Progression Of Pathology Research Articles

Multiparametric Chemical Exchange Saturation Transfer MRI Detects Metabolic Changes in Mild Cognitive Impairment Cases at 3.0 Tesla.

This study aimed to assess the potential of multiparametric chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) for MCI detection. Twenty-eight patients with MCI and 31 age- and gender-matched normal controls (NCs) were enrolled. CEST MRI was performed with a gradient and spin-echo sequence on a 3T scanner. Multi-parametric CEST parameters were analyzed, such as amide CEST, amine CEST, amine and amide concentration independent assay (AACID), magnetization transfer ratio yielding rex (MTRrex-amide), and downfield rNOE suppressed apparent exchange-dependent relaxation amide proton (DNS-AREX-amide). Statistical analyses of CEST parameters were performed to evaluate group differences, their correlations with Montreal cognitive assessment (MoCA) score, and diagnostic performance for MCI. Compared with NC group, amide CEST as well as MTRrex-amide decreased in the left hippocampus and amine CEST as well as AACID increased in the right hippocampus in the MCI group; In both hippocampi, the DNS-AREX-amide were significantly lower in the MCI group versus the NC group (all P < 0.05). Amine CEST in the right hippocampus was negatively correlated with MoCA score (r = - 0.457, p = 0.017); DNS-AREX-amide in the bilateral hippocampus was positively correlated with MoCA score (left: r = 0.449, P = 0.019; right: AUC = 0.529, P = 0.05). DNS-AREX-amide in the bilateral hippocampus have a good ability to identify MCI (left: AUC = 0.756, P < 0.01; right: AUC = 0.762, P < 0.01). CEST MRI provides a potential imaging diagnostic strategy for MCI, which may promote early detection of MCI and provide novel insights into the pathological progress toward AD.

The role of ferroptosis-related non-coding RNA in liver fibrosis

Liver fibrosis represents a reversible pathophysiological process, caused by chronic inflammation stemming from hepatocyte damage. It delineates the initial stage in the progression of chronic liver disease. This pathological progression is characterized by the excessive accumulation of the extracellular matrix (ECM), which leads to significant structural disruption and ultimately impairs liver function. To date, no specific antifibrotic drugs have been developed, and advanced liver fibrosis remains largely incurable. Liver transplantation remains the sole efficacious intervention for advanced liver fibrosis; nevertheless, it is constrained by exorbitant costs and the risk of postoperative immune rejection, underscoring the imperative for novel therapeutic strategies. Ferroptosis, an emergent form of regulated cell death, has been identified as a pivotal regulatory mechanism in the development of liver fibrosis and is intricately linked with the progression of liver diseases. Recent investigations have elucidated that a diverse array of non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, are involved in the ferroptosis pathway, thereby modulating the progression of various diseases, including liver fibrosis. In recent years, the roles of ferroptosis and ferroptosis-related ncRNAs in liver fibrosis have attracted escalating scholarly attention. This paper elucidates the pathophysiology of liver fibrosis, explores the mechanisms underlying ferroptosis, and delineates the involvement of ncRNA-mediated ferroptosis pathways in the pathology of liver fibrosis. It aims to propose novel strategies for the prevention and therapeutic intervention of liver fibrosis.

Inhibition of Bone Morphogenetic Protein Signaling Prevents Tau Pathology in iPSC Derived Neurons and PS19 Mice.

Many neurodegenerative disorders share a common pathologic feature involving the deposition of abnormal tau protein in the brain (tauopathies). This suggests that there may be some shared pathophysiologic mechanism(s). The largest risk factor for the majority of these disorders is aging, suggesting involvement of the aging process in the shared pathophysiology. We test the hypothesis that an increase in bone morphogenetic protein (BMP) signaling that occurs during aging contributes to the onset and progression of tauopathies. Human induced pluripotent stem cell (iPSC)-derived neurons from patients with Alzheimer's disease (AD) were used to investigate the effects of BMP signaling on tau phosphorylation and release and the mechanisms underlying these effects. Wildtype mice were used to examine effects of BMP signaling in vivo. P301S (PS19) mice were examined for the effects of BMP signaling in a model of tauopathy. Here, we show that BMP signaling, mediated by non-canonical p38 signaling, increases tau phosphorylation and release of p-tau in human iPSC-derived AD neurons. Further, there is an interaction between BMP signaling and apolipoprotein E4 (ApoE4) that significantly increases tau phosphorylation and release compared with ApoE3 neurons. Inhibiting BMP signaling reduces the changes in tau in the cultured human neurons, and it limits tau pathology and prevents cognitive decline in PS19 mice. Our study suggests that the age-related increase in BMP signaling may participate in the onset and progression of tau pathology. Thus, therapeutic interventions that reduce BMP signaling in the aging brain could potentially slow or prevent development of diseases involving tau hyperphosphorylation. ANN NEUROL 2024.

Neurodegeneration with iron accumulation in the brain, peculiarities of course and approach to treatment

Neurodegenerations with brain iron accumulation (NBIA) constitute a group of genetically determined and clinically heterogeneous forms of progressive neurological pathology associated with the accumulation of iron in the basal ganglia and other structures of the brain, which, in turn, causes their dysfunction. Both childhood and adulthood onset of the disease is possible. Objective: to draw the attention of doctors to the importance of timely diagnosis of neurodegenerative diseases, which are manifested by movement disorders and abnormal accumulation of iron in various structures of the brain. Movement disorders, mostly a combination of parkinsonism, dystonia, pyramidal insufficiency and ataxia, are dominant in the clinical picture of NBIA. Areas of iron deposition are detected on magnetic resonance imaging as bilateral hypodense zones, in the center of which hyperdense foci are determined in many cases, probably due to the gliosis, mainly in the area of the globus pallidus (eye-of-the-tiger sign). Typical neuroimaging signs help make a preliminary diagnosis of NBIA with a high probability, in the presence and sometimes even before the appearance of clinical manifestations of the disease, reducing costs and time for additional research. The paper describes a clinical case of NBIA associated with the protein of the mitochondrial membrane, and also highlights the latest data on clinical manifestations, diagnosis and modern management of this pathology. The possibility and importance of modern diagnosis and therapy in childhood have been demonstrated. Genetic examination remains crucial for the verification of the hereditary degenerative disease and determination of its form. The analysis of literature data and the results of own observations confirm the importance of the given main directions of available symptomatic treatment, as well as approaches to pathogenetic therapy, which still require further clinical trials. The given clinical observation and the analysis of literature data on the problem of NBIA reflect the expediency of searching for characteristic neuroimaging patterns in patients with motor (extrapyramidal, pyramidal, coordination) disorders with further verification of the diagnosis by means of molecular genetic research.

NOD3 Reduces Sepsis-Induced Acute Lung Injury by Regulating the Activation of NLRP3 Inflammasome and the Polarization of Alveolar Macrophages.

The pathogenesis of sepsis-induced Acute lung injury (ALI) progresses rapidly, and no effective treatment drugs are known, resulting in a high mortality rate. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation plays an important role in the pathological progression of ALI, and often coincide with the inflammatory activation and polarization of macrophages. NLR family CARD domain-containing protein 3 (NOD3) was reported protecting against sepsis-induced pulmonary pathological injury and inhibiting the inflammatory response in lung tissue. NOD3 can also inhibit NLRP3 inflammasome activation by competitively inhibiting the binding of pro-caspase-1 to apoptosis-related ASC or reducing NLRP3/cryopyrin-induced ASC speckle formation. In this study, we aimed to explore whether NOD3 decrease sepsis-induced lung injury by interfering with NLRP3 inflammasome activation and regulating alveolar macrophages (AMs) polarization. To investigate whether NOD3 reduce sepsis-induced ALI by inhibiting the activation of NLRP3 inflammasome to regulate the polarization of AMs. Sepsis-induced WT (C57BL/6) and NLRC3-/--C57BL/6 mice ALI models were established by intraperitoneal injection of lipopolysaccharide (LPS). In vitro experiments, AMs and bone marrow-derived macrophages (BMDMs) were isolated from WT and NLRC3-/- mice. Using in vivo and in vitro experiments, we found that NOD3 knockout promoted the sepsis-induced inflammatory response in lung tissue. In addition, NOD3 knockout promoted the activation of the TRAF6-NF-κB signaling pathway and the NLRP3 inflammasome in AMs, enhanced the M1-type polarization of AMs and decreased the M2-type polarization of AMs in sepsis-induced lung injury model mice. NOD3 interfered with NLRP3 inflammasome activation by inhibiting NLRP3 inflammasome assembly or negatively regulating the TRAF6-NF-κB signaling pathway, and regulating the polarization of AMs, thereby alleviating sepsis-induced lung injury.

Genetics and Neuropathology of Neurodegenerative Dementias.

This article provides an overview of the current understanding of the genetic and pathologic features of neurodegenerative dementias, with an emphasis on Alzheimer disease and related dementias. In recent years, there has been substantial progress in genetic research, contributing significant knowledge to our understanding of the molecular risk factors involved in neurodegenerative dementia syndromes. Several genes have been linked to monogenic forms of dementia (eg, APP, PSEN1, PSEN2, SNCA, GRN, C9orf72, MAPT) and an even larger number of genetic variants are known to influence susceptibility for developing dementia. As anti-amyloid therapies for patients with early-stage Alzheimer disease have entered the clinical arena, screening for the apolipoprotein E ε4 high-risk allele has come into focus, emphasizing the importance of genetic counseling. Similarly, advances in the pathologic classifications of neurodegenerative dementia syndromes and molecular pathology highlight their heterogeneity and overlapping features and provide insights into the pathogenesis of these conditions. Recent progress in neurogenetics and molecular pathology has improved our understanding of the complex pathogenetic changes associated with neurodegenerative dementias, facilitating improved disease modeling, enhanced diagnostics, and individualized counseling. The hope is that this knowledge will ultimately pave the way for the development of novel therapeutics.

Ebeiedinone and peimisine inhibit cigarette smoke extract-induced oxidative stress injury and apoptosis in BEAS-2B cells.

Ebeiedinone and peimisine are the major active ingredients of Fritillariae Cirrhosae Bulbus. In this study, we looked at how these two forms of isosteroidal alkaloids protect human bronchial epithelial BEAS-2B cells from oxidative stress and apoptosis caused by cigarette smoke extract (CSE). First, the cytotoxicity was determined using the CCK8 assay, and an oxidative stress model was established. Then the antioxidative stress activity and mechanism were investigated by ELISA, flow cytometry, and Western blotting. By the CCK-8 assay, exposure to CSE (20%, 40%, and 100%) reduced the viability of BEAB-2S cells. The flow cytometry findings indicated that CSE-induced production of ROS (0.5% to maximum) and treatments with 10μM ebeiedinone and 20μM peimisine attenuated the production of ROS. The western blot assay results indicate that ebeiedinone and peimisine reduce CSE-induced oxidative stress, DNA damage, apoptosis, and autophagy dysregulation by inhibiting ROS, upregulating SOD and GSH/GSSG, and downregulating MDA, 4-HNE, and 8-OHdG through the NRF2/KEAP1 and JNK/MAPK-dependent pathways, thereby delaying the pathological progression of COPD caused by CS.Our data suggest that CSE causes oxidative stress, DNA damage, and apoptosis in BEAS-2B cells, as well as the progression of COPD. Ebeiedinone and peimisine fight CS-induced COPD by suppressing autophagy deregulation and apoptosis.

Sphingosine kinase 2 (SphK2) depletion alters redox metabolism and enhances inflammation in a diet-induced MASH mouse model

Background: Sphingosine-1 phosphate (S1P) is a bioactive lipid molecule that modulates inflammation and hepatic lipid metabolism in MASLD, which affects 1 in 3 people and increases the risk of liver fibrosis and hepatic cancer. S1P can be generated by 2 isoforms of sphingosine kinase (SphK). SphK1 is well-studied in metabolic diseases. In contrast, SphK2 function is not well characterized. Both sphingolipid and redox metabolism dysregulation contribute to MASLD pathologic progression. While SphK2 localizes to both the nucleus and mitochondria, its specific role in early MASH is not well defined. Methods: This study examined SphK2 depletion effects on hepatic redox metabolism, mitochondrial function, and inflammation in a 16-week western diet plus sugar water (WDSW)-induced mouse model of early MASH. Results: WDSW-SphK2 −/− mice exhibit increased hepatic lipid accumulation and hepatic redox dysregulation. In addition, mitochondria-localized cholesterol and S1P precursors were increased. We traced SphK2 −/− -mediated mitochondrial electron transport chain impairment to respiratory complex-IV and found that decreased mitochondrial redox metabolism coincided with increased oxidase gene expression and oxylipin production. Consistent with this relationship, we observed pronounced increases in hepatic inflammatory gene expression, prostaglandin accumulation, and innate immune homing in WDSW-SphK2 −/− mice compared to WDSW-wild-type mice. Conclusions: These studies suggest SphK2-derived S1P maintains hepatic redox metabolism and describe the potential consequences of SphK2 depletion on proinflammatory gene expression, lipid mediator production, and immune infiltration in MASH progression.

Modelling pathological spread through the structural connectome in the frontotemporal dementia clinical spectrum.

The ability to predict the pathology spreading in patients with frontotemporal dementia (FTD) is crucial for early diagnosis and targeted interventions. This study examined the relationship between network vulnerability and longitudinal atrophy progression in FTD patients, using Network Diffusion Model (NDM) of pathology spread. Thirty behavioural-variant FTD (bvFTD), 13 semantic-variant primary progressive aphasia (svPPA), 14 nonfluent-variant PPA (nfvPPA) and 12 semantic behavioral variant FTD (sbvFTD) patients underwent longitudinal T1-weighted MRI. Fifty young controls (YC) (20-31 years) underwent multi-shell diffusion MRI scan. NDM was developed to model FTD pathology progression as a spreading process from a seed through the healthy structural connectome, using connectivity measures from fractional anisotropy (FA) and intra-cellular volume fraction (ICVF) in YC. Four disease epicenters were initially identified from the peaks of atrophy of each FTD variant: left insula (bvFTD), left temporal pole (svPPA), right temporal pole (sbvFTD) and left supplementary motor area (nfvPPA). Pearson's correlations were calculated between NDM-predicted atrophy in YC and the observed longitudinal atrophy in FTD patients over a follow-up of 24 months. The NDM was then run for all the 220 brain seeds to verify whether the four epicenters were among those that yielded the highest correlation. Using NDM, predictive maps in YC showed pathology progression from the peaks of atrophy in svPPA, nfvPPA, and sbvFTD over 24-months. svPPA exhibited early involvement of left temporal and occipital lobes, progressing to extensive left hemisphere impairment. nfvPPA and sbvFTD similarly spread bilaterally to frontal, sensorimotor, and temporal regions, with sbvFTD additionally affecting the right hemisphere. Moreover, the NDM-predicted atrophy of each region was positively correlated to longitudinal real atrophy, with a greater effect in svPPA and sbvFTD. In bvFTD, the model starting from the left insula (the peak of atrophy) demonstrated a highly left-lateralized pattern, with pathology spreading to frontal, sensorimotor, temporal, and basal ganglia regions, with minimal extension to the contralateral hemisphere by 24 months. However, unlike the atrophy peaks observed in the other three phenotypes, the left insula did not show the strongest correlation between the estimated and actual atrophy. Instead, the bilateral superior frontal gyrus emerged as optimal seeds for modelling atrophy spread, showing the highest correlation ranking in both hemispheres. Overall, NDM applied on ICVF connectome yielded higher correlations relative to NDM applied on FA maps. The NDM implementation using cross-sectional structural connectome is a valuable tool to predict atrophy patterns and pathology spreading in FTD clinical variants.

The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model

Background/Objectives: Interleukin-1 (IL-1) is a pivotal mediator in the pathological progression of osteoarthritis (OA), playing a central role in disease progression. However, the rapid clearance of IL-1 receptor antagonist (IL-1Ra) from the joints may hinder the efficacy of intra-articular IL-1Ra injections in reducing OA-associated pain or cartilage degradation. Methods: Sustaining sufficient levels of IL-1Ra within the joints via adeno-associated virus (AAV)-mediated gene therapy presents a promising therapeutic strategy for OA. In this study, we constructed an IL-1Ra expression cassette employing intron insertion in the coding sequence (CDS) region to enhance protein expression levels. Furthermore, we incorporated precisely targeted liver-specific microRNA (miRNA) sequences to specifically downregulate transgene expression within hepatic tissues, thereby ensuring more targeted and controlled regulation of gene expression. Results: A rat model of OA was employed to compare the efficacy of AAV5 and AAV9 for IL-1Ra delivery at both high and low doses. It was observed that low-dose, but not high-dose, AAV9-IL-1Ra resulted in a significant reduction in joint swelling, accompanied by a decrease in the diameter of the affected area and the preservation of biomarkers associated with trabecular bone integrity. Conclusions: These results highlight the great potential of AAV9-IL-1Ra in osteoarthritis therapy, with the promise of achieving long-term improvement through a single intra-articular injection.

Inflammatory microenvironment promotes extracellular matrix degradation of chondrocytes through ALKBH5-dependent Runx2 m6A modification in the pathogenesis of osteoarthritis

BackgroundOsteoarthritis (OA) is a chronic degenerative joint disease characterized by the breakdown of cartilage and extracellular matrix (ECM). The degradation of ECM in chondrocytes plays a crucial role in OA pathogenesis, but the underlying molecular mechanisms remain largely unclear. MethodsA sodium monoiodoacetate (MIA) mouse model was used to mimic OA. ECM integrity was accessed by Hematoxylin and Eosin (H&E) staining, Safranin O/fast green staining, and microcomputerized tomography. Enzyme-linked immunosorbent assay measured circulating proinflammatory cytokines. Reverse transcription-quantitative polymerase chain reaction and western blotting analyzed mRNA and protein expression levels. RNA and chromatin immunoprecipitation evaluated RNA-protein and DNA-protein interactions. ResultsMIA mice showed significant upregulation of the RNA m6A demethylase ALKBH5 (alkylated DNA repair protein AlkB homolog 5), the transcription factor Runx2 (runt-related transcription factor 2), and matrix-degrading enzymes Mmps (matrix metallopeptidase) and Adamts(s) (a disintegrin and metalloproteinase with thrombospondin motifs). In vitro, proinflammatory cytokines induced these proteins in chondrocytes. Mechanically, Alkbh5 cooperated with Ythdf1 (YTH N6-methyladenosine RNA binding protein 1) in the inflammatory microenvironment to regulate the expression and stability of RUNX2 mRNA. Runx2, in turn, activated the expression of MMPs and ADAMTSs, promoting ECM degradation in chondrocytes, thereby contributing to OA progression. Notably, inhibition of Alkbh5 and Runx2 in MIA-treated mice significantly alleviated the pathological progression of OA. ConclusionOur results reveal a novel mechanism of OA pathogenesis and suggest that targeting Alkbh5 and Runx2 may represent a new therapeutic strategy for OA treatment.

Hyperglycemia Exacerbates Periodontal Destruction via Systemic Suppression of Regulatory T Cell Number and Function.

Diabetes is a significant risk factor that exacerbates the pathological progression of periodontal disease. In recent years, attention has focused on the effect of regulatory T cells (Tregs), which play a central role in immune tolerance, on inflammatory processes in periodontal tissue, suggesting a link with diabetes-associated periodontitis. In this study, we examined the dynamics of Tregs in periodontal tissue of mice with streptozotocin (STZ)-induced hyperglycemia. Eleven-week-old male C57BL/6J mice were divided into four treatment groups: Untreated (C group), ligature placed around the maxillary second molars with silk sutures (PD group), intraperitoneal administration of STZ (HG group), and ligature placed after STZ administration (PHG group). Establishment of hyperglycemia was assessed 14 days after STZ administration, and ligation was performed 7 days later. After another 7 days of ligation, the mice were euthanized. The right side of the maxilla was observed histopathologically, whereas the palatal gingiva on the left side of the maxilla was analyzed genetically, and the microstructure of the alveolar bone was also assessed. In addition, lymphocytes from peripheral blood, spleen, and periodontal tissue were analyzed using flow cytometry. In bone structure analyses, alveolar bone height, bone volume/tissue volume (BV/TV), and bone mineral density (BMD) were lower in the PHG group than the PD group. In the gingival tissue, expression of the Foxp3 gene was up-regulated in the PHG group compared with the C group, and IL-17a was up-regulated in the PHG group compared with the PD group. Flow cytometry analyses showed that the number of Tregs (CD4+CD25+Foxp3+ cells) in the blood and gingival tissue was significantly higher in the PD and PHG groups than the C group. The number of CD4+CD25-Foxp3+ cells, which are reportedly functionally attenuated as Tregs, was increased in blood of the PHG group. Immunofluorescence staining of periodontal tissue showed that the number of CD25+Foxp3+ cells was significantly increased only in the PD group, whereas a trend toward an increased number of CD25-Foxp3+ cells was observed in the PHG group. The present study showed that STZ-induced hyperglycemia numerically and functionally attenuates Tregs in a mouse model of experimental periodontitis. Furthermore, impaired immune tolerance capacity appears to be involved in exacerbating inflammation and bone destruction in periodontal tissue.

Moderate-intensity aerobic exercise inhibits cell pyroptosis to improve myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MI/RI) significantly impacts the patients with acute myocardial infarction (AMI), with the NLRP3-mediated necrosis exacerbates the pathological progression of myocardial infarction. Exercise, recognized as a crucial approach for both disease prevention and treatment, is widely utilized in clinical practice worldwide and has demonstrated broad effectiveness in cardiovascular disease (CVD) prevention. To explore the cardio protective effect of exercise preconditioning and the mechanism by which exercise modulation of NLRP3 improves myocardial ischemia and reperfusion injury. In this study, C57BL/6N mice were employed to establish an exercise preconditioning model and a MI/RI model. The exercise intervention involved moderate-intensity aerobic exercise on a treadmill (50-70% VO2max) for small animals. Our research findings indicate that moderate-intensity aerobic exercise intervention improved cardiac function, reduced myocardial injury and inflammatory response, decreased myocardial infarction area and degree of cell apoptosis in mice compared to those raised under conventional conditions. Additionally, the expression of NLRP3 in the myocardial tissue of mice with MI/RI was reduced after exercise intervention. Moreover, exercise inhibited the activation of apoptosis related proteins such as Caspase-1 and GSDMD, while reducing the levels of inflammatory factors such as IL-1β and IL-18. This study found that moderate-intensity aerobic exercise can reduce the inflammatory response, reduce the degree of cell pyroptosis, reduce myocardial ischemia and reperfusion injury, and achieve endogenous protective effects on the myocardium.

MALAT1 promotes colonic epithelial cell apoptosis and pyroptosis by sponging miR-22-3p to enhance NLRP3 expression.

Colonic epithelial cell apoptosis and pyroptosis had a close relationship with the pathological progression of ulcerative colitis (UC). LncRNA play a crucial role in the progression of UC. However, the role of the lncRNA MALAT1 in colonic epithelial cell apoptosis and pyroptosis remains unclear. UC colitis cell model was established through lipopolysaccharide (LPS) treatment. MiR-22-3p and MALAT1 expression in fetal human colon (FHC) cells were analyzed by qRT-PCR. Proliferation and apoptosis of FHCs were measured using CCK-8 assay and flow cytometry, respectively. Pyroptosis indicators including interleukin (IL)-1β, IL-18, tumor necrosis factor-α (TNF-α), NLR family pyrin domain containing 3 (NLRP3), caspase-1, and N-gasdermin D (N-GSDMD) in FHCs were detected using ELISA, qRT-PCR, western blotting, and immunofluorescence. In this study, apoptosis was facilitated, IL-1β, IL-18, and TNF-α levels were enhanced, NLRP3, caspase-1, N-GSDMD protein were increased, and MALAT1 expression was markedly increased in LPS-treated FHCs (LTFs). MALAT1 knockdown remarkably facilitated proliferation and suppressed apoptosis, reduced IL-1β, IL-18, and TNF-α levels, and decreased the protein of NLRP3, caspase-1, N-GSDMD. Furthermore, NLRP3 overexpression remarkably reversed the effect of MALAT1-downexpression in LTFs. In addition, miR-22-3p could bind with MALAT1 and NLRP3 3' UTR. Furthermore, miR-22-3p inhibition remarkably reversed the effect of MALAT1 overexpression in LTFs. These findings suggest that MALAT1 represents a promising therapeutic target for the treatment of UC by modulating the miR-22-3p/NLRP3 pathway, potentially leading to novel strategies for reducing inflammation and cell death in the colon.

B cells abnormalities in asthma

Abstract. Asthma is a chronic inflammation in the respiratory tract, which is an abnormal immune response of type I allergic reaction with elevated IgE levels. The abnormality of B cell contributing to asthma development has not been elucidated completely. Recently, data from different research groups showed that both CD27+CD38+ plasmablasts and CD24hiCD38hi transitional B cells are capable to induce the production of IgE antibody. In contrast, Bregs is crucial for inhibiting type 2 inflammation through secreting cytokines IL-10 in asthma patients of both children and adults. With the advancement of high-throughput sequencing and analysis technology in recent years, there has been further displaying of the association between B subgroups and asthma besides Breg and plasmablast subsets. This article briefly summarized the pathogenesis and pathological progression of Breg cells in animal models and patients of asthma, with a particular focus on high-throughput sequencing revealing new mechanisms and diagnostic

Transitional B cells in PBMCs and its pathogenesis in SLE using sc-RNA sequencing data

Abstract. Systemic lupus erythematosus (SLE) is a autoimmune disorders with multisystems and organs such as kidney, lung and heart et. al. The abnormal functions of B cells induced the pathogenesis and pathological progression of this disease. The therapeutic strategies targeting B cells have been used clinically to treat SLE, achieved encouraging result. However, some patients have side effects such as infection caused by excessive humoral immune suppression. Sc-RNA sequencing technology can sequence the overall RNA in the level of single cell, aiming to classify cells, thus achieving to target B cell subgroups precisely. This article utilized transcriptome sequencing data of single cell from PBMCs in the GEO database, and subsequently analysed for dimensionality reduction clustering and data screening using R packages. Ultimately, the author discovered highly variable genes and related pathways of SLE samples transitional B cells, providing possible directions to explore SLE related treatment candidates in future.

Targeting NAMPT-OPA1 for treatment of senile osteoporosis.

Senescence of bone marrow mesenchymal stem cells (BMSCs) impairs their stemness and osteogenic differentiation, which is the principal cause of senile osteoporosis (SOP). Imbalances in nicotinamide phosphoribosyltransferase (NAMPT) homeostasis have been linked to aging and various diseases. Herein, reduction of NAMPT and impaired osteogenesis were observed in BMSCs from aged human and mouse. Knockdown of Nampt in BMSCs promotes lipogenic differentiation and increases age-related bone loss. Overexpression of Nampt ameliorates the senescence-associated (SA) phenotypes in BMSCs derived from aged mice, as well as promoting osteogenic potential. Mechanistically, NAMPT inhibits BMSCs senescence by facilitating OPA1 expression, which is essential for mitochondrial dynamics. The defect of NAMPT reduced mitochondrial membrane potential, interfered with mitochondrial fusion，and increased SA protein and phenotypes. More importantly, we have confirmed that P7C3, the NAMPT activator, is a novel strategy for reducing SOP bone loss. P7C3 treatment significantly prevents BMSCs senescence by improving mitochondrial function through the NAMPT-OPA1 signaling axis. Taken together, these results reveal that NAMPT is a regulator of BMSCs senescence and osteogenic differentiation. P7C3 is a novel molecule drug to prevent the pathological progression of SOP.

Drosophila glial system: an approach towards understanding molecular complexity of neurodegenerative diseases.

Glia is pivotal in regulating neuronal stem cell proliferation, functioning, and nervous system homeostasis, significantly influencing neuronal health and disorders. Dysfunction in glial activity is a key factor in the development and progression of brain pathology. However, a deeper understanding of the intricate nature of glial cells and their diverse role in neurological disorders is still required. To this end, we conducted data mining to retrieve literature from PubMed and Google Scholar using the keywords: glia, Drosophila, neurodegeneration, and mammals. The retrieved literature was manually screened and used to comprehensively understand and present the different glial types in Drosophila, i.e., perineurial, subperineurial, cortex, astrocyte-like and ensheathing glia, their relevance with mammalian counterparts, mainly microglia and astrocytes, and their potential to reveal complex neuron-glial molecular networks in managing neurodegenerative processes.

Calcium bridges built by mitochondria-associated endoplasmic reticulum membranes: potential targets for neural repair in neurological diseases.

The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels. Mitochondria-associated endoplasmic reticulum membranes serve as physical contact channels between the endoplasmic reticulum membrane and the mitochondrial outer membrane, formed by various proteins and protein complexes. This microstructural domain mediates several specialized functions, including calcium (Ca2+) signaling, autophagy, mitochondrial morphology, oxidative stress response, and apoptosis. Notably, the dysregulation of Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes is a critical factor in the pathogenesis of neurological diseases. Certain proteins or protein complexes within these membranes directly or indirectly regulate the distance between the endoplasmic reticulum and mitochondria, as well as the transduction of Ca2+ signaling. Conversely, Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes influences other mitochondria-associated endoplasmic reticulum membrane-associated functions. These functions can vary significantly across different neurological diseases-such as ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-and their respective stages of progression. Targeted modulation of these disease-related pathways and functional proteins can enhance neurological function and promote the regeneration and repair of damaged neurons. Therefore, mitochondria-associated endoplasmic reticulum membranes-mediated Ca2+ signaling plays a pivotal role in the pathological progression of neurological diseases and represents a significant potential therapeutic target. This review focuses on the effects of protein complexes in mitochondria-associated endoplasmic reticulum membranes and the distinct roles of mitochondria-associated endoplasmic reticulum membranes-mediated Ca2+ signaling in neurological diseases, specifically highlighting the early protective effects and neuronal damage that can result from prolonged mitochondrial Ca2+ overload or deficiency. This article provides a comprehensive analysis of the various mechanisms of Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes in neurological diseases, contributing to the exploration of potential therapeutic targets for promoting neuroprotection and nerve repair.

The Lymphatic Vasculature in Lung Homeostasis and Disease.

The lymphatic vasculature maintains lung homeostasis via fluid drainage in the form of lymph and by facilitating immune surveillance and leukocyte trafficking to the draining lymph nodes. Previous studies in both humans and animal models have demonstrated an important role for lymphatics in lung function from the neonatal period through adulthood. In addition, changes in the lymphatic vasculature have been observed in many respiratory diseases, and there is emerging evidence of a causative role for lymphatic dysfunction in the initiation and progression of lung pathology. Despite advances in the field, there are still many unanswered questions, and a more comprehensive understanding of the mechanisms by which the lymphatics affect lung homeostasis and the response to lung injury is needed. In this review, we discuss our current knowledge of the structure, function, and role of the lymphatics in the lung and how these vessels are involved in respiratory disease.