Alterations In Signaling Pathways Research Articles

The Role of Chronic Infections in Immune System Dysregulation and Autoimmune Diseases

Chronic infections significantly impact the immune system, contributing to dysregulation and the development of autoimmune diseases. Persistent pathogens, such as viruses and bacteria, can evade immune clearance, leading to a sustained inflammatory response that disrupts the delicate balance of immune tolerance and activation. This review explores the mechanisms through which chronic infections influence immune system dynamics, focusing on the role of cytokines, immune cell modulation, and the alteration of immune signaling pathways. Infections like hepatitis C, Epstein-Barr virus, and others have been linked to autoimmune conditions such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. The persistent presence of these pathogens may lead to molecular mimicry, epitope spreading, and the activation of autoreactive T and B cells, driving the pathogenesis of autoimmunity. Additionally, we discuss the implications of chronic infections on therapeutic strategies for autoimmune diseases, emphasizing the need for a comprehensive understanding of the interplay between infections and autoimmune dysregulation. By elucidating the complex relationships between chronic infections and the immune system, this review aims to highlight potential avenues for developing targeted interventions and improving patient outcomes in autoimmune disorders. Keywords: Chronic Infections, Immune Dysregulation, Autoimmune Diseases, Cytokines, Pathogenesis

Single-cell transcriptome analysis reveals status changes of immune cells in chronic kidney disease

Background and aimsThe immune system plays a crucial role in the development of kidney diseases. Chronic kidney disease (CKD) can lead to various complications, potentially affecting multiple systems throughout the body. Currently, the description of the immune system in human CKD is not comprehensive enough. Constructing a CKD kidney atlas using single-cell RNA sequencing (scRNA-seq) can provide deeper insights into the composition and functional changes of immune cells in CKD, facilitating the discovery of new therapeutic targets.MethodsWe processed and integrated scRNA-seq datasets from healthy and CKD kidneys from three independent cohorts using the same approach (including 42 normal samples and 23 chronic kidney disease samples). Subsequently, we conducted gene enrichment and intercellular communication analysis to construct an immune cell atlas of the kidneys in CKD patients.ResultsWe identified nine major kidney cell clusters. Further clustering analysis of different immune cell clusters revealed that, compared to normal kidneys, CKD patients’ kidneys had decreased CD16+ NK cells while CD4+ naive helper T cells and CCR7+ DC increased. Partial activation of the WNT signaling pathway was observed in T cells and NK cells of CKD patients, while some metabolism-related genes were inhibited. Myeloid cell subgroups also exhibited abnormal signaling pathway alterations. Additionally, we discovered a unique population of SPP1 macrophages in CKD, which are recruited by chemokines released from aPT and aTAL cell subpopulations. These SPP1 macrophages may promote cellular fibrosis through the signaling of SPP1, FN1, and various receptors.ConclusionWe established a human CKD kidney immune cell atlas and identified SPP1 macrophages as a unique cell type in CKD. The interaction between SPP1 macrophages and damaged cells may serve as a potential therapeutic target for treating CKD in the future.

Placental growth factor deficiency initiates obesity- and aging-associated metabolic syndrome

Obesity often leads to inadequate angiogenesis in expanding adipose tissue, resulting in inflammation and insulin resistance. We explored the role of placental growth factor (PlGF) in metabolic syndrome (MS) using mice models of type 2 diabetes, high-fat diet, or aging. Reduced serum PlGF levels were associated with decreased insulin sensitivity and development of MS features. PlGF was localized within endothelial cells and pericytes of adipose tissue. In vitro, low PlGF levels in hypoxic conditions worsened oxidative stress, apoptosis, and reduced autophagy. This was associated with a reduction in expression of vascular endothelial growth factor (VEGF)-A/VEGF-R1/−R2, which was influenced by a decrease and increase in PlGF/pAMPK/PI3K-pAkt/PLCγ1-iCa++/eNOS and PTEN/GSK3β axes, respectively. PlGF-knockout mice exhibited MS traits through alterations in the same signaling pathways, and these changes were mitigated by recombinant PlGF and metformin. These enhanced angiogenesis and lipid metabolism, underscoring PlGF's role in age-related MS and its potential as a therapeutic target.

Raphe and ventrolateral medulla proteomics in sudden unexplained death in childhood with febrile seizure history

Sudden unexplained death in childhood (SUDC) is death of a child ≥ 12 months old that is unexplained after autopsy and detailed analyses. Among SUDC cases, ~ 30% have febrile seizure (FS) history, versus 2–5% in the general population. SUDC cases share features with sudden unexpected death in epilepsy (SUDEP) and sudden infant death syndrome (SIDS), in which brainstem autonomic dysfunction is implicated. To understand whether brainstem protein changes are associated with FS history in SUDC, we performed label-free quantitative mass spectrometry on microdissected midbrain dorsal raphe, medullary raphe, and the ventrolateral medulla (n = 8 SUDC-noFS, n = 11 SUDC-FS). Differential expression analysis between SUDC-FS and SUDC-noFS at p < 0.05 identified 178 altered proteins in dorsal raphe, 344 in medullary raphe, and 100 in the ventrolateral medulla. These proteins were most significantly associated with increased eukaryotic translation initiation (p = 3.09 × 10–7, z = 1.00), eukaryotic translation elongation (p = 6.31 × 10–49, z = 6.01), and coagulation system (p = 1.32 × 10–5, z = 1.00). The medullary raphe had the strongest enrichment for altered signaling pathways, including with comparisons to three other brain regions previously analyzed (frontal cortex, hippocampal dentate gyrus, cornu ammonus). Immunofluorescent tissue analysis of serotonin receptors identified 2.1-fold increased 5HT2A in the medullary raphe of SUDC-FS (p = 0.025). Weighted gene correlation network analysis (WGCNA) of case history indicated that longer FS history duration significantly correlated with protein levels in the medullary raphe and ventrolateral medulla; the most significant gene ontology biological processes were decreased cellular respiration (p = 9.8 × 10–5, corr = − 0.80) in medullary raphe and decreased synaptic vesicle cycle (p = 1.60 × 10–7, corr = − 0.90) in the ventrolateral medulla. Overall, FS in SUDC was associated with more protein differences in the medullary raphe and was related with increased translation-related signaling pathways. Future studies should assess whether these changes result from FS or may in some way predispose to FS or SUDC.

Loss of peroxiredoxin 6 (PRDX6) alters lipid composition and distribution resulting in increased sensitivity to ferroptosis.

Peroxiredoxin 6 (PRDX6) is a multifunctional enzyme involved in phospholipid peroxide repair and metabolism. In this study we investigated the global lipid composition of a human hepatocarcinoma cell line SNU475 lacking PRDX6 and lipid related cellular processes. There was a general decrease in multiple lipids species upon loss of PRDX6, in particular sphingomyelins and acylcarnitines, consistent with previously observed alterations in cell signaling pathways and mitochondrial dysfunction. Deprivation of docosahexaenoic acid and related species was also evident. However, a few striking exceptions are worth highlighting: 1) Three specific arachidonic acid (AA) containing phophatidylcholines (PC) increased significantly. The increase of sn1-stearic/sn2-PUFA containing PC and sn2-AA containing plasmenyls are indicative of a preference of PRDX6 iPLA2 activity for these AA storage glycerophospholipids. 2) Several polyunsaturated fatty acids (PUFA) and PUFA containing triacylglycerols accumulated together with increased formation of lipid droplets, an indication of altered FA flux and PUFA sequestration in PRDX6 knockout cells. Loss of PRDX6 resulted in increased sensitivity to erastin-induced ferroptosis, independent of selenium and GPX4, as a consequence of increased levels of lipid hydroperoxides, that reverted to normal levels upon rescue with PRDX6. <SPAN style="font-weight: 400;">The results presented demonstrate that all three enzymatic activities of PRDX6 contribute to the role of this multifunctional enzyme in diverse cellular processes, including membrane phospholipid remodeling and glycerophospholipid functional diversity, resulting in altered lipid peroxides and modulation of AA disposition and traffic. These contributions highlight the complexity of the changes that loss of PRDX6 exerts on cell functionality.</SPAN>.

Trichostatin A mitigates acute and late effects of radiation in intestine by regulation of DNA damage repair and Wnt/TGFβ/Smad signaling

Purpose Radiation accidents and misuse of nuclear weapons elevate the risk of development of acute life-threatening injuries as well as their late effects are noted in survivors. Currently, no countermeasure agents are available for the management of radiation-induced GI injury (RIGI) in humans. In the present study, the radiomitigative potential of Trichostatin A (TSA) was evaluated against acute and late RIGI. Methods 15 Gy gamma radiation was delivered to the whole abdomen of C57BL/6 mice, followed by intravenous TSA (150 ng/kg) administration after 1 h and 24 h. Acute changes were checked 24 h and 3.5 days post irradiation. Mice were monitored for development of fibrosis, survival for 1 year and alteration in different signaling pathways. Result 15 Gy abdominal irradiation activated the DNA damage marker (γ-H2AX) by nearly 3.2 ± 0.29 fold and regulated the repair proteins, XRCC1 and PARP1 in the intestine, which was differentially regulated by TSA. The Wnt signaling pathway and stem cell proliferation in the intestine were also positively regulated by TSA. The TSA administered mice demonstrated improved intestinal morphology. 12.5% of TSA administered mice survived upto 1 year whereas 100% of 15 Gy exposed mice died by 6 months. The surviving mice that had received TSA showed reduced intestinal fibrosis than 15 Gy group, possibly via downregulation of TGFβ/Smad signaling. Conclusion The findings suggest that TSA have the potential to mitigate both acute and late effects of radiation in the intestine and can be explored as promising agent in the management of RIGI.

Collagen (peptide) extracted from sturgeon swim bladder: Physicochemical characterization and protective effects on cyclophosphamide-induced premature ovarian failure in mice

Premature ovarian failure (POF) is a common female reproductive disorder, with oxidative damage playing a significant role in its development. Studies had demonstrated the beneficial antioxidant, anti-aging, and other biological properties of swim bladder collagen (peptide). In this study, acid extraction, water extraction, and enzymatic hydrolysis methods were used to extract collagen (peptide) from sturgeon (Acipenser sinensis) swim bladder, all of which exhibited significant antioxidant activity. Moreover, the effects observed in POF mice were enhanced, including an increasing in the number of growing ovarian follicles, regulation of serum hormone levels, and alterations in signaling pathways, as evidenced by the up-regulation of Phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) and B cell lymphoma-2/ Bcl-associated x protein (Bcl-2/Bax) pathways, alongside the down-regulation of the mitogen-activated protein kinases (MAPK) signaling pathway. Sturgeon swim bladder collagen (peptide) could protect against cyclophosphamide-induced POF in mice, which could be very beneficial in the future advancement of health products.

Role of Dual Specificity Phosphatase 1 (DUSP1) in influencing inflammatory pathways in macrophages modulated by Borrelia burgdorferi lipoproteins.

Borrelia burgdorferi , the agent of Lyme disease, encodes numerous lipoproteins that play a crucial role as a pathogen associated molecular pattern affecting interactions with tick- and vertebrate-host cells. Single cell transcriptomics validated using unbiased proteomics and conventional molecular biology approaches have demonstrated significant differences in gene expression patterns in a dose- and time-dependent manner following treatment of murine bone marrow derived macrophages with borrelial lipoproteins. Distinct populations of macrophages, alterations in immune signaling pathways, cellular energy production and mitochondrial responses were identified and validated using primary murine macrophages and human reporter cell lines. Notably, the role of Dual Specificity Phosphatase 1 (DUSP1) in influencing several inflammatory, metabolic and mitochondrial responses of macrophages were observed in these studies using known pharmacological inhibitors. Significant outcomes include novel strategies to interfere with immunomodulatory and survival capabilities of B. burgdorferi in reservoir hosts affecting its natural infectious life cycle between ticks and vertebrate hosts.

Inflammatory mediators-induced DNA damage in liver and brain injury: Therapeutic approach of 5-Methoy-N-acetyltryptamine

The pathophysiology of hepatic and cerebral damage includes various molecular and signalling pathways. Assessment of inflammation-induced DNA damage is one of the principal issues for investigating organ distortion and mutation. The current study was premeditated to discover the prophylactic role of 5-Methoy-N-acetyltryptamine (5-MNAT) and/or Quercetin (QR) versus sodium nitrite (NaNO2) induced liver and brain injury in a rat model, as well as to clarify the different cross-linked inflammatory pathways and neurotransmitters. Pre-treatment with QR and 5-MNAT was followed with NaNO2 administration in a dose of (75 mg/kg BW). NaNO2-intoxication significantly caused alleviation in inflammatory biomarkers including C-reactive protein (CRP) and interleukin-6 (IL-6). The above-mentioned antioxidants noticeably amended the altered inflammatory biomarkers signalling pathways and liver function biomarkers including alanine aminotransferase (ALT) and lactate dehydrogenase (LDH). Furthermore, they modulated brain neurotransmitters including, GABA and serotonin in brain tissue. Likewise, the COMET assay revealed that these antioxidants successfully modified NaNO2-induced liver and brain DNA damage. In conclusion, treatment with both QR and 5-MNAT revealed the most effective therapeutic index in improving NaNO2-induced liver and brain injury, confirming the effectiveness of this combination as a powerful treatment for brain hypoxia. Nevertheless, this was confirmed with histopathological investigation.

Abstract A004: RNA splicing alterations in the development of acquired MAPKi resistance in melanoma

Abstract The standard treatment for melanoma with a BRAF mutation involves Mitogen-Activated Protein Kinase inhibitors (MAPKi), which target the aberrant MAPK signaling pathway. Although patients initially respond well to this therapy, many develop acquired resistance over time. This resistance can be attributed to various altered signaling pathways, including the reactivation of the MAPK pathway, activation of alternative survival pathways like PI3K/PTEN/AKT, engagement of receptor tyrosine kinases (RTKs) such as PDGFRβ and EGFR, and developmental pathways. Despite extensive omics studies aimed at deciphering the mechanisms behind acquired resistance, the specific alterations within these pathways remain poorly understood. To gain further insights into acquired MAPKi resistance in melanoma, we explored the role of RNA splicing events by analyzing publicly available datasets of pre- and post-MAPKi treated melanoma from patient-derived cell lines and in vitro studies using PDX models. We investigated differential transcript usage (DTU) to detect specific splice variants altered during the development of resistance. Our analysis revealed significant transcript alterations during on-treatment that reverted to baseline states once resistance was established, underscoring the dynamic and adaptive nature of these changes. Genes with DTU were enriched in pathways related to MAPKi resistance, such as the MAPKi signaling pathway, PI3K/AKT pathway, and signaling by RTKs. Furthermore, the DTU-centered analysis provided better insights into MAPKi resistance mechanisms compared to standard differential gene expression (DEG) analysis, with DTUs showing higher enrichment scores in MAPKi resistance-related pathways. Further, identifying developmental splicing signatures highlights the complexity of MAPKi resistance, as it reveals significant upregulation of transcripts associated with embryonic melanoblast stem cells (MSCs) among the altered transcripts in on-treatment cell lines. This reprogramming through RNA splicing may confer an adaptive advantage, enabling melanoma cells to revert to a more plastic, stem-like state, with developmental splicing events playing a crucial role in the adaptive response to MAPKi therapy. Next, using a regulatory model based on the expression of splicing factors (SFs), we accurately predicted transcript alterations in on-treatment samples and identified key SFs. Our study highlights the crucial role of RNA splicing in the adaptive response of melanoma cells to MAPKi treatment. These insights pave the way for future research and therapeutic strategies focusing on RNA splicing to combat drug resistance in cancer. Citation Format: Sumit Mukherjee, Arashdeep Singh, Hyunjeong Joo, Sumeet Patiyal, Hyungsoo Kim, Lipika R. Pal, Kun Wang, Chi-Ping Day, Ze’ev A Ronai, Eytan Ruppin, Sridhar Hannenhalli. RNA splicing alterations in the development of acquired MAPKi resistance in melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A004.

CD40 agonist on patient-derived xenograft mice for the treatment of B-cell acute lymphoblastic leukemia.

Cluster of differentiation 40 (CD40) is expressed on B-cell acute lymphoblastic leukemia (B-ALL) cases. However, the effect of CD40 activation on B-ALL cells has never been tested in vivo. The aim of our preclinical study was to investigate the therapeutic potential of a CD40 agonist in the treatment of B-ALL using patient-derived xenograft (PDX) mouse models. Intravenous administration of the CD40 agonist significantly impeded B-ALL cell proliferation and growth in vivo, accompanied by rapid activation of the extracellular signal-regulated kinase (ERK) pathway, leading to the induction of apoptosis and disruption of cell cycle progression. Co-treatment with a specific inhibitor of ERK further demonstrated that CD40 stimulation induced the pro-apoptosis of B-ALL cells in an ERK-dependent manner. Proteomic analysis revealed alterations in key signaling pathways associated with B-ALL expansion and maintenance. Moreover, the CD40 agonist markedly reduced the frequency of leukemia-initiating cells and leukemia development in PDX mice. Our study showed that the CD40 agonist can be associated with chemotherapeutic agents such as vincristine and dexamethasone, and this combination showed improved effectiveness. Additionally, the CD40 agonist was more effective on pre-B-ALL (EGIL B-III) that expressed CD40, than on common B-ALL (EGIL B-II) that lacked CD40 expression. These findings suggest that CD40 agonists are promising immunotherapeutic candidates for pediatric B-ALL, warranting further clinical investigations to improve patient outcomes in CD40-expressing B-ALL.

The role of the KEAP1-NRF2 signaling pathway in form deprivation myopia guinea pigs

In recent years, the global prevalence of myopia has reached an unprecedented level, especially‌ in East Asia. Multitude of studies has shown that the etiology of myopia is complex. Some researchers have suggested that oxidative stress (OS) may contribute to myopia, although there are limited reports on the alterations of related signaling pathways. Notably, the Kelch-like ECH-associated protein 1 (KEAP1) -nuclear factor erythroid 2-related factor 2 (NRF2), which plays a significant role in regulating OS and the mechanism, has not been explored in myopia. To investigate the modulation of KEAP1-NRF2 signaling pathway and its downstream superoxide dismutase (SOD) during the development of form-deprivation myopia, three-week-old guinea pigs were randomly assigned to four groups: negative control (NC), self-control (SC), form-deprivation myopia (FDM), and FDM group treated with tert-butylhydroquinone (TBHQ). Spherical equivalent (SE) and axial length (AL) were measured by retinoscopy and A-scan ultrasound, respectively. The results revealed that TBHQ treatment decelerated the progression in SE and AL changes. Immunohistochemistry (IHC) assessed the distribution and expression of KEAP1, NRF2, and SOD. The results shown that they located in the retinal ganglion cells (RGC). Subsequently, retinal mRNA and protein expression levels of KEAP1, NRF2, and SOD were quantified using real-time polymerase chain reaction (RT-PCR) and Western blot (WB) analysis. The RT-PCR and WB results demonstrated that TBHQ could activate NRF2, induce KEAP1 degradation, and enhance the expression of the antioxidant SOD. In summary, the modulation of KEAP1-NRF2 and it downstream SOD expression could alter the retinal antioxidant capacity and influence the development of myopia.

Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway: a potential therapeutic approach for neurodegenerative diseases.

The interaction between the gut microbiota and cyclic adenosine monophosphate (cAMP)- protein kinase A (PKA) signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut-brain axis. The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites, which activates the vagus nerve and modulates the immune and neuroendocrine systems. Conversely, alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota, creating a dynamic network of microbial-host interactions. This reciprocal regulation affects neurodevelopment, neurotransmitter control, and behavioral traits, thus playing a role in the modulation of neurological diseases. The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation, mitochondrial dysfunction, abnormal energy metabolism, microglial activation, oxidative stress, and neurotransmitter release, which collectively influence the onset and progression of neurological diseases. This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway, along with its implications for potential therapeutic interventions in neurological diseases. Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders. This can be achieved through various methods such as dietary modifications, probiotic supplements, Chinese herbal extracts, combinations of Chinese herbs, and innovative dosage forms. These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.

New therapies for hormone-positive HER2-negative metastatic breast cancer with AKT signaling alterations: the Expert Panel Decision

On May 20, 2024, the Expert Panel discussed key issues of the diagnosis of alterations of the AKT signaling pathway, the effectiveness and safety of targeted therapy for hormone-positive (HR+) HER2-negative metastatic breast cancer (BC) concerning the emergence of a new selective AKT inhibitor capivasertib. The results of the CAPItello-291 study are presented. The experts concluded that a new effective treatment line has become available for patients with hormone-resistant advanced hormone-positive HER2-negative BC with genetic alterations in the AKT signaling pathway and relapse on previous adjuvant endocrine therapy with aromatase inhibitors or within the first year after the therapy or with progression during previous therapy with aromatase inhibitors for metastatic BC. Modern genetic testing methods for the alterations in the AKT signaling pathway can confirm the presence of this key biological target in the tumor for tailoring effective targeted therapy.

Neutrophil and mononuclear leukocyte pathways and upstream regulators revealed by serum proteomics of adult and juvenile dermatomyositis

ObjectivesSerum protein abundance was assessed in adult and juvenile dermatomyositis (DM and JDM) patients to determine differentially regulated proteins, altered pathways, and candidate disease activity biomarkers.MethodsSerum protein expression from 17 active adult DM and JDM patients each was compared to matched, healthy control subjects by a multiplex immunoassay. Pathway analysis and protein clustering of the differentially regulated proteins were examined to assess underlying mechanisms. Candidate disease activity biomarkers were identified by correlating protein expression with disease activity measures.ResultsSeventy-eight of 172 proteins were differentially expressed in the sera of DM and JDM patients compared to healthy controls. Forty-eight proteins were differentially expressed in DM, 32 proteins in JDM, and 14 proteins in both DM and JDM. Twelve additional differentially expressed proteins were identified after combining the DM and JDM cohorts. C-X-C motif chemokine ligand 10 (CXCL10) was the most strongly upregulated protein in both DM and JDM sera. Other highly upregulated proteins in DM included S100 calcium binding protein A12 (S100A12), CXCL9, and nicotinamide phosphoribosyltransferase (NAMPT), while highly upregulated proteins in JDM included matrix metallopeptidase 3 (MMP3), growth differentiation factor 15 (GDF15), and von Willebrand factor (vWF). Pathway analysis indicated that phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), and toll-like receptor 7 (TLR7) signaling were activated in DM and JDM. Additional pathways specific to DM or JDM were identified. A protein cluster associated with neutrophils and mononuclear leukocytes and a cluster of interferon-associated proteins were observed in both DM and JDM. Twenty-two proteins in DM and 24 proteins in JDM sera correlated with global, muscle, and/or skin disease activity. Seven proteins correlated with disease activity measures in both DM and JDM sera. IL-1 receptor like 1 (IL1RL1) emerged as a candidate global disease activity biomarker in DM and JDM.ConclusionCoordinate analysis of protein expression in DM and JDM patient sera by a multiplex immunoassay validated previous gene expression studies and identified novel dysregulated proteins, altered signaling pathways, and candidate disease activity biomarkers. These findings may further inform the assessment of DM and JDM patients and aid in the identification of potential therapeutic targets.

R-Spondin 1 Suppresses Inflammatory Cytokine Production in Human Cortical Astrocytes

Background/Objectives: Wnt signaling pathways are essential in various biological processes, including embryonic development and tissue homeostasis, and are implicated in many diseases. The R-Spondin (RSpo) family, particularly RSpo1, plays a significant role in modulating Wnt signaling. This study aims to explore how RSpo1 binding to astrocytic LGR6 receptors influences central nervous system (CNS) homeostasis, particularly in the context of inflammation. Methods: Human-induced pluripotent stem cell-derived astrocytes were treated with RSpo1 to assess its impact on inflammatory cytokine release. A proteomic analysis was conducted using a Human Cytokine Array Kit to measure differential protein expression. Pathway enrichment analysis was performed to identify affected signaling pathways. Results: RSpo1 treatment led to a suppression of inflammatory cytokines such as IL-10, IFN-γ, and IL-23 in astrocytes, while TNF-α and CXCL12 levels were increased. Pathway analysis revealed significant alterations in key signaling pathways, including cytokine–cytokine receptor interaction, chemokine signaling, and TNF signaling pathways, suggesting RSpo1’s role in modulating immune responses within the CNS. Conclusions: RSpo1 significantly influences inflammatory responses in astrocytes by modulating cytokine release and altering key signaling pathways. These findings enhance our understanding of the interaction between cell-specific Wnt signaling and CNS inflammation, suggesting potential therapeutic applications of RSpo1 in neuroinflammatory and neurodegenerative diseases.

Alzheimer's Disease as Type 3 Diabetes: Understanding the Link and Implications.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two prevalent conditions that present considerable public health issue in aging populations worldwide. Recent research has proposed a novel conceptualization of AD as "type 3 diabetes", highlighting the critical roles of insulin resistance and impaired glucose metabolism in the pathogenesis of the disease. This article examines the implications of this association, exploring potential new avenues for treatment and preventive strategies for AD. Key evidence linking diabetes to AD emphasizes critical metabolic processes that contribute to neurodegeneration, including inflammation, oxidative stress, and alterations in insulin signaling pathways. By framing AD within this metabolic context, we can enhance our understanding of its etiology, which in turn may influence early diagnosis, treatment plans, and preventive measures. Understanding AD as a manifestation of diabetes opens up the possibility of employing novel therapeutic strategies that incorporate lifestyle modifications and the use of antidiabetic medications to mitigate cognitive decline. This integrated approach has the potential to improve patient outcomes and deepen our comprehension of the intricate relationship between neurodegenerative diseases and metabolic disorders.

Garcinol enriched fraction of Garcinia morella (Gaertn.) Desr. fruit rind improves gut health and reduces the risk of nonalcoholic fatty liver disease by regulating PCK1/ACC/SREBP1/FASn pathway in a mouse model

Nonalcoholic fatty liver disease (NAFLD), a fast-emerging global burden, is an umbrella term for several liver manifestations that result in excessive accumulation of fat in the liver. NAFLD leads to gut microbiome dysbiosis, loss in gut epithelia, increased gut permeability, etc. The limited availability of registered drugs for NAFLD highlights the urgent need to focus on understanding its pathogenesis and discovering new treatments, including the potential exploration of herbal therapies for managing the condition. In this study, we evaluated the bioactive potential of garcinol enriched fraction from Garcinia morella fruit rind in preventing NAFLD-associated increased gut permeability. Administration of garcinol-enriched fraction (GEF) significantly reduced body weight, serum lipids (triglyceride and total cholesterol) levels, and enzymes (alkaline phosphatase and aspartate aminotransferase) responsible for liver dysfunction in high-fat diet (HFD)-fed C57BL/6 mice. GEF treatment also regulated the alteration in signaling pathways of lipid metabolism in HFD-fed mice by inhibiting the overexpression of genes involved in de novo lipogenesis. Mice treated with GEF had increased gut microbial diversity, reduced pathogenic bacteria, and increased Lactococcus and Streptococcaceae genera. Additionally, GEF treatment could increase the expression of intestinal tight junction proteins, which were otherwise decreased in HFD-fed mice, stipulating its protective effect in maintaining gut barrier integrity. Our study demonstrated that GEF treatment reduces obesity in mice and improves gut health by keeping junctions tight and maintaining a healthy gut microbiome.

Renewed Insight into Cancer Mechanism and Therapy: Advances, Challenges, and Future Directions

Cancer remains a complex and multifactorial disease characterized by genetic mutations, epigenetic changes, and alterations in cellular signaling pathways. While traditional treatments such as surgery, chemotherapy, and radiation have been the backbone of cancer therapy, their limitations, including drug resistance, recurrence, and significant side effects, have driven the search for more targeted and personalized treatment approaches. This review provides an in-depth exploration of recent advances in cancer research and therapy, focusing on molecular mechanisms, genetic alterations, and the tumor microenvironment, all of which play pivotal roles in tumor initiation and progression. Key discoveries in oncogenes, tumor suppressor genes, and immune evasion strategies have led to the development of targeted therapies and immunotherapies. These advancements have revolutionized the treatment landscape, with therapies like immune checkpoint inhibitors, CAR T-cell therapy, and personalized medicine offering improved patient outcomes. However, challenges such as tumor heterogeneity, acquired drug resistance, therapy-related toxicities, and the high costs of these novel treatments continue to limit their effectiveness and accessibility. The review also delves into emerging therapeutic strategies, including next-generation immunotherapies, precision oncology enhanced by artificial intelligence, tumor vaccines, microbiome-based therapies, and the application of nanotechnology for drug delivery. As cancer therapies evolve, addressing these challenges is crucial for future breakthroughs. The review emphasizes the need for continued research into overcoming resistance mechanisms, reducing treatment-related side effects, and enhancing global access to cutting-edge treatments. Looking ahead, the integration of new technologies and the development of more equitable healthcare strategies will be essential to ensuring that advances in cancer therapy translate into improved survival and quality of life for patients worldwide. In conclusion, while remarkable progress has been made in cancer treatment, a multifaceted approach that blends scientific innovation, precision medicine, and healthcare accessibility will be key to overcoming the ongoing challenges in the fight against cancer. Keywords: Cancer Mechanism, Therapy, Advances, Challenges, Future Directions

Myelin debris phagocytosis in demyelinating disease.

Demyelinating diseases are often caused by a variety of triggers, including immune responses, viral infections, malnutrition, hypoxia, or genetic factors, all of which result in the loss of myelin in the nervous system. The accumulation of myelin debris at the lesion site leads to neuroinflammation and inhibits remyelination; therefore, it is crucial to promptly remove the myelin debris. Initially, Fc and complement receptors on cellular surfaces were the primary clearance receptors responsible for removing myelin debris. However, subsequent studies have unveiled the involvement of additional receptors, including Mac-2, TAM receptors, and the low-density lipoprotein receptor-related protein 1, in facilitating the removal process. In addition to microglia and macrophages, which serve as the primary effector cells in the disease phase, a variety of other cell types such as astrocytes, Schwann cells, and vascular endothelial cells have been demonstrated to engage in the phagocytosis of myelin debris. Furthermore, we have concluded that oligodendrocyte precursor cells, as myelination precursor cells, also exhibit this phagocytic capability. Moreover, our research group has innovatively identified the low-density lipoprotein receptor as a potential phagocytic receptor for myelin debris. In this article, we discuss the functional processes of various phagocytes in demyelinating diseases. We also highlight the alterations in signaling pathways triggered by phagocytosis, and provide a comprehensive overview of the various phagocytic receptors involved. Such insights are invaluable for pinpointing potential therapeutic strategies for the treatment of demyelinating diseases by targeting phagocytosis.