showed high internal consistency, and its validity was established through exploratory factor analysis. Results showed that the mean mark for the unit with formative assessment and feedback was significantly higher than for the units without formative assessment and feedback. Students showed positive perception of formative assessment and feedback conducted after practical anatomy sessions. They reported useful insights regarding the benefits they gained from formative assessment and feedback as well as constructive suggestions for future improvements. Conclusion: The study indicates that students positively perceived formative assessment and feedback sessions after practical anatomy sessions. Findings also refer to a positive effect of formative assessment on students' performance in summative practical assessment in anatomy.

Recent advances in nanoformulation-based delivery for cancer immunotherapy.

Cancer is one of the leading causes of mortality worldwide, and its treatment faces several challenges. Phytoconstituents derived from recently discovered medicinal plants through nanotechnology potentially target cancer cells via PI3K/Akt/mTOR pathways and exert their effects selectively through the generation of reactive oxygen species through ß-catenin inhibition, DNA damage, and increasing caspase 3/9 and p53 expression. These nanocarriers act specifically against different cancer cell lines such as HT-29, MOLT-4 human leukemia cancer and MCF-7 cell lines SKOV-3, Caov-3, SW-626, HepG2, A-549, HeLa, and MCF-7. This review comprehensively elaborates on the cellular and molecular mechanisms, and therapeutic prospects of various plant-mediated nanoformulations to attain a revolutionary shift in cancer immunotherapy.

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Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: The end of a diagnostic odyssey.

Angelman syndrome (AS, MIM #105830) is a neurodevelopmental disorder characterized by severe intellectual disability, profound developmental delay, movement or balance problems, an excessively cheerful disposition, and seizures. AS results from inadequate expression of the maternal UBE3A gene (MIM #601623), which encodes an E3 ligase in the ubiquitin-proteasome pathway. Here we present the case of two sisters with features consistent with AS who had negative methylation analyses. An autism/intellectual disability expanded panel revealed a maternally inherited novel UBE3A (NM_001354506.2) variant c.2443C>T p.(Pro815Ser) in both patients that was initially classified as a variant of uncertain significance. The patients were enrolled in Indiana University's Undiagnosed Rare Disease Clinic (URDC) to further investigate the variant. Additional data, including deep phenotyping, familial segregation analysis, and in silico studies, suggest that the variant is likely pathogenic. 3D modeling studies based on the available crystal structure revealed that the Pro815Ser variant can introduce more flexibility into the protein and alter its enzymatic activity. Recent literature confirms the pathogenic nature of the variant. Reanalysis of the UBE3A variant has heightened existing knowledge of AS and has offered this family an end to their diagnostic odyssey.

Biochemical characterization of bioinspired nanosuspensions from Swertia chirayita extract and their therapeutic effects through nanotechnology approach.

Swertia chirayita is used as a traditional medicinal plant due to its pharmacological activities, including antioxidant, antidiabetic, antimicrobial, and cytotoxic. This study was aimed to evaluate the therapeutic efficacy of newly synthesized nanosuspensions from Swertia chirayita through nanotechnology for enhanced bioactivities. Biochemical characterization was carried out through spectroscopic analyses of HPLC and FTIR. Results revealed that extract contained higher TPCs (569.6 ± 7.8 mg GAE/100 g)) and TFCs (368.5 ± 9.39 mg CE/100 g) than S. chirayita nanosuspension, TPCs (500.6 ± 7.8 500.6 ± 7.8 mg GAE/100 g) and TFCs (229.5± 3.85 mg CE/100 g). Antioxidant activity was evaluated through DPPH scavenging assay, and nanosuspension exhibited a lower DPPH free radical scavenging potential (06 ±3.61) than extract (28.9± 3.85). Anti-dabetic potential was assessed throughα-amylase inhibition and anti-glycation assays. Extract showed higher (41.4%) antiglycation potential than 35.85% nanosuspension and 19.5% α-amylase inhibitory potential than 5% nanosuspension. Biofilm inhibition activity against E. coli was higher in nanosuspension (69.12%) than extract (62.08%). The extract showed high cytotoxicity potential (51.86%) than nanosuspension (33.63%). These nanosuspensions possessed enhanced bioactivities for therapeutic applications could be explored further for the development of new drugs.

Innovative technologies for removal of micro plastic: A review of recent advances.

Plastics are becoming a pervasive pollutant in every environmental matrix, particularly in the aquatic environment. Due to increased plastic usage and its impact on human and aquatic life, microplastic (MP) pollution has been studied extensively as a global issue. The production of MP has been linked to both consumer and commercial practices. There is a significant amount of MP's that must be removed by wastewater treatment plants before they can be bioaccumulated. Many researchers have recently become interested in the possibility of eliminating MPs in wastewater treatment plants (WWTP). Many studies have analyzed MP's environmental effects, including its emission sources, distribution, and impact on the surrounding environment. The effectiveness of their removal by various wastewater treatment technologies requires a critical review that accounts for all these methods. In this review, we have covered the most useful technologies for the removal of MP during WWTP. The findings of this review should help scientists and policymakers move forward with studies, prototypes, and proposals for significant remediation impact on water quality.

Mitigation of sciatica injury-induced neuropathic pain through active metabolites derived from medicinal plants.

Sciatica characterized by irritation, inflammation, and compression of the lower back nerve, is considered one of the most common back ailments globally. Currently, the therapeutic regimens for sciatica are experiencing a paradigm shift from the conventional pharmacological approach toward exploring potent phytochemicals from medicinal plants. There is a dire need to identify novel phytochemicals with anti-neuropathic potential. This review aimed to identify the potent phytochemicals from diverse medicinal plants capable of alleviating neuropathic pain associated with sciatica. This review describes the pathophysiology of sciatic nerve pain, its cellular mechanisms, and the pharmacological potential of various plants and phytochemicals using animal-based models of sciatic nerve injury-induced pain. Extensive searches across databases such as Medline, PubMed, Web of Science, Scopus, ScienceDirect, and Google Scholar were conducted. The findings highlights 39 families including Lamiaceae, Asteraceae, Fabaceae, and Apocyanaceae and Cucurbitaceae, effectively treating sciatic nerve injury-induced pain. Flavonoids made up 53% constituents, phenols and terpenoids made up 15%, alkaloids made up 13%, and glycosides made up 6% to be used in neuorpathic pain. Phytochemicals derived from various medicinal plants can serve as potential therapeutic targets for both acute and chronic sciatic injury-induced neuropathic pain.

A case of stuck mechanical Tricuspid Valve.

A 34-year-old non hypertensive, non-diabetic and ill looking weak woman came to our emergency department with shortness of breath NYHA III-IV, severe bilateral pedal edema extending up to the thighs and gross ascites. Physical examination revealed 3mm pitting ankle and leg edema and hemodynamically was stable with raised jugular venous pressure. There was a closing and opening mechanical click on Cardiac auscultation. At the lower left sternal border, there was grade 2/6 holodiastolic rumble and a grade 2/6 systolic murmur. She had history of mitral valve replacement and tricuspid valve replacement in 2017 with mechanical valves then she had Redo tricuspid valve replacement with mechanical prosthesis again after four months. No known food or drug allergy and psychosocial issues. Her routine bloods Labs were normal and COVID-19 was negative. On chest X-ray P/A view images and echo showed markedly gross left sided pleural effusion. In Coronary angiogram showed normal coronaries and stuck tricuspid valve (Fig.1). Echocardiography report showed preserved LV systolic function (EF=57%), dilated left atrium and right atrium. Prosthetic mitral valve was seen at mitral position, well seated and well-functioning. The mechanical mitral valve was functioning well with normal disc motion with no thrombus formation. Prosthetic tricuspid valve was seen at tricuspid level with peak gradient of 22mmHg and shown stuck mechanical tricuspid discs stuck throughout the cardiac cycle, in a fully open position (Fig.2A and 2B). Atrial fibrillation was shown on ECG. The diagnosis was made as; pannus formation resulting in mechanical TV thrombosis.

Advances in nanotechnology-assisted photodynamic therapy for neurological disorders: a comprehensive review.

Neurological disorders such as neurodegenerative diseases and nervous system tumours affect more than one billion people throughout the globe. The physiological sensitivity of the nervous tissue limits the application of invasive therapies and leads to poor treatment and prognosis. One promising solution that has generated attention is Photodynamic therapy (PDT), which can potentially revolutionise the treatment landscape for neurological disorders. PDT attracted substantial recognition for anticancer efficacy and drug conjugation for targeted drug delivery. This review thoroughly explained the basic principles of PDT, scientific interventions and advances in PDT, and their complicated mechanism in treating brain-related pathologies. Furthermore, the merits and demerits of PDT in the context of neurological disorders offer a well-rounded perspective on its feasibility and challenges. In conclusion, this review encapsulates the significant potential of PDT in transforming the treatment landscape for neurological disorders, emphasising its role as a non-invasive, targeted therapeutic approach with multifaceted applications.

Photodynamic therapy is a promising tool to revolutionise the treatment landscape for neurological disorders.The nexus between photodynamic therapy and biological drug conjugation is best suited for non-invasive neurological disorder treatment.

Omicron variant (B.1.1.529) challenge the integrity of blood brain barrier: Evidence from protein structural analysis.

Studies on nonhuman primates, wild-type and transgenic mice have shown the presence of SARS-CoV-2 RNA components in the brains. Despite the Blood-Brain Barrier (BBB) provides protection there are less evidences on how the SARS-CoV-2 crosses the BBB. Given that there is an increase of Omicron reinfection rates, transmissibility rate and involvement to cause neurological dysfunctions, we hypothesized to investigate how the Omicron variant (B.1.1.529) binds structurally to key BBB-maintaining proteins and thus can possibly challenge the integrity and transportation to the brain. By using molecular dynamics simulation approaches we examined the interaction of Omicron variant (B.1.1.529) with different structural and transporter proteins located at the BBB. Our results show that in Zona Ocludin 1-RBD complex, we observe a distinct pattern. Omicron demonstrates a docking score of -88.9 ± 6.8 kcal/mol and six interactions, while the wild type (WT) presents a higher score of -94.0 ± 2.3 kcal/mol, forming eight interactions. Comparing affinities, the WT-RBD displays a stronger preference for Claudin-5, boasting a docking score of -110.2 ± 3.0 and nine interactions, versus Omicron-RBD's slightly reduced engagement, with a docking score of -105.6 ± 0.2 and seven interactions. Interestingly, the Omicron variant exhibits heightened stability in interactions with Glucose Transporter and ABC transporters, registering docking scores of -110.6 ± 1.9 and -112.0 ± 3.6 kcal/mol, respectively. This surpasses the WT's respective scores of -95.2 ± 2.2 and -104.0 ± 6.2 kcal/mol, reflecting a unique interaction profile. Rigorous molecular dynamics simulations validate our findings. Our study emphasizes the Omicron variant's increased affinity towards transporter proteins, illuminating potential implications for BBB integrity and brain transportation. While these insights offer a valuable framework, comprehensive experimental validation is indispensable for a comprehensive understanding.

A case of MBTPS1-related disorder due to compound heterozygous variants in MBTPS1 gene: Genotype-phenotype expansion and the emergence of a novel syndrome.

MBTPS1 (NM_003791.4) encodes Site-1 protease, a serine protease that functions sequentially with Site-2 protease regulating cholesterol homeostasis and endoplasmic reticulum stress response. MBTPS1 pathogenic variants are associated with spondyloepiphyseal dysplasia, Kondo-Fu type (MIM:618392; cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, and Silver-Russell-like syndrome). In this report, we describe a 14-year-old female with a complex medical history including white matter volume loss, early-onset cataracts, retrognathia, laryngomalacia, inguinal hernia, joint hypermobility, feeding dysfunction, and speech delay. Additionally, features of ectodermal dysplasia that she has include decreased sweating, heat intolerance, dysplastic nails, chronically dry skin, and abnormal hair growth issues. Exome sequencing analysis identified compound heterozygous variants in the MBTPS1 gene: c.2255G > T p.(Gly752Val) predicted to affect important function of the protein, which was inherited from the mother, and a splice site variant c.2831 + 5G > T, which was inherited from the father. The RNA-seq analysis of the splice variant showed skipping of exon 21, predicted to result in frameshifting p.(Ser901fs28*) leading to non-sense mediated decay. To our knowledge, only eight studies have been published that described the MBPTS1-related disorders. Interestingly, we observed the features of ectodermal dysplasia in our patient that further expands the phenotypic spectrum of MBTPS1 gene-related disorders.

Symptomatic Interarterial Course Of Coronary Arteries In Middle Aged Patients.

Anomalous aortic origin of a coronary artery (AAOCA) is the most common congenital abnormality and is sometimes associated with various life-threatening conditions. We present the cases of a 35-year-old male and a 50-year-old female with complaints of chest pain. Patients had anomalous aortic origin of coronary arteries with the interarterial course and were treated surgically. By literature review, we came to know that the approach to treat patients with anomalous aortic origin of coronary arteries should be largely individualized and there is no ample scientific data to support any specific diagnostic modality and treatment option.