Pathogenesis Of Disease Research Articles

16S rRNA Sequencing Reveals Alterations of Gut Bacteria in Hirschsprung-Associated Enterocolitis.

Hirschsprung-associated enterocolitis (HAEC) stands as most common and serious complication of Hirschsprung's disease. Variations in the microbiota composition may account for the differences observed between HAEC and healthy individuals, offering crucial insights into the disease's pathogenesis. Here, we performed a study to changes in the gut microbiome using 16sRNA amplicon sequencing in a cohort of HAEC patients ( n = 16) and healthy controls ( n = 14). Our result revealed a significant disparity in beta diversity between the two groups. Following correction for false discovery rate, a rank-sum test at the genus level indicated a notable decrease in the relative abundance of Bifidobacterium , Lactobacillus , and Veillonella , whereas the Enterococcus genus exhibited a substantial increase in HAEC, a finding further supported by additional linear discriminant analysis effect size analysis. Functional analysis showed that putative transport and catabolism, digestive system, and metabolism of cofactors and vitamins were proved to be some abundant KOs (Kyoto Encyclopedia of Genes and Genomes [KEGG] orthologs) in healthy group, whereas infectious disease, membrane transport, and carbohydrate metabolism were the three KOs with the higher abundance in the HAEC group. Our data increased our insight into the HAEC, which may shed further light on HAEC pathogenesis. Our study firstly demonstrated the difference between fecal microbiota of HAEC patients and healthy individuals, which made a step forward in the understanding of the pathophysiology of HAEC.

Role of Nitric oxide synthase II in the cognitive impairment due to experimental cerebral malaria

The role of nitric oxide (NO) in the pathogenesis of cerebral malaria and its cognitive sequelae remains controversial. Cerebral malaria is still the worst complication of Plasmodium falciparum infection, which is characterized by high rates of morbidity and mortality. Even after recovery from infection due to antimalarial therapy, the development of cognitive impairment in survivors reinforces the need to seek new therapies that demonstrate efficacy in preventing long-lasting sequelae. During disease pathogenesis, reactive oxygen and nitrogen species (RONS) are produced after the established intense inflammatory response. Increased expression of the enzyme inducible nitric oxide synthase (iNOS) seems to contribute to tissue injury and the onset of neurological damage. Elevated levels of NO developed by iNOS can induce the production of highly harmful nitrogen-reactive intermediates such as peroxynitrite. To adress this, we performed biochemical and behavioral studies in C57BL6 mice, aminoguanidine (specific pharmacological inhibitor of the enzyme iNOS) treated and iNOS-/-, infected with Plasmodium berghei ANKA (PbA), with the aim of clarifying the impact of iNOS on the pathogenesis of cerebral malaria. Our findings underscore the effectiveness of both strategies in reducing cerebral malaria and providing protection against the cognitive impairment associated with the disease. Here, the absence or blockade of the iNOS enzyme was effective in reducing the signs of cerebral malaria detected after six days of infection. This was accompanied by a decrease in the production of pro-inflammatory cytokines and reactive oxygen and nitrogen species. In addition, nitrotyrosine (NT-3), a marker of nitrosative stress, was also reduced. Futher, cognitive dysfunction was analyzed fifteen days after infection in animals rescued from infection by chloroquine treatment (25 mg/kg bw). We observed that both interventions on the iNOS enzyme were able to improve memory and learning loss in mice. In summary, our data suggest that the iNOS enzyme has the potential to serve as a therapeutic target to prevent cognitive sequelae of cerebral malaria.

Autoreactive B cells remain active despite clinical disease control in rheumatoid arthritis

BackgroundAutoimmune diseases (AIDs) are frequently hallmarked by the presence of autoreactive B cell responses which are involved in disease pathogenesis. However, the dynamics of such responses and their relation to clinical disease activity in humans is poorly understood. Rheumatoid arthritis (RA), a prototypic chronic AID, is hallmarked by B cell responses directed against citrullinated proteins. ObjectiveTo determine the relation between the activity of the anti-citrullinated protein antibody (ACPA) B cell response and clinical disease activity in ACPA+ patients with RA. MethodsExpression of B cell activation markers by ACPA+, tetanus toxoid (TT)+ and ACPA− memory B cells (MBCs) from peripheral blood of ACPA+ RA patients receiving different treatments was analyzed by flow cytometry. Results were correlated to clinical disease activity. ResultsCompared to TT+ and ACPA− MBCs, ACPA+ MBCs displayed a highly activated phenotype as evidenced by increased expression of Ki-67, CD86, CD80, CD19 and CD20 and reduced expression of CD32. The activated phenotype of ACPA+ MBCs did not associate with clinical disease activity in a cross-sectional analysis of RA patients treated with various therapeutic agents. Also, in a longitudinal analysis of patients treated with Janus kinase (JAK) inhibitors, ACPA+ MBCs retained their activated phenotype despite effective control of inflammation and clinical disease. ConclusionACPA+ MBCs remain active despite clinical disease control in patients with RA across a range of interventions. This persistent activity indicates the absence of immunological remission and might explain why ACPA+ patients rarely reach sustained drug-free remission and frequently flare upon drug tapering.

The interplay between epidermal barrier distribution, microbiota composition, and immune infiltrate defines and stratifies psoriasis patients and is associated with disease severity

Psoriasis is a chronic inflammatory autoimmune skin disease characterized by keratinocyte hyperproliferation, primarily driven by the IL-23/IL-17 axis. In addition to immune response, various skin components, including the epidermal barrier and the skin microbiota, have been individually implicated in the disease pathogenesis. Here, we aimed to investigate the interplay between epidermal tight junctions, Staphylococcus aureus enterotoxin B (SEB), and CD4 T cell-mediated immune responses. By immunofluorescence analyses of skin biopsies, we observed that claudin-1 distribution was significantly altered in psoriatic patients, which correlated with the localization of Staphylococcus aureus and SEB across skin layers and with disease severity. Furthermore, functional CD4 TCRvβ17 cells were associated with SEB presence in patients skin and positively correlated with psoriasis severity. Notably, in patients with SEB detected in the dermis, CD4 TCRvβ17 IL-17 cells were linked to barrier abnormalities.Unsupervised analysis stratified psoriasis patients into three groups based on SEB presence and location, supporting the previous findings. The patient group with SEB in the dermis exhibited improved responses to biological therapy, including reductions in PASI score, claudin-1 fragmentation, S. aureus and SEB presence, and CD4 TCRvβ17 cell percentages. Our findings emphasize the complex interplay between epidermal barrier distribution, SEB localization, and functional CD4 TCRvβ17 cells in psoriatic skin, highlighting their potential in patient stratification in association with the severity of the disease.

Characterization of D1R and D2R neuronal subpopulations in the globus pallidus interna: Implications for Parkinson's disease pathogenesis.

Parkinson's disease (PD) ranks as the second most prevalent and rapidly growing neurodegenerative disorder. As a primary output nucleus within the basal ganglia (BG), the globus pallidus interna (GPi) is a key structure in BG information processing. It is also a key target for deep brain stimulation (DBS) to alleviate motor symptoms of PD. Previous studies have identifiedPD patients exhibiting abnormal neuronal activity in the GPi. On the other hand, various types of dopamine receptor (DR)-positive neurons have been identified within the GPi. However, the electrophysiological properties of specific DR-positive neurons within the GPi and their alterations in PD have not been addressed. In the present study, we used whole-cell patch-clamp recordings to identify two neuronal subpopulations within the GPi, dopamine D1 receptor (D1R)-positive, and dopamine D2 receptor (D2R)-positive neurons, which exhibited distinct electrophysiological properties. Additionally, significant alterations of electrophysiological properties of D2R-positive neurons within the GPi were observed in 6-hydroxydopamine (6-OHDA)-lesioned mice. These data suggest that the distinct electrophysiological properties of specific DR-positive neurons and their abnormal alteration in the GPi may be associated with PD's pathogenesis.

Role and clinical value of serum hsa_tsr011468 in lung adenocarcinoma.

Transfer RNA‑derived small RNAs (tsRNAs) are novel non‑coding RNAs that are associated with the pathogenesis of various diseases. However, their association with lung adenocarcinoma (LUAD) has not been studied comprehensively. Therefore, the present study aimed to explore the diagnostic value of a tsRNA, hsa_tsr011468, in LUAD. The OncotRF database was used to screen tsRNAs and reverse transcription‑quantitative PCR (RT‑qPCR) was performed to detect the expression levels of hsa_tsr011468 in various samples. Subsequently, the diagnostic and prognostic values of hsa_tsr011468 for LUAD were determined via receiver operating characteristic (ROC) curve and survival curve analyses, and by assessing clinicopathological parameters. In addition, both nuclear and cytoplasmic RNA were extracted to assess the location of hsa_tsr011468. The OncotRF database identified high expression of hsa_tsr011468 in LUAD. In addition, the results of RT‑qPCR showed that the relative expression levels of hsa_tsr011468 in the serum and tissues of patients with LUAD were higher than those in normal controls. Furthermore, its expression was lower in postoperative serum samples than in preoperative serum samples from patients with LUAD. ROC and survival curves indicated that hsa_tsr011468 had good diagnostic and prognostic value. Furthermore, the clinicopathological analysis revealed that hsa_tsr011468 was associated with tumor size. In addition, hsa_tsr011468 was mainly localized in the cytoplasm of LUAD cells. The present study indicated that hsa_tsr011468 has good diagnostic value and, therefore, could be employed as a serum marker for LUAD.

The Beneficial Effects of Curcumin on Lipids: Possible Effects on Dyslipidemia-induced Cardiovascular Complications.

Dyslipidemia and altered lipid metabolism are closely involved in the pathogenesis and clinical manifestation of many metabolic and non-metabolic diseases. Therefore, mitigation of pharmacological and nutritional factors together with lifestyle modifications is paramount. One potential nutraceutical exhibiting cell signaling and lipid-modulating properties implicated in dyslipidemias is curcumin. Specifically, recent evidence suggest that curcumin may improve lipid metabolism and prevent dyslipidemia-induced cardiovascular complications via several pathways. Although the exact molecular mechanisms involved are not well understood, the evidence presented in this review suggests that curcumin can provide significant lipid benefits via modulation of adipogenesis and lipolysis, and prevention or reduction of lipid peroxidation and lipotoxicity via different molecular pathways. Curcumin can also improve the lipid profile and reduce dyslipidemia- dependent cardiovascular problems by impacting important mechanisms of fatty acid oxidation, lipid absorption, and cholesterol metabolism. Although only limited direct supporting evidence is available, in this review we assess the available knowledge regarding the possible nutraceutical effects of curcumin on lipid homeostasis and its possible impacts on dyslipidemic cardiovascular events from a mechanistic viewpoint.

The aryl hydrocarbon receptor: A crucial mediator in ocular disease pathogenesis and therapeutic target.

The aryl hydrocarbon receptor (AHR) is a pivotal nuclear receptor involved in mediating cellular responses to a wide range of environmental pollutants and endogenous ligands. AHR plays a central role in regulating essential physiological processes, including xenobiotic metabolism, immune response modulation, cell cycle control, tumorigenesis, and developmental events. Recent studies have identified AHR as a critical mediator and a potential therapeutic target in the pathogenesis of ocular diseases. This review provides a thorough analysis of the various functions of AHR signalling in the ocular environment, with a specific emphasis on its effects on the retina, retinal pigment epithelium (RPE), choroid, and cornea. We provide a detailed discussion on the molecular mechanisms through which AHR integrates environmental and endogenous signals, influencing the development and progression of age-related macular degeneration (AMD), retinitis pigmentosa, uveitis, and other major ocular disorders. Furthermore, we evaluate the therapeutic potential of modulating AHR activity through novel ligands and agonists as a strategy for treating eye diseases. Understanding the molecular mechanisms of AHR in ocular tissues may facilitate the development of AHR-targeted therapies, which is crucial for addressing the pressing clinical demand for novel treatment strategies in ocular diseases.

Pre-diagnostic plasma advanced glycation end-products and soluble receptor for advanced glycation end-products and mortality in colorectal cancer patients.

Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, Nε-[carboxy-methyl]lysine (CML), Nε-[carboxy-ethyl]lysine (CEL) and Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (Pinteraction = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HRQ5vs.Q1 = 1.67, 95% CI: 1.21-2.30, Ptrend = .02) or any cause (HRQ5vs.Q1 = 1.38, 95% CI: 1.05-1.83, Ptrend = .09). These associations tended to be stronger among cases with diabetes (Pinteraction = .03) and pre-diabetes (Pinteraction <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes.

Bacillus amyloliquefaciens SC06 alleviates LPS-induced intestinal damage by inhibiting endoplasmic reticulum stress and mitochondrial dysfunction in piglets

Endoplasmic reticulum stress (ERS) and mitochondrial dysfunction play an important role in the pathogenesis of intestinal diseases. Our studies investigated the effects of Bacillus amyloliquefaciens SC06 on jejunal mitochondria and ER in piglets under the LPS-induced intestinal injury model. Eighteen piglets (male, 21 days old) were randomly assigned to three treatments: CON (basal diet), LPS (basal diet +100 μg/kg LPS), and SC06 + LPS (basal diet +1 × 108 cfu/kg SC06 + 100 μg/kg LPS). Compared to the LPS group, administration of SC06 improved jejunal morphology and barrier function. In addition, SC06 reduced reactive oxygen species (ROS) and MDA generation in the jejunum by activating the Nrf2/keap1 pathway, which increased the activity of CAT, GSH and SOD in LPS-challenged pigs. In addition, SC06 reduced LPS-induced mitochondrial dysfunction and ERS as evidenced by a decrease in ROS, an improvement in mitochondrial membrane potential and an increase in adenosine triphosphate levels. The results of in vitro IPEC-J2 cell experiments also indicate that SC06 can reduce LPS-induced oxidative stress, mitochondrial dysfunction, ERS, and intestinal barrier function damage by activating the Nrf2/keap1 signaling pathway. Finally, treatment with the Nrf2-specific inhibitor ML-385 inhibited the upregulated effect of SC06 on antioxidant capacity and intestinal barrier function in IPEC-J2 cells. In conclusion, SC06 ameliorated intestinal damage and mitochondrial dysfunction and attenuated endoplasmic reticulum stress via activation of the Nrf2/keap1 signaling pathway in LPS-challenged piglets.

Epidemiology, pathogenesis, clinical characteristics, and treatment of mucormycosis: a review.

This review aims to summarize the epidemiology, etiology, pathogenesis, clinical manifestations, and current diagnostic and therapeutic approaches for mucormycosis. The goal is to improve understanding of mucormycosis and promote early diagnosis and treatment to reduce mortality. A comprehensive literature review was conducted, focusing on recent studies and data on mucormycosis. The review includes an analysis of the disease's epidemiology, etiology, and pathogenesis, as well as current diagnostic techniques and therapeutic strategies. Mucormycosis is increasingly prevalent due to the growing immunocompromised population, the COVID-19 pandemic, and advances in detection methods. The pathogenesis is closely associated with the host immune status, serum-free iron levels, and the virulence of Mucorales. However, the absence of typical clinical manifestations complicates diagnosis, leading to missed or delayed diagnoses and higher mortality. An enhanced understanding of the epidemiology, pathogenesis, and clinical presentation of mucormycosis, along with the adoption of improved diagnostic and therapeutic approaches, is essential for reducing mortality rates associated with this opportunistic fungal infection. Early diagnosis and prompt treatment are critical to improving patient outcomes.

Haematological and Biochemical Profiles, Including Vitamin A and Zinc Status, in Clinical and Subclinical Oriental Theileriosis in Cattle

Aim: The present study investigated the clinical, haematological and biochemical profiles in cattle infected with Theileria orientalis, correlating disease severity with various parameters. Study Design: A total of 32 clinically ill, 10 subclinically infected, and 10 healthy control animals were included. Place and Duration of Study: Department of Veterinary Epidemiology and Preventive Medicine, College of Veterinary and Animal Sciences, Kerala Veterinary and Animal Sciences University, Pookode, Wayanad, Kerala, between November 2023 to September 2024. Methodology: Theileria piroplasms, observed via Giemsa staining, appeared as thick and thin rods with trailing cytoplasm and annular, pyriform, garland, and signet-ring shapes. PCR amplification of the T. orientalis major piroplasm surface protein (MPSP) yielded a specific 776 bp product in clinically and subclinically infected animals. Results: Haematological analysis revealed significant anaemia and thrombocytopenia in infected groups, without notable changes in leukocyte counts. Serum protein analysis indicated hypoproteinemia and hypoalbuminemia, while liver enzymes, particularly AST, were elevated in clinically infected cattle, suggesting hepatic involvement. Additionally, serum vitamin A and zinc concentrations were significantly lower in infected cattle, underscoring a possible role for oxidative stress in disease pathogenesis. Conclusion: These findings suggest that T. orientalis infection is associated with multi-systemic impacts, including haematological abnormalities, liver damage, and nutrient deficiencies, which are crucial for accurate diagnosis and effective management strategies.

Zasocitinib (TAK-279), a Selective, Oral TYK2 Inhibitor, Reduces Body Surface Area Involvement in a Phase 2b Trial in Moderate-to-Severe Plaque Psoriasis

Background: Zasocitinib (TAK-279) is an oral, allosteric, and highly selective inhibitor of tyrosine kinase 2 (TYK2). TYK2 mediates signaling from cytokines involved in the pathogenesis of psoriasis and other immune-mediated inflammatory diseases. In a phase 2b trial in patients with moderate-to-severe plaque psoriasis (NCT04999839), zasocitinib was well tolerated and demonstrated safety and efficacy, with a greater proportion of patients achieving skin clearance at doses ≥5 mg compared with placebo, with the two highest doses (15mg and 30mg) showing the strongest responses at Week 12. This analysis further evaluated the efficacy of the 15mg and 30mg doses of zasocitinib using body surface area (BSA) involvement. Methods: In this randomized, multicenter, double-blind, placebo-controlled trial, patients with moderate-to-severe plaque psoriasis were randomized 1:1:1:1:1 to receive oral zasocitinib (2, 5, 15 or 30mg) or placebo, once daily for 12 weeks. BSA outcome measures assessed at Week 12 were mean change in BSA from baseline, mean percentage change in BSA from baseline and the proportion of patients achieving a BSA threshold of ≤1% by visit. Mean change in BSA from baseline was prespecified. Results: Baseline mean (standard deviation [SD]) percentage BSA was generally consistent across the zasocitinib 15mg (n=53; 18.3 [10.3]), zasocitinib 30mg (n=52; 22.2 [14.3]) and placebo (n=52; 21.3 [13.6]) groups. Mean percentage BSA decreased as early as Week 2 and continued to decrease through to Week 12 in the zasocitinib groups, whereas scores slightly decreased in the placebo group. At Week 12, mean(SD) percentage BSA was 4.4 (5.3) (least-squares [LS] mean change: −14.7; LS mean percentage change: −72.9%) in the 15mg group, 6.5 (12.5) (LS mean change: −15.7; LS mean percentage change: −73.1%) in the 30mg group and 18.2 (13.6) (LS mean change: −4.0; LS mean percentage change: −19.3%) in the placebo group (p&lt;0.001 for both doses versus placebo). From Week 8 onwards, higher proportions of patients achieved a BSA threshold of ≤1% in the zasocitinib 15mg and 30mg groups than in the placebo group (35.8% and 44.2% versus 0% at Week 12, respectively). Conclusion: Patients with moderate-to-severe plaque psoriasis who received the two highest doses of zasocitinib (15mg and 30mg) in the phase 2b trial achieved greater reductions in BSA than those who received placebo over 12 weeks. Further investigation of the efficacy and safety of zasocitinib in phase 3 studies in psoriasis is ongoing (NCT06088043; NCT06108544).

Advances in the Construction and Application of Bone‐on‐a‐Chip Based on Microfluidic Technologies

ABSTRACTBone‐on‐a‐chip (BOC) models that based on microfluidic technology have widely applied to understand bone physiology and the pathogenesis of related diseases. In this review, we provide an overview of bone biology and related diseases, explain the advantages and applications of microfluidic technology in the construction of BOC models, and summarize their progress in physiology, pathology, and drug development. Finally, we discussed the problems to be solved and the future directions of microfluidic technology and BOC platforms, so as to provide a reference for researchers to design better BOC models.

Novel Approach to Fat Reduction: A Phase I Study Evaluating Safety and Tolerability of STP705 in Abdominoplasty

Background: RNAi therapeutics are a rapidly developing technology with broad medical applications predicated on reducing the expression of genes with key links to disease pathogenesis. The TGF-β1/Smad3 and COX-2 signaling pathways are strongly implicated in obesity and type 2 diabetes. Reducing the expression of TGF-β1 and COX-2 may have benefits in fat reduction procedures. The aim of this study was to assess the safety and tolerability of STP705 (a TGF-β1/COX-2 siRNA complex in a polypeptide nanoparticle vehicle) injections in persons undergoing abdominoplasty. A secondary aim was to make initial histologic observations on the efficacy of STP705 injections in inducing adipocyte apoptosis for the purpose of focal fat reduction. Methods: The study treatment consisted of 3 rounds of treatment with 7 subcutaneous abdominal injections of STP705 or placebo. Eight female subjects aged 18-65 years received 120 μg, 240 μg, or 360 μg STP705 in 0.5 or 1.0 ml doses (per injection) or an equivalent amount of placebo injected randomly across seven 1 cm2 areas. Treatments were administered 28 days apart with follow-ups occurring at 2 and 7 days’ post-procedure. Tissue samples from each of the 7 injection sites were harvested from total abdominoplasty excisional specimens obtained 28 days after the final injection. Safety assessments were conducted, including physical examination, clinical laboratory tests, electrocardiograms, evaluation of local skin reactions (LSRs), and collection of adverse events (AEs). Lipolytic and inflammatory effects of STP705 were assessed by blinded histologic analysis of harvested tissue samples. Results: There were no clinically significant changes in clinical labs, vital signs, or ECGs. The incidence of LSRs was low throughout the study. There were 3 moderate AEs deemed likely to be related to STP705 injection; none required intervention, and all resolved without dose modification. Histology revealed marginally dose-dependent tissue response with adipocyte destruction and fat remodeling. Conclusion: In general, STP705 was well tolerated at all concentrations and volumes studied. STP705 demonstrated excellent safety, and initial histologic analysis is suggestive of its efficacy in adipocyte destruction. The lack of cutaneous side effects with STP705 injection is an advantage over current treatments for similar indications.

Role of apoptosis-associated proteins p53 and bcl-2 in the pathogenesis of nervous system diseases

Diseases of the central nervous system occupy a leading place, along with cardiovascular and oncological diseases, and the proportion of patients suffering from diseases of the nervous system is increasing as the population ages. This group of diseases includes acute conditions, such as ischemic stroke, and chronic multifactorial diseases — Alzheimer's and Parkinson's diseases, epilepsy, etc. The development of specific methods for their treatment is difficult, and these drugs are not very effective. Almost all brain diseases are based on common mechanisms such as oxidative stress, inflammation and neuronal death. Most often, cells die by apoptosis due to an imbalance between pro-apoptotic and anti-apoptotic factors. This work examines two of them: the apoptosis-promoting transcription factor and tumor suppressor p53 and its opposing B-cell lymphoma protein Bcl-2. The choice of these proteins for study is due to the fact that both proteins are key regulators of apoptosis and are important in the pathogenesis of nervous diseases, since neurons are not highly proliferating cells. The p53 protein is involved in the regulation of many genes responsible for DNA repair, apoptosis, and other biochemical cellular processes; this is especially important when studying neuronal pathology. Bcl-2 suppresses apoptosis in various cells, including neurons, by controlling mitochondrial membrane permeability and inhibiting caspases. In diseases, its expression can either increase, for example, in the case of malignant tumors, or decrease, as in the case of neurodegenerative processes. It has been established that p53 and Bcl-2 are in close interaction in the process of regulating apoptosis; their ratio may be an important prognostic factor. The purpose of this work was to assess the role of these proteins in the pathogenesis of various diseases of the nervous system, and to search for general patterns of changes in their expression and coexpression.

Deciphering the Monomeric and Dimeric Conformational Landscapes of the Full-Length TDP-43 and the Impact of the C-Terminal Domain.

The aberrant aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in cells leads to the pathogenesis of multiple fatal neurodegenerative diseases. Decoding the proposed initial transition between its functional dimeric and aggregation-prone monomeric states can potentially design a viable therapeutic strategy, which is presently limited by the lack of structural detail of the full-length TDP-43. To achieve a complete understanding of such a delicate phase space, we employed a multiscale simulation approach that unearths numerous crucial features, broadly summarized in two categories: (1) state-independent features that involve inherent chain collapsibility, rugged polymorphic landscape dictated by the terminal domains, high β-sheet propensity, structural integrity preserved by backbone-based intrachain hydrogen bonds and electrostatic forces, the prominence of the C-terminal domain in the intrachain cross-domain interfaces, and equal participation of hydrophobic and hydrophilic (charged and polar) residues in cross-domain interfaces; and (2) dimerization-modulated characteristics that encompass slower collapsing dynamics, restricted polymorphic landscape, the dominance of side chains in interchain hydrogen bonds, the appearance of the N-terminal domain in the dimer interface, and the prominence of hydrophilic (specifically polar) residues in interchain homo- and cross-domain interfaces. In our work, the ill-known C-terminal domain appears as the most crucial structure-dictating domain, which preferably populates a compact conformation with a high β-sheet propensity in its isolated state stabilized by intrabackbone hydrogen bonds, and these signatures are comparatively faded in its integrated form. Validation of our simulated observables by a complementary spectroscopic approach on multiple counts ensures the robustness of the computationally predicted features of the TDP-43 aggregation landscape.

Biological Effects and Clinical Application of the Anti-Immunoglobulin E Antibody

Immunoglobulin E (IgE) plays a crucial role in the occurrence and development of allergic diseases. Since the discovery of IgE in 1967, the pathogenesis of allergic inflammatory diseases has been progressively revealed thereby providing a theoretical foundation for the development of therapeutic anti-IgE antibodies, which have emerged as a new method for the treatment of allergic diseases. In this paper, we aim to summarize and elaborate on the mechanism of biological effects and clinical application of anti-IgE antibodies by examining related global literature, particularly regarding Omalizumab in the past 5 years. We seek to establish theoretical foundations for the formation of new strategies for anti-allergic treatment.

Altered colonic microflora and its metabolic profile in mice with acute viral myocarditis induced by coxsackievirus B3.

Mounting evidence suggests that the gut-heart axis is critical in the pathogenesis of cardiovascular diseases. The gut serves as the primary pathway through which Coxsackievirus B3 (CVB3) infects its host, leading to acute viral myocarditis (AVMC). However, little is known about the role of gut microflora and its metabolites in the development of AVMC. The AVMC model was established by intraperitoneal injection of CVB3 in mice. Then, 16S ribosomal RNA (16S rRNA) gene sequencing and ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) untargeted metabolomics profiling were performed to analyze the microflora composition and metabolic profile of colonic contents. Compared to the Control mice, the AVMC mice displayed a significant reduction in gut microflora richness and diversity, as revealed by an increased abundance of Proteobacteria and a decreased abundance of Cyanobacteria and Desulfobacterota. LEfSe analysis indicated that the main genera differing between the two groups were Escherichia-Shigella, Lactobacillus, Clostridium_sensu_stricto_1, Prevotellaceae_UCG-001, and Odoribacter. Based on the criterion of OPLS-DA VIP ≥ 1.0 and p-value < 0.05, a total of 198 differential metabolites (DMs) were identified in the gut, including 79 upregulated and 119 downregulated metabolites, of which lipids and lipid-like molecules accounted for the largest proportion. Notably, both altered gut bacterial taxa and metabolites were significantly enriched in the Lipid metabolism pathway, with Traumatic acid (TA), Alpha-Linolenic acid (ALA), Eicosapentaenoic acid (EPA), and Docosahexaenoic acid (DHA) being the key DMs in the pathway. Additionally, significant positive correlations (|r| > 0.80 and p < 0.05) were found between TA levels and Anaerotruncus and Bilophila abundance, between EPA levels and Clostridium_sensu_stricto_1 abundance, and between DHA levels and Escherichia-Shigella abundance, respectively. CVB3 infection leads to notable alterations in gut microflora composition and its metabolic profile, which may participate in AVMC development. Our findings provide important clues for future in-depth studies on AVMC etiology.

Excitatory amino acids as therapeutic agents: Reversing neurodegenerative trajectory by tackling excitotoxicity.

Neurodegenerative diseases pose significant challenges to healthcare systems globally due to their complex etiology and relentless progression, often rendering conventional treatments ineffective. Recent advances have spotlighted excitatory amino acids, particularly D-amino acids, once considered as products of metabolism of the microbiota or deriving from food intake. This review explores the role of D-amino acids in mitigating excitotoxicity-a process characterized by excessive calcium influx through aberrant N-methyl-D-aspartate receptor (NMDAR) activation, which is implicated in the pathogenesis of diseases like Alzheimer's disease. By providing alternative pathways for neuronal signaling and protecting against excitotoxic damage, D-amino acids offer a novel approach to reversing neurodegenerative trajectories. Future research should focus on elucidating the detailed mechanisms of action of these compounds, evaluating their therapeutic potential through rigorous preclinical and clinical trials, and developing effective delivery systems to optimize their neuroprotective effects. This emerging field holds promise for developing innovative treatment strategies that could significantly improve outcomes for patients with neurodegenerative disorders.