Promising Avenue For Therapeutic Intervention Research Articles

Normal Mode Analysis Elicits Conformational Shifts in Proteins at Both Proximal and Distal Regions to the Phosphosite Stemming from Single-Site Phosphorylation.

Phosphorylation, a fundamental biochemical switch, intricately regulates protein function and signaling pathways. Our study employs extensive computational structural analyses on a curated data set of phosphorylated and unphosphorylated protein pairs to explore the multifaceted impact of phosphorylation on protein conformation. Using normal mode analysis (NMA), we investigated changes in protein flexibility post-phosphorylation, highlighting an enhanced level of structural dynamism. Our findings reveal that phosphorylation induces not only local changes at the phosphorylation site but also extensive alterations in distant regions, showcasing its far-reaching influence on protein structure-dynamics. Through in-depth case studies on polyubiquitin B and glycogen synthase kinase-3 beta, we elucidate how phosphorylation at distinct sites leads to variable structural and dynamic modifications, potentially dictating functional outcomes. While phosphorylation largely preserves the residue motion correlation, it significantly disrupts low-frequency global modes, presenting a dualistic impact on protein dynamics. We also explored alterations in the total accessible surface area (ASA), emphasizing region-specific changes around phosphorylation sites. This study sheds light on phosphorylation-induced conformational changes, dynamic modulation, and surface accessibility alterations, leveraging an integrated computational approach with RMSD, NMA, and ASA, thereby contributing to a comprehensive understanding of cellular regulation and suggesting promising avenues for therapeutic interventions.

Inflammatory macrophage reprogramming strategy of fucoidan microneedles-mediated ROS-responsive polymers for rheumatoid arthritis

During the pathogenesis of rheumatoid arthritis, inflammatory cells usually infiltrate synovial tissues, notably, M1-type macrophages, whose redox imbalance leads to the degradation of joint structures and deterioration of function. Natural active products play a vital role in immune modulation and antioxidants. In this study, we constructed a ROS-responsive nanoparticle called FTL@SIN, which consists of fucoidan (Fuc) and luteolin (Lut) connected by a ROS-responsive bond, Thioketal (TK), and encapsulated with an anti-rheumatic drug, Sinomenine (SIN), for synergistic anti-inflammatory effects. The FTL@SIN is then dispersed in high molecular weight Fuc-fabricated dissolvable microneedles (FTL@SIN MNs) for local administration. Therapy of FTL@SIN MNs afforded a significant decrease in macrophage inflammation while decreasing key pro-inflammatory cytokines and repolarizing M1 type to M2 type, thereby ameliorating synovial inflammation, and promoting cartilage repair. Additionally, our investigations have revealed that Fucoidan (Fuc) demonstrates synergistic effects, exhibiting superior mechanical strength and enhanced physical stability when compared to microneedles formulated solely with hyaluronic acid. This study combines nanomedicine with traditional Chinese medicine, a novel drug delivery strategy that presents a promising avenue for therapeutic intervention in rheumatoid arthritis.

Guardians of the Gut: Harnessing the Power of Probiotic Microbiota and Their Exopolysaccharides to Mitigate Heavy Metal Toxicity in Human for Better Health.

Heavy metal pollution is a significant global health concern, posing risks to both the environment and human health. Exposure to heavy metals happens through various channels like contaminated water, food, air, and workplaces, resulting in severe health implications. Heavy metals also disrupt the gut's microbial balance, leading to dysbiosis characterized by a decrease in beneficial microorganisms and proliferation in harmful ones, ultimately exacerbating health problems. Probiotic microorganisms have demonstrated their ability to adsorb and sequester heavy metals, while their exopolysaccharides (EPS) exhibit chelating properties, aiding in mitigating heavy metal toxicity. These beneficial microorganisms aid in restoring gut integrity through processes like biosorption, bioaccumulation, and biotransformation of heavy metals. Incorporating probiotic strains with high affinity for heavy metals into functional foods and supplements presents a practical approach to mitigating heavy metal toxicity while enhancing gut health. Utilizing probiotic microbiota and their exopolysaccharides to address heavy metal toxicity offers a novel method for improving human health through modulation of the gut microbiome. By combining probiotics and exopolysaccharides, a distinctive strategy emerges for mitigating heavy metal toxicity, highlighting promising avenues for therapeutic interventions and health improvements. Further exploration in this domain could lead to groundbreaking therapies and preventive measures, underscoring probiotic microbiota and exopolysaccharides as natural and environmentally friendly solutions to heavy metal toxicity. This, in turn, could enhance public health by safeguarding the gut from environmental contaminants.

Triiodothyronine enhances various forms of kidney-specific Klotho protein and suppresses the Wnt/β-catenin pathway: Insights from in-vitro, in-vivo and in-silico investigations

Age-related diseases are intricately linked to the molecular processes underlying aging, with the decline of the antiaging protein Klotho being a key factor. Investigating these processes is crucial for developing therapeutic strategies. The age-associated reduction in Klotho expression, coupled with a decline in the endocrine hormone triiodothyronine (T3), prompted a detailed exploration of their potential interplay. Our research, conducted through both in-vitro and in-vivo studies on BALB/c mice, unveiled a significant capacity of T3 to upregulate various forms of Klotho via ATF-3/p-c-Jun transcription factor. This effect was particularly noteworthy in aged individuals, where Klotho expression had waned compared to their younger counterparts. Importantly, T3 demonstrated a promising therapeutic impact in rejuvenating Klotho expression in this context. Further investigations elucidated the molecular mechanisms underlying T3's impact on aging-related pathways. In-vitro and in-vivo experiments established T3's ability to downregulate the Wnt/β-Catenin pathway by enhancing Klotho expression. In-silico analyses provided insights into Klotho's intricate role, showing its capacity to inhibit Wnt ligands such as Wnt3 and Wnt8a, consequently disrupting their interaction with the Wnt receptor. Additionally, T3 was found to downregulate kidney-specific GSK-3β expression through the augmentation of Klotho expression. The study also highlighted T3's role in maintaining calcium and phosphate homeostasis via Klotho. This comprehensive investigation not only sheds light on the intricate mechanisms governing aging processes but also presents promising avenues for therapeutic interventions targeting the Wnt/β-Catenin pathway implicated in various age-associated diseases.

Role of cytokines in immunomodulation during malaria clearance.

Malaria remains a significant global health challenge, demanding a deeper understanding of host immune responses for effective clearance of the parasitic infection. Cytokines, as crucial mediators of the immune system, orchestrate a complex interplay during the various stages of malaria infection. Throughout the course of the disease, an intricate balance of pro-inflammatory and anti-inflammatory cytokines dictate the immune response's outcome, influencing parasitic clearance and disease severity. During the initial stages, interleukins such as interleukin-12 (IL-12), interferon-gamma (IFN-γ), and tumour necrosis factor-alpha (TNF-α) play pivotal roles in activating innate immune cells, initiating the anti-parasitic response. Simultaneously, regulatory cytokines like interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) modulate this immune activation, preventing excessive inflammation and tissue damage. As the infection progresses, a delicate shift occurs, characterized by a transition to adaptive immunity, guided by cytokines like interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), promoting antibody production and T-cell responses. Notably, the resolution of malaria infection crucially relies on a fine-tuned balance of cytokine networks. Dysregulation or imbalances in these mediators often result in immune hyperactivation, contributing to severe manifestations and prolonged infection. Understanding the multi-faceted roles of cytokines in malaria clearance offers promising avenues for therapeutic interventions. Targeting cytokine pathways to restore immune equilibrium or bolster protective responses could potentially enhance treatment strategies and vaccine development. In conclusion, the pivotal role of cytokines in immunomodulation during malaria clearance underscores their significance as potential targets for therapeutic interventions, offering promising prospects in the global fight against this infectious disease.

Circadian Clock in Muscle Disease Etiology and Therapeutic Potential for Duchenne Muscular Dystrophy.

Circadian clock and clock-controlled output pathways exert temporal control in diverse aspects of skeletal muscle physiology, including the maintenance of muscle mass, structure, function, and metabolism. They have emerged as significant players in understanding muscle disease etiology and potential therapeutic avenues, particularly in Duchenne muscular dystrophy (DMD). This review examines the intricate interplay between circadian rhythms and muscle physiology, highlighting how disruptions of circadian regulation may contribute to muscle pathophysiology and the specific mechanisms linking circadian clock dysregulation with DMD. Moreover, we discuss recent advancements in chronobiological research that have shed light on the circadian control of muscle function and its relevance to DMD. Understanding clock output pathways involved in muscle mass and function offers novel insights into the pathogenesis of DMD and unveils promising avenues for therapeutic interventions. We further explore potential chronotherapeutic strategies targeting the circadian clock to ameliorate muscle degeneration which may inform drug development efforts for muscular dystrophy.

CENPK orchestrates ovarian cancer progression via GOLPH3-Mediated activation of mTOR signaling

Ovarian cancer stands as a formidable clinical challenge, with limited therapeutic options. This investigation delves into the intricate molecular mechanisms governing ovarian cancer progression and uncovers Centromere Protein K (CENPK) as a central figure in disease pathogenesis. Elevated CENPK levels within ovarian cancer tissues conspicuously align with adverse clinical outcomes, positioning CENPK as a promising prognostic biomarker. Deeper exploration reveals a direct transcriptional connection between CENPK and the E2F1 transcription factor and clearly establishes E2F1's role as the master regulator of CENPK expression in ovarian cancer. Our inquiry revealing a suppression of tumor-promoting signaling pathways, most notably the mTOR pathway, upon CENPK silencing. Intriguingly, CENPK renders ovarian cancer cells more responsive to the mTOR inhibitor rapamycin, introducing a promising avenue for therapeutic intervention. In summation, our study unravels the multifaceted role of CENPK in ovarian cancer progression. It emerges as a prognostic indicator, a pivotal mediator of cell proliferation and tumorigenicity, and a regulator of the mTOR pathway, shedding light on potential therapeutic avenues for this formidable disease.

Abstract 3074: Regulating lactate levels in triple negative breast cancer presents a promising avenue for therapeutic intervention

Abstract Introduction: Among all subtypes of breast cancer, triple-negative breast cancer (TNBC) is associated with the most unfavorable prognosis, emphasizing the critical need to pinpoint therapeutic targets tailored to TNBCs. Lactate, produced as a by-product of aerobic glycolysis, acts as an oncometabolite and plays a substantial role in promoting tumor aggressiveness, particularly in TNBCs. In our ongoing laboratory investigations, we are actively exploring strategies to mitigate the influence of lactate on TNBCs. Methods: The experiments utilized two triple-negative breast cancer (TNBC) cell lines, i.e., MDA-MB231 and MDA-MB468. The inhibitors employed in this study are FOXY5, XAV939, PFK15, and Quercetin. Protein expression was examined using Western blotting and Immunofluorescence assays. Trans-well and wound healing assays were employed to assess cell migration and invasion. Colony formation assays (CFU) were utilized to investigate stem cell potential and proliferation. In vivo experiments were conducted using 4T1-orthotopic Balb/c mice. Results: Using triple-negative breast cancer (TNBC) cells, we have demonstrated the pivotal role of the WNT/β-catenin signaling pathway in promoting the generation of extracellular lactate, thus driving the progression and metastasis of TNBCs. Additionally, we have shown that inhibiting lactate production in TNBC cells, and consequently impeding cell migration and invasion, can be achieved by using recombinant WNT5A or its mimicking hexa-peptide FOXY5. Similarly, employing a β-catenin inhibitor such as XAV939 can yield comparable outcomes in relation to TNBC cells. In an alternative approach, we conducted inhibition experiments targeting PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase), a key regulator of aerobic glycolysis in cancer cells. Our findings indicate that a combined approach involving siPFKL and iPFKFB3 is more promising in suppressing lactate production in TNBCs when compared to the effects of individual iPFKFB3 treatment. Conclusions: Our present investigations suggest that employing inhibitors targeting the WNT/β-catenin signaling pathway, PFKP, and PFKEB3 could be a promising therapeutic strategy to effectively reduce lactate levels in TNBCs. Citation Format: Chandra Prakash Prasad, Sheikh Mohammad Umar, Arundhathi Dev J. R., Akanksha Kashyap, Meetu Rathee. Regulating lactate levels in triple negative breast cancer presents a promising avenue for therapeutic intervention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3074.

CYP14 family in Caenorhabditis elegans: Mitochondrial function, detoxification, and lifespan.

CYP-14 members of the Caenorhabditis elegans (C. elegans) Cytochrome P450 (CYP) enzyme family, plays important roles in mitochondrial dysfunction, detoxification, lipid metabolism, defense and lifespan regulation. The review identifies CYP-14 members: cyp-14A1, cyp-14A2, cyp-14A3, cyp-14A4, cyp-14A5 and their homology with human CYP families. Despite limited studies on C. elegans cyp-14 members, the findings unraveled their complex crosstalk between mitochondrial stress, detoxification mechanisms, and lifespan regulation, emphasizing the complexity of these interconnected pathways as well as how their regulation depends on environmental cues changes including pH, nutrients, ROS and chemical stressors. The review underscores the translational relevance to human health, shedding light on potential human homologues and their implications in age-related, metabolic and respiratory diseases. Among other genes, cyp-14A2 and cyp-14A4 predominate the mitochondrial function, heat resistance, lipid metabolism, detoxification and lifespan pathways. In conclusion, these insights pave the way for future research, offering promising avenues for therapeutic interventions targeting CYP-14 activity to address age-related diseases and promote healthy aging.

Exploring epigenetic strategies for the treatment of osteoporosis.

The worldwide trend toward an aging population has resulted in a higher incidence of chronic conditions, such as osteoporosis. Osteoporosis, a prevalent skeletal disorder characterized by decreased bone mass and increased fracture risk, encompasses primary and secondary forms, each with distinct etiologies. Mechanistically, osteoporosis involves an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Current pharmacological interventions for osteoporosis, such as bisphosphonates, denosumab, and teriparatide, aim to modulate bone turnover and preserve bone density. Hormone replacement therapy and lifestyle modifications are also recommended to manage the condition. While current medications offer therapeutic options, they are not devoid of limitations. Recent studies have highlighted the importance of epigenetic mechanisms, including DNA methylation and histone modifications, in regulating gene expression during bone remodeling. The use of epigenetic drugs, or epidrugs, to target these mechanisms offers a promising avenue for therapeutic intervention in osteoporosis. In this review, we comprehensively examine the recent advancements in the application of epidrugs for treating osteoporosis.

Abstract WP233: Histone Lactylation in Neuronal Mitochondria Fission: Implications for Stress-Exacerbated Ischemic Stroke Outcomes

Introduction: Mental stress was linked with adverse outcomes following ischemic stroke. Accumulation of lactate due to mental stress is well-documented, especially in skeletal muscles. Importantly, lactate serves as a key substrate for lactylation, a novel post-translational protein modification, which triggers mitochondrial fission. This study investigates the pivotal role of histone lactylation in driving neuronal mitochondrial fission, which may amplify the detrimental outcomes of stroke under mental stress. Methods: A total of 120 C57BL/6J mice were divided into four groups: control, chronic restraint stress (CRS), lactylationantagonist (C646, 10mg/kg, i.p.) and C646+CRS. CRS for mice was induced in a 50mL tube for 6 hours per day for consecutive 28 days. On the day 29 th , Western blot was applied to detect the expression of fission related proteins (DRP1, MFF and FIS1). The effects of lactylation on mitochondria function was determined through JC-1 and mitoSOX™ staining by adding exogenous lactate (10mM) and C646 (20mM) in neuronal cells. The stressed mice then were subjected to 45 minute-middle-cerebral -artery-occlusion (MCAO). At 6 and 24 hours of reperfusion, apoptotic cell death and apoptotic proteins (Bcl-2, BAX and cleaved caspase-3) were measured by TUNEL and Western blot. Infarct volume and neurological deficits were determined by TTC staining and scoring systems at 48 hours of reperfusion. Results: CRS aggravated ischemic injury and apoptosis after stroke. C646, a lactylation antagonist, significantly decreased protein expressions of DRP1, MFF and FIS1 and reversed CRS-associated stroke injury. Furthermore, mitochondria membrane potential (MMP) was decreased and ROS was increased upon exogenous lactate in neuronal cells, accompanied by increased mitochondria fission. Again, C646 reverses mitochondria dysfunction and fission. Conclusions: Our results shed light on how CRS intensifies the ischemic damage post-stroke. Central mechanism is histone lactylation which triggers neuronal mitochondria fission, thereby impacting the outcomes related to stress-associated stroke. Lactylation antagonists offer promising avenues for therapeutic interventions, mitigating the adverse effects of stress on stroke outcomes.

Pan-Cancer Analysis Reveals Disulfidoptosis-Associated Genes as Promising Immunotherapeutic Targets: Insights Gained from Bulk Omics and Single-Cell Sequencing Validation.

Disulfidoptosis, a novel form of cell death, is distinct from other well-known cell death mechanisms. Consequently, a profound investigation into disulfidoptosis elucidates the fundamental mechanisms underlying tumorigenesis, presenting promising avenues for therapeutic intervention. Comprehensive analysis of disulfidoptosis-associated gene (DRG) expression in pan cancer utilized TCGA, GEO, and ICGC datasets, including survival and Cox-regression analyses for prognostic evaluation. We analyzed the association between DRG expression and both immune cell infiltration and immune-related gene expression using the ESTIMATE and TISDIB datasets. We obtained our single-cell RNA sequencing (scRNA-seq) data from the GEO repository. Subsequently, we assessed disulfidoptosis activity in various cell types. Evaluation of immune cell infiltration and biological functions was analyzed via single-sample gene set enrichment (ssGSEA) and gene set variation analysis (GSVA). For in vitro validation experiments, the results from real-time PCR (RT-qPCR) and Western blot were used to explore the expression of SLC7A11 in hepatocellular carcinoma (HCC) tissues and different cancer cell lines, while siRNA-mediated SLC7A11 knockdown effects on HCC cell proliferation and migration were examined. Expression levels of DRGs, especially SLC7A11, were significantly elevated in tumor samples compared to normal samples, which was associated with poorer outcomes. Except for SLC7A11, DRGs consistently exhibited high CNV and SNV rates, particularly in HCC. In various tumors, DRGs were negatively associated with DNA promoter methylation. TME analyses further illustrated a negative correlation of DRG expression with ImmuneScore and StromalScore and a positive correlation with tumor purity. Our analysis unveiled diverse cellular subgroups within HCC, particularly focusing on Treg cell populations, providing insights into the intricate interplay of immune activation and suppression within the tumor microenvironment (TME). These findings were further validated through RT-qPCR, Western blot analyses, and immunohistochemical analyses. Additionally, the knockdown of SLC7A11 induced a suppression of proliferation and migration in HCC cell lines. In conclusion, our comprehensive pan-cancer analysis research has demonstrated the significant prognostic and immunological role of disulfidoptosis across a spectrum of tumors, notably HCC, and identified SLC7A11 as a promising therapeutic target.

Probiotics suppress LL37 generated rosacea-like skin inflammation by modulating the TLR2/MyD88/NF-κB signaling pathway.

Rosacea, a chronic inflammatory dermatological condition, is characterized by facial erythema and pustules. Recent investigations have delved into the interplay between the gut microbiota and rosacea pathogenesis, unveiling promising avenues for therapeutic intervention. In this study, we screened and isolated strains Ligilactobacillus salivarius 23-006 and Lacticaseibacillus paracasei 23-008 from the feces of healthy volunteers and evaluated the intervention effects of probiotics on rosacea by constructing an LL37 induced rosacea-like mouse model. Our results showed that both L. salivarius 23-006 and L. paracasei 23-008 were probiotic strains with favourable properties. In specific, we observed that both L. salivarius 23-006 and L. paracasei 23-008 alleviated skin lesions, reduced skin inflammatory infiltrates, and decreased the expression of inflammatory factors in mice, with the combination of L. salivarius 23-006 and L. paracasei 23-008 having the most significant effect. Moreover, the combination of strains reduced the expression of cathelicidin LL37 and rosacea-associated factors by inhibiting the TLR2/MyD88/NF-κB pathway. The 16S rRNA analysis showed that the combination enhanced the intestinal barrier, restored intestinal microbiota homeostasis, and up-regulated the abundance of Lactobacillus while down-regulating the abundance of Coprococcus and Oscillospira. We also explored the effects of postbiotics of L. salivarius 23-006 and L. paracasei 23-008 on rosacea. While postbiotics could also ameliorate the rosacea-like phenotype in mice via the TLR2/MyD88/NF-κB pathway, the effects were not as pronounced as those observed with probiotic treatment. However, the postbiotics still enhanced the intestinal barrier, up-regulated the Lactobacillus abundance, and modulated the intestinal microbiota. In conclusion, our study revealed that L. salivarius 23-006 and L. paracasei 23-008 improved rosacea by regulating the TLR2/MyD88/NF-κB pathway and intestinal microbiota, providing a theoretical basis for the treatment of rosacea.

A red-emitting mitochondria targetable fluorescent probe for detecting viscosity in HeLa, zebrafish, and mice.

Viscosity, an essential parameter of the cellular microenvironment, has the ability to indicate the condition of living cells. It is closely linked to numerous diseases like Alzheimer's disease, diabetes, and cardiovascular disorders. Therefore, it is necessary to design tools to effectively monitor viscosity changes, which could provide promising avenues for therapeutic interventions in these diseases. Herein, we report a novel mitochondria-targeting fluorescent probe GX-VS which was suitable for the detection of viscosity changes in vivo and in vitro. The probe GX-VS had many advantages such as long emission wavelength (650 nm), large Stokes shift (105 nm), significant fluorescence enhancement (59-fold), high sensitivity, good biocompatibility and so on. Biological experiments showed that the probe could target mitochondria and detect viscosity alterations in HeLa cells. Moreover, it has been successfully utilized to monitor viscosity changes induced by lipopolysaccharides (LPS) in inflammatory zebrafishes and living mice, which further underscored the capacity of GX-VS to explore fluctuations in viscosity within living organisms.

The Emerging Role of Brain Mitochondria in Fear and Anxiety.

The functional complexity of brain circuits underlies the broad spectrum of behaviors, cognitive functions, and their associated disorders. Mitochondria, traditionally known for their role in cellular energy metabolism, are increasingly recognized as central to brain function and behavior. This review examines how mitochondria are pivotal in linking cellular energy processes with the functioning of neural circuits that govern fear and anxiety. Following an introductory section in which we summarize current knowledge about fear and anxiety neural circuits, we provide a brief summary of mitochondria fundamental roles (e.g., from energy production and calcium buffering to their involvement in reactive oxygen species (ROS) generation, mitochondrial dynamics, and signaling), particularly emphasizing their contribution to synaptic plasticity, neurodevelopment, and stress response mechanisms. The review's core focuses on the current state of knowledge regarding how mitochondrial function and dysfunction impact the neural substrates of fear and anxiety. Furthermore, we explore the implications of mitochondrial alterations in the context of posttraumatic stress disorder (PTSD) and anxiety disorders, underscoring the potential of mitochondrial pathways as new therapeutic targets. Integrating insights from genetic, biochemical, neurobiological, behavioral, and clinical studies, we propose a model in which mitochondrial function is critical for regulating the neural circuits that underpin fear and anxiety behaviors, highlighting how mitochondrial dysfunction can lead to their pathological manifestations. This integration emphasizes the potential for developing novel treatments targeting the biological roots of fear, anxiety, and related disorders. By merging mitochondrial biology with behavioral and circuit neuroscience, we enrich our neurobiological understanding of fear and anxiety, uncovering promising avenues for therapeutic intervention.

A Natural Metabolite and Inhibitor of the NLRP3 Inflammasome: 4-hydroxynonenal.

The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, crucial in the innate immune response, is linked to various human diseases. However, the effect of endogenous metabolites, like 4-hydroxynonenal (HNE), on NLRP3 inflammasome activity remains underexplored. Recent research highlights HNE's inhibitory role in NLRP3 inflammasome activation, shedding light on its potential as an endogenous regulator of inflammatory responses. Studies demonstrate that HNE blocks NLRP3 inflammasome-mediated pyroptosis and IL-1β secretion. Additionally, covalent targeting emerges as a common mechanism for inhibiting NLRP3 inflammasome assembly, offering promising avenues for therapeutic intervention. Further investigation is needed to understand the impact of endogenous HNE on NLRP3 inflammasome activation, especially in settings where lipid peroxidation byproducts like HNE are produced. Understanding the intricate interplay between HNE and the NLRP3 inflammasome holds significant potential for unraveling novel therapeutic strategies for inflammatory disorders.

Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission.

Fibroblast activation and proliferation is an essential phase in the progression of renal fibrosis. Despite the recognized significance of glutamine metabolism in cellular growth and proliferation, its precise pathophysiological relevance in renal fibrosis remains uncertain. Therefore, this study aims to investigate the involvement of glutamine metabolism in fibroblast activation and its possible mechanism. Our findings highlight the importance of glutamine metabolism in fibroblast activation and reveal that patients with severe fibrosis exhibit elevated serum glutamine levels and increased expression of kidney glutamine synthetase. Furthermore, the deprivation of glutamine metabolism in vitro and in vivo could inhibit fibroblast activation, thereby ameliorating renal fibrosis. It was also detected that glutamine metabolism is crucial for maintaining mitochondrial function and morphology. These effects may partially depend on the metabolic intermediate α-ketoglutaric acid. Moreover, glutamine deprivation led to upregulated mitochondrial fission in fibroblasts and the activation of the mammalian target of rapamycin / mitochondrial fission process 1 / dynamin-related protein 1 pathway. Thus, these results provide compelling evidence that the modulation of glutamine metabolism initiates the regulation of mitochondrial function, thereby facilitating the progression of renal fibrosis. Consequently, targeting glutamine metabolism emerges as a novel and promising avenue for therapeutic intervention and prevention of renal fibrosis.

MRNA vaccines: a new era in vaccine development.

The advent of RNA therapy, particularly through the development of mRNA cancer vaccines, has ushered in a new era in the field of oncology. This article provides a concise overview of the key principles, recent advancements, and potential implications of mRNA cancer vaccines as a groundbreaking modality in cancer treatment. mRNA cancer vaccines represent a revolutionary approach to combatting cancer by leveraging the body's innate immune system. These vaccines are designed to deliver specific mRNA sequences encoding cancer-associated antigens, prompting the immune system to recognize and mount a targeted response against malignant cells. This personalized and adaptive nature of mRNA vaccines holds immense potential for addressing the heterogeneity of cancer and tailoring treatments to individual patients. Recent breakthroughs in the development of mRNA vaccines, exemplified by the success of COVID-19 vaccines, have accelerated their application in oncology. The mRNA platform's versatility allows for the rapid adaptation of vaccine candidates to various cancer types, presenting an agile and promising avenue for therapeutic intervention. Clinical trials of mRNA cancer vaccines have demonstrated encouraging results in terms of safety, immunogenicity, and efficacy. Pioneering candidates, such as BioNTech's BNT111 and Moderna's mRNA-4157, have exhibited promising outcomes in targeting melanoma and solid tumors, respectively. These successes underscore the potential of mRNA vaccines to elicit robust and durable anti-cancer immune responses. While the field holds great promise, challenges such as manufacturing complexities and cost considerations need to be addressed for widespread adoption. The development of scalable and cost-effective manufacturing processes, along with ongoing clinical research, will be pivotal in realizing the full potential of mRNA cancer vaccines. Overall, mRNA cancer vaccines represent a cutting-edge therapeutic approach that holds the promise of transforming cancer treatment. As research progresses, addressing challenges and refining manufacturing processes will be crucial in advancing these vaccines from clinical trials to mainstream oncology practice, offering new hope for patients in the fight against cancer.

Targeting STAT6 to mitigate sepsis-induced muscle atrophy and weakness: Modulation of mitochondrial dysfunction, ferroptosis, and CHI3L1-Mediated satellite cell loss

Sepsis-induced muscle weakness is a debilitating consequence of prolonged critical illness, often associated with a poor prognosis. While recent research has shown that STAT6 functions as an inhibitor of myogenesis, its role in sepsis-induced muscle weakness remains unclear. In this study, we hypothesized that inhibiting STAT6 could attenuate sepsis-induced muscle atrophy and weakness, and we explored the underlying mechanisms. Leveraging a microarray dataset from sepsis patients, we identified significant enrichment of genes related to muscle function, ferroptosis, and the p53 signalling pathway in muscle tissue from sepsis patients. Using a murine sepsis model induced by cecum ligation and puncture (CLP), we explore the multifaceted role of STAT6 inhibition. Our findings demonstrate that STAT6 inhibition effectively attenuates muscle atrophy, enhances grip strength, preserves mitochondrial integrity, and modulates ferroptosis in septic mice. Additionally, we identify elevated levels of CHI3L1 in septic muscle tissue, which are significantly reduced by STAT6 inhibition. In-depth analysis of primary muscle satellite cells reveals that CHI3L1 overexpression is associated with increased expression of key regulators of satellite cell myogenicity, while negatively impacting cell viability. Silencing CHI3L1 expression mitigates satellite cell injury and loss, highlighting its pivotal role in sepsis-induced muscle damage. In summary, this study unveils the potential of STAT6 as a therapeutic target for mitigating sepsis-induced muscle atrophy and weakness. Our findings underscore the regulation of mitochondrial dysfunction, ferroptosis, and CHI3L1-mediated satellite cell damage by STAT6, offering promising avenues for therapeutic intervention in the management of sepsis-induced muscle weakness.

The Gut Microbiome Alterations and Inflammation-driven Pathogenesis of Alzheimer's Disease

Recent scientific discoveries underscore the vital role of the gut microbiota in bidirectional communication with the brain, suggesting that the human gut microbiota may serve as a “second brain” with implications for neurodegenerative disorders like Alzheimer’s Disease (AD). Although human-associated microbial communities are generally stable, common activities, such as antibiotics and high-fat diets, can disrupt them persistently. These enteric bacteria, encompassing commensal and pathogenic microorganisms, significantly influence immune function, brain development, and behavior. They can produce neurotransmitters, neuromodulators, and amyloids. Brain damage mechanisms leading to dementia and AD start with dysbiosis in the intestinal microbiome, causing local and systemic inflammation and disrupting the gut-brain axis. This heightened gut permeability allows various bacteria, viruses, and their neuroactive products, like toxic proteins and inflammatory molecules, to invade. The inflammatory-infectious hypothesis of AD, emphasizing the role of the gut microbiome, gains traction over the longstanding amyloid cascade hypothesis. In conclusion, AD’s origin in the gut and its close link to gut microbiota imbalance present a promising avenue for therapeutic intervention. Modulating gut microbiota through personalized diets or beneficial microbiota interventions to alter microbial partners and their products, including amyloid protein, may emerge as a novel AD treatment.