Gray Matter Atrophy in a 6-OHDA-induced Model of Parkinson's Disease.

INTRODUCTION: Magnetic resonance imaging (MRI) based brain morphometric changes in unilateral 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD) model can be elucidated using voxel-based morphometry (VBM), study of alterations in gray matter volume and Machine Learning (ML) based analyses. METHODS: We investigated gray matter atrophy in 6-OHDA induced PD model as compared to sham control using statistical and ML based analysis. VBM and atlas-based volumetric analysis was carried out at regional level. Support vector machine (SVM)-based algorithms wherein features (volume) extracted from (a) each of the 150 brain regions (b) statistically significant features (only) and (c) volumes of each cluster identified after application of VBM (VBM_Vol) were used for training the decision model. The lesion of the 6-OHDA model was validated by estimating the net contralateral rotational behaviour by the injection of apomorphine drug and motor impairment was assessed by rotarod and open field test. RESULTS AND DISCUSSION: In PD, gray matter volume (GMV) atrophy was noted in bilateral cortical and subcortical brain regions, especially in the internal capsule, substantia nigra, midbrain, primary motor cortex and basal ganglia-thalamocortical circuits in comparison with sham control. Behavioural results revealed an impairment in motor performance. SVM analysis showed 100% classification accuracy, sensitivity and specificity at both 3 and 7 weeks using VBM_Vol. CONCLUSION: Unilateral 6-OHDA induced GMV changes in both hemispheres at 7th week may be associated with progression of the disease in the PD model. SVM based approaches provide an increased classification accuracy to elucidate GMV atrophy.

Drug Screening and Validation Targeting TDP-43 Proteinopathy for Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) stands as a rare, yet severely debilitating disorder marked by the deterioration of motor neurons (MNs) within the brain and spinal cord, which is accompanied by degenerated corticobulbar/corticospinal tracts and denervation in skeletal muscles. Despite ongoing research efforts, ALS remains incurable, attributed to its intricate pathogenic mechanisms. A notable feature in the pathology of ALS is the prevalence of TAR DNA-binding protein 43 (TDP-43) proteinopathy, detected in approximately 97% of ALS cases, underscoring its significance in the disease's progression. As a result, strategies targeting the aberrant TDP-43 protein have garnered attention as a potential avenue for ALS therapy. This review delves into the existing drug screening systems aimed at TDP-43 proteinopathy and the models employed for drug efficacy validation. It also explores the hurdles encountered in the quest to develop potent medications against TDP-43 proteinopathy, offering insights into the intricacies of drug discovery and development for ALS. Through this comprehensive analysis, the review sheds light on the critical aspects of identifying and advancing therapeutic solutions for ALS.

Step-Up Management in Acute Pancreatitis: A Tertiary Care Center's Experience From Southern India.

Background The clinical spectrum of acute pancreatitis (AP) ranges from mild disease to severe form associated with multiorgan failure, prolonged hospital stay, high morbidity, and mortality. Acute necrotizing pancreatitis (ANP) is a severe form of AP. This study evaluates AP's outcomes after applying principles of the step-up approach in a tertiary healthcare center in south India. Methodology This prospective observational study was carried out from January 2021 to December 2022. The study population includes patients admitted to our department with AP. Results Ninety patients were included in the study, most of them were middle-aged males with ethanol ingestion as the common etiology. Thirty-seven (41.1%) patients had mild AP, 25 (27.7%) had moderately severe AP, and 28 (31.1%) had severe AP. Organ failure at admission was noted in 36 (40%) patients. Twenty-three (25.5%) patients developed ANP. Infected necrosis was noted in 3 (3.33%) patients. Eighteen (20%) patients needed image-guided percutaneous drainage. Seven (38.8%) needed necrosectomy following percutaneous drainage. Mortality was observed in 8 (8.8%) patients. Specifically, mortality was noted in 6 (6.6%) patients who presented later in their disease course. Conclusions Percutaneous catheter drainage is a safe and effective therapy to tide over the initial phase of AP. It also serves as a bridging therapy till the patient is clinically fit for a necrosectomy. Severe AP cases presenting late in their course are associated with significant mortality even after step-up management. Standardized protocols for referral and management are essential to obtain a good clinical outcome.

Exploration of Voids, Acoustic Properties and Vibration Damping Ratio of Cyperus Pangorei Rottb Fiber and Ramie Fiber Reinforced with Epoxy Resin Hybrid Composites.

Noise pollution is a major threat to the health and well-being of the entire world; this issue forces researchers to find new sound absorption and insulating material. In this paper, the sound absorption coefficient and vibration damping factor of panels manufactured from Cyperus pangorei rottb and ramie fiber reinforced with epoxy resin are explored. Cyperus pangorei rottb grass fiber and ramie fiber are widely available natural fibers. Cyperus pangorei rottb grass fiber is used in mat manufacturing, whereas ramie is widely used as a fabric. Using both of these fibers, six variant panels using a vacuum resin infusion process (VRIP) were fabricated. The panels were named C, R, CR, RCR-Flat, RCR-Curved, and RCR-Perforated. All the panels were tested for the sound absorption coefficient using an impedance tube with a frequency ranging up to 6300 Hz. Modal analysis was carried out by using the impulse hammer excitation method. A micro X-ray computed tomography (CT) scan was used to study the voids present in the panels. The results were compared among the six variants. The results show that the RCR-curved panel had the highest sound-absorbing coefficient of 0.976 at a frequency range between 4500 Hz to 5000 Hz. These panels also showed better natural frequency and damping factors. The presence of internal voids in these panels enhances sound absorption properties. These panels can be used at higher frequencies.

Association of cigarette smoking with cerebrospinal fluid biomarkers of insulin sensitivity and neurodegeneration.

INTRODUCTION: Cigarette smoking increases both the risk for insulin resistance and amyloid-ß (Aß) aggregation, and impaired brain insulin/insulin-like growth factor 1 (IGF1) signaling might increase risk factors for Alzheimer's disease (AD). We aimed to investigate the association among cerebrospinal fluid (CSF) insulin sensitivity/IGF1, glucose/lactate, and Aß42 and further explore whether insulin sensitivity contributed to the risk for AD in active smokers. METHODS: In this cross-sectional study, levels of insulin, IGF1, and lactate/glucose of 75 active smokers and 78 nonsmokers in CSF were measured. Three polymorphisms regulating IGF1 were genotyped. Analysis of variance was used to compare differences of variables between groups. Partial correlation was performed to test the relationship between CSF biomarkers and smoking status. General linear models were applied to test the interaction of the effect of single nucleotide polymorphisms and cigarette smoking on CSF IGF1 levels. RESULTS: In the CSF from active smokers, IGF1 and lactate levels were significantly lower (p = .016 and p = .010, respectively), whereas Aß42 (derived from our earlier research) and insulin levels were significantly higher (p < .001 and p = .022, respectively) as compared to the CSF from nonsmokers. The AG + GG genotype of rs6218 in active smokers had a significant effect on lower CSF IGF1 levels (p = .004) and lower CSF insulin levels in nonsmokers (p = .016). CONCLUSIONS: Cigarette smoking as the "at-risk" factor for AD might be due to lower cerebral insulin sensitivity in CSF, and the subjects with rs6218G allele seem to be more susceptible to the neurodegenerative risks for cigarette smoking.

Usage Patterns of Traditional Chinese Medicine for Patients with Bipolar Disorder: A Population-Based Study in Taiwan.

BACKGROUND: Patients with bipolar disorder (BD) receive traditional Chinese medicine (TCM) for clinical needs unmet with psychotropic medications. However, the clinical characteristics of practices and outcomes of TCM in BD are not fully understood. This cohort study investigated the clinical characteristics, principal diagnoses, TCM interventions, and TCM prescriptions in patients with BD. METHODS: Data for a total of 12,113 patients with BD between 1996 and 2013 were withdrawn from Taiwan's longitudinal health insurance database 2000 (LHID 2000). The chi-square test was used for categorical variables, and the independent t-test was used for continuous variables. A p-value less than 0.05 indicated significance. RESULTS: One thousand three hundred nineteen patients who visited TCM clinics after the diagnosis of BD were in the TCM group, while those who never visited TCM were in the non-TCM group (n = 1053). Compared to the non-TCM group, patients in the TCM group had younger average age, a higher percentage of female individuals, more comorbidities of anxiety and alcohol use disorders, and higher mood stabilizer usage rates. The TCM group exhibited pain-related indications, including joint pain, myalgia, myositis, headache, and sleep disturbances. Corydalis yanhusuo and Shu-Jing-Huo-Xue-Tang were the most useful single herbs and herbal formulae. CONCLUSIONS: Physicians need to be aware of the use of TCM in patients with BD.

Macrofungal Mediated Biosynthesis of Silver Nanoparticles and Evaluation of Its Antibacterial and Wound-Healing Efficacy.

Recently, the utilization of biological agents in the green synthesis of nanoparticles has been given interest. In this study, silver nanoparticles were synthesized from an aqueous extract of macrofungus (mushroom), namely Phellinus adamantinus, in a dark room using 20 µL of silver nitrate. Biosynthesized silver nanoparticles were confirmed by analyzing them using a UV-Vis (ultraviolet-visible) spectrophotometer. The synthesized silver nanoparticles were optimized at different pH and temperatures with various dosages of AgNO3 (silver nitrate) and fungal extracts. The synthesized AgNPs (silver nanoparticles) were characterized using TEM (transmission electron microscopy) and EDX (energy-dispersive X-ray) analyses, which confirmed the presence of silver nanoparticles. The size of the nanosilver particles was found to be 50 nm with higher stability. The mycosynthesized AgNPs showed effective antibacterial activity against strains of Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (E. coli and Pseudomonas aeruginosa) bacteria. The minimum inhibitory concentration (MIC) was found to be 3.125 µg/mL by MIC assay. The MTT assay (3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyl-2H-tetrazolium bromide) was performed to study cytotoxicity, and reduced cell viability was recorded at 100 µg/mL. Silver-Polygalacturonic acid-Polyvinyl alcohol ((Ag-PGA)-PVA) nanofiber was prepared using the electrospinning method. The in vitro wound scratch assay was demonstrated to study the wound-healing efficacy of the prepared nanofiber. The wound-healing efficacy of the AgNP-incorporated nanofiber was found to be 20% after 24 h. This study will lay a platform to establish a unique route to the development of a novel nanobiomaterial and its application in antibacterial and wound-healing therapy.

Unraveling the impact of Omega-3 polyunsaturated fatty acids on blood-brain barrier (BBB) integrity and glymphatic function.

Alzheimer's disease (AD) and other forms of dementia represent major public health challenges but effective therapeutic options are limited. Pathological brain aging is associated with microvascular changes and impaired clearance systems. The application of omega-3 polyunsaturated fatty acids (n-3 or omega-3 PUFAs) is one of the most promising nutritional interventions in neurodegenerative disorders from epidemiological data, clinical and pre-clinical studies. As essential components of neuronal membranes, n-3 PUFAs have shown neuroprotection and anti-inflammatory effects, as well as modulatory effects through microvascular pathophysiology, amyloid-beta (Aß) clearance and glymphatic pathways. This review meticulously explores these underlying mechanisms that contribute to the beneficial effects of n-3 PUFAs against AD and dementia, synthesizing evidence from both animal and interventional studies.

Molecular dynamics simulations assisted investigation of phytochemicals as potential lead candidates against anti-apoptotic Bcl-B protein.

Due to the multifarious nature of cancer, finding a single definitive cure for this dreadful disease remains an elusive challenge. The dysregulation of the apoptotic pathway or programmed cell death, governed by the Bcl-2 family of proteins plays a crucial role in cancer development and progression. Bcl-B stands out as a unique anti-apoptotic protein from the Bcl-2 family that selectively binds to Bax which inhibits its pro-apoptotic function. Although several inhibitors are reported for Bcl-2 family proteins, no specific inhibitors are available against the anti-apoptotic Bcl-B protein. This study aims to address this research gap by using virtual screening of an in-house library of phytochemicals from seven anti-cancer medicinal plants to identify lead molecules against Bcl-B protein. Through pharmacokinetic analysis and molecular docking studies, we identified three lead candidates (Enterolactone, Piperine, and Protopine) based on appreciable drug-likeliness, ADME properties, and binding affinity values. The identified molecules also exhibited specific interactions with critical amino acid residues of the binding cleft, highlighting their potential as lead candidates. Finally, molecular dynamics simulations and MM/PBSA based binding free energy analysis revealed that Enterolactone (CID_114739) and Piperine (CID_638024) molecules were on par with Obatoclax (CID_11404337), which is a known inhibitor of the Bcl-2 family proteins.Communicated by Ramaswamy H. Sarma.

Roles of Omega-3 Polyunsaturated Fatty Acids in Managing Cognitive Impairment in Chronic Obstructive Pulmonary Disease: A Review.

Chronic obstructive pulmonary disease (COPD) contributes significantly to the death of people worldwide, especially the elderly. An essential feature of COPD is pulmonary inflammation, which results from long-term exposure to noxious substances from cigarette smoking and other environmental pollutants. Pulmonary inflammatory mediators spill over to the blood, leading to systemic inflammation, which is believed to play a significant role in the onset of a host of comorbidities associated with COPD. A substantial comorbidity of concern in COPD patients that is often overlooked in COPD management is cognitive impairment. The exact pathophysiology of cognitive impairment in COPD patients remains a mystery; however, hypoxia, oxidative stress, systemic inflammation, and cerebral manifestations of these conditions are believed to play crucial roles. Furthermore, the use of medications to treat cognitive impairment symptomatology in COPD patients has been reported to be associated with life-threatening adverse effects, hence the need for alternative medications with reduced side effects. In this Review, we aim to discuss the impact of cognitive impairment in COPD management and the potential mechanisms associated with increased risk of cognitive impairment in COPD patients. The promising roles of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in improving cognitive deficits in COPD patients are also discussed. Interestingly, ω-3 PUFAs can potentially enhance the cognitive impairment symptomatology associated with COPD because they can modulate inflammatory processes, activate the antioxidant defence system, and promote amyloid-beta clearance from the brain. Thus, clinical studies are crucial to assess the efficacy of ω-3 PUFAs in managing cognitive impairment in COPD patients.

Cellular and molecular mechanisms in vascular repair after traumatic brain injury: a narrative review.

Traumatic brain injury (TBI) disrupts normal brain function and is associated with high morbidity and fatality rates. TBI is characterized as mild, moderate or severe depending on its severity. The damage may be transient and limited to the dura matter, with only subtle changes in cerebral parenchyma, or life-threatening with obvious focal contusions, hematomas and edema. Blood vessels are often injured in TBI. Even in mild TBI, dysfunctional cerebral vascular repair may result in prolonged symptoms and poor outcomes. Various distinct types of cells participate in vascular repair after TBI. A better understanding of the cellular response and function in vascular repair can facilitate the development of new therapeutic strategies. In this review, we analyzed the mechanism of cerebrovascular impairment and the repercussions following various forms of TBI. We then discussed the role of distinct cell types in the repair of meningeal and parenchyma vasculature following TBI, including endothelial cells, endothelial progenitor cells, pericytes, glial cells (astrocytes and microglia), neurons, myeloid cells (macrophages and monocytes) and meningeal lymphatic endothelial cells. Finally, possible treatment techniques targeting these unique cell types for vascular repair after TBI are discussed.

Racial disparities in women with ST elevation myocardial infarction: A National Inpatient Sample review of baseline characteristics, co-morbidities, and outcomes in women with STEMI.

BACKGROUND: A third of the patients admitted with Acute coronary syndrome (ACS) have ST-elevation myocardial infarction (STEMI). Previous studies showed that females with STEMI have higher mortality than men. HYPOTHESIS: There exist significant disparities in outcomes among women of different races presenting with STEMI. METHODS: National inpatient sample (NIS) data was obtained from January 2016 to December 2018 for the hospitalization of female patients with STEMI. We compared outcomes, using an extensive multivariate regression analysis amongst women from different races. Our primary outcome was in-hospital mortality. Secondary outcomes were revascularization use, procedure complications, and healthcare utilization. RESULTS: Of 202 223 female patients with STEMI; 11.3% were African American, 7.4% Hispanic, 2.4% Asian, and 4.3% another race. In-hospital mortality was higher in non-Caucasian groups. African American (adjusted odds ratio [aOR] 1.2; 95% confidence interval [CI]: 1.07-1.30; p < .01) and another race (aOR 1.37; 95% CI: 1.15-1.63; p < .01) had higher odds of mortality when compared with white women. African American (aOR 0.69; 95% CI: 0.62-0.72; p < .01), Hispanics (aOR 0.81; 95% CI: 0.74-0.88; p < .01), and Asian (aOR 0.79; 95% CI: 0.69-0.90; p < .01) had lower odds of percutaneous intervention (PCI) when compared with whites. African Americans had fewer odds of Coronary Artery Bypass Graft (CABG) and use of Mechanical Circulatory Support (MCS) during the index admission. Non-Caucasians had more comorbidities, complications, and healthcare utilization costs. CONCLUSION: There are significant racial disparities in clinical outcomes and revascularization in female patients with STEMI. African American women have a higher likelihood of mortality among the different races. Females from minority groups are also less likely to undergo PCI.

Omega-3 Polyunsaturated Fatty Acids in Managing Comorbid Mood Disorders in Chronic Obstructive Pulmonary Disease (COPD): A Review.

Chronic obstructive pulmonary disease (COPD) is the third-leading cause of mortality globally, significantly affecting people over 40 years old. COPD is often comorbid with mood disorders; however, they are frequently neglected or undiagnosed in COPD management, thus resulting in unintended treatment outcomes and higher mortality associated with the disease. Although the exact link between COPD and mood disorders remains to be ascertained, there is a broader opinion that inflammatory reactions in the lungs, blood, and inflammation-induced changes in the brain could orchestrate the onset of mood disorders in COPD. Although the current management of mood disorders such as depression in COPD involves using antidepressants, their use has been limited due to tolerability issues. On the other hand, as omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a vital role in regulating inflammatory responses, they could be promising alternatives in managing mood disorders in COPD. This review discusses comorbid mood disorders in COPD as well as their influence on the progression and management of COPD. The underlying mechanisms of comorbid mood disorders in COPD will also be discussed, along with the potential role of n-3 PUFAs in managing these conditions.

Clinical efficacy and immune effects of acupuncture in patients with comorbid chronic pain and major depression disorder: A double-blinded, randomized controlled crossover study.

BACKGROUND: Depression and pain are highly comorbid and share biological mechanisms. Acupuncture is commonly used to manage both pain and depression, but the choice of acupoints for specific disorders differs. This study aimed to investigate whether specific acupuncture intervention on pain- and depression-acupoints would have specific efficacy and immune effects in patients with comorbid chronic pain and major depressive disorder (MDD). METHODS: We performed a subject- and assessor-blinded, crossover, and randomized controlled clinical trial of depression- and pain-specific acupuncture intervention and measured clinical responses and proinflammatory cytokines in patients with comorbid chronic pain and MDD. Specific acupoints for pain and depression were used in random order with a washout interval. Forty-seven patients were enrolled and randomly assigned to two groups: (1) the depression-pain group (23 patients who were treated with depression-specific acupoints and then the pain-specific acupoints after the washout) and (2) pain-depression group (24 patients with the reverse order). RESULTS: The pain-specific acupoints for pain did not reduce Brief Pain Inventory scores to a significantly greater degree (-0.97 ± 1.69) than the depression-specific acupoints (-0.28 ± 1.88); likewise, the depression-specific acupoints did not significantly ameliorate Hamilton Depression Rating Scale (-4.59 ± 6.02) than the pain-specific acupoints (-6.69 ± 6.61). The pain-specific acupoints improved Beck Depression Inventory-Second Edition (-6.74 ± 9.76) even better than the depression-specific acupoints (-1.92 ± 10.74). The depression-specific acupoints did not significantly decrease the depression-related interleukin (IL)-6 level (-1.24 ± 6.67) than the pain-specific acupoints (-0.60 ± 4.36). The changed levels of IL-1ß, tumor necrosis factor (TNF)-α between the depression-specific acupoints (-37.41 ± 194.49; -12.53 ± 54.68) and the pain-specific acupoints (-15.46 ± 87.56; -7.28 ± 27.86) could not reach significantly different, too. CONCLUSION: This study rejected our hypothesis that the pain-specific acupoints might produce superior analgesic effects than the depression-specific acupoints and vice versa. The cytokine results might imply that pain and depression share common biological mechanisms. (trial registration: https://www. CLINICALTRIALS: gov: NCT03328819).

Anti-Inflammatory Effect of Traditional Chinese Medicine on the Concept of Mind-Body Interface.

In this chapter, we conducted a systemic literature review for the anti-inflammatory effects of Traditional Chinese Medicine (TCM) applying molecular mechanisms focusing on the neuroinflammation and gut-brain axis in three neuropsychiatric disorders: major depressive disorder, Alzheimer's disease, and Parkinson's disease. We demonstrated the anti-inflammation or immunomodulation effects of TCM, including acupuncture, from basic and clinical research, including cellular and molecular approaches. In conclusion, inflammation plays a critical role in the neuropsychopathological process. At the same time, anti-inflammation seems to be the common biological pathway for the effects of TCM and acupuncture in depression, Alzheimer's disease, and Parkinson's disease.

DIAPH3 condensates formed by liquid-liquid phase separation act as a regulatory hub for stress-induced actin cytoskeleton remodeling.

Membraneless condensates, such as stress granules (SGs) and processing bodies (P-bodies), have attracted wide attention due to their unique feature of rapid response to stress without first requiring nuclear feedback. In this study, we identify diaphanous-related formin 3 (DIAPH3), an actin nucleator, as a scaffold protein to initiate liquid-liquid phase separation (LLPS) and form abundant cytosolic phase-separated DIAPH3 granules (D-granules) in mammalian cells such as HeLa, HEK293, and fibroblasts under various stress conditions. Neither mRNAs nor known stress-associated condensate markers, such as G3BP1, G3BP2, and TIA1 for SGs and DCP1A for P-bodies, are detected in D-granules. Using overexpression and knockout of DIAPH3, pharmacological interventions, and optogenetics, we further demonstrate that stress-induced D-granules spatially sequester DIAPH3 within the condensation to inhibit the assembly of actin filaments in filopodia. This study reveals that D-granules formed by LLPS act as a regulatory hub for actin cytoskeletal remodeling in response to stress.