Interrelated Pathways Research Articles

Human chorionic gonadotropin-based clinical treatments for infertile men with non-obstructive azoospermia.

Spermatogenesis is primarily controlled by follicle-stimulating hormone and luteinizing hormone-driven testosterone. Luteinizing hormone acts on the Leydig cells, stimulating steroid production, predominantly testosterone, and activating critical inter-related spermatogenesis regulatory pathways. Despite evidence that exogenous gonadotropins containing luteinizing hormone activity, particularly human chorionic gonadotropin, can effectively restore spermatogenesis in azoospermic males with hypogonadotropic hypogonadism, the use of these drugs to treat other forms of non-obstructive azoospermia is the subject of an ongoing debate. In this review, we delve into the molecular properties and functions of human chorionic gonadotropin in spermatogenesis regulation and explore available preparations for therapeutic use. We examine the evidence regarding the effectiveness of human chorionic gonadotropin in treating infertility in men with pre-testicular or testicular non-obstructive azoospermia and, additionally, identify the main areas for future research. Our review highlights the critical role of luteinizing hormone activity in spermatogenesis and emphasizes the potential of human chorionic gonadotropin in treating male infertility. The variation in the characteristics of patients with non-obstructive azoospermia underscores the importance of assessing hormonal profiles when contemplating hormonal treatment for these patients. A novel stratification of male infertility patients, the APHRODITE criteria, which considers clinical and laboratory indicators, may assist in identifying individuals who could benefit from human chorionic gonadotropin therapy. While accumulating evidence suggests promising venues for pharmacological treatment in male infertility, including non-obstructive azoospermia, further research is required to completely elucidate the mechanisms underlying the effects of exogenous gonadotropins with luteinizing hormone activity on sperm production and to establish the most effective dosages and treatment durations.

Hawthorn carbon dots: a novel therapeutic agent for modulating body weight and hepatic lipid profiles in high-fat diet-fed mice.

Obesity, a chronic metabolic disorder characterized by excessive body weight and adipose tissue accumulation, is intricately linked to a spectrum of health complications. It is driven by a confluence of factors, including gut microbiota dysbiosis, inflammation, and oxidative stress, which are pivotal in its pathogenesis. A multifaceted therapeutic strategy that targets these interrelated pathways is essential for effective obesity management. In this context, biomass-derived carbon dots have emerged as a promising avenue due to their diverse biological activities and potential in nanomedicine. Our study presents the synthesis of multi-modal hawthorn carbon dots (HCD), employing a green hydrothermal carbonization method that diverged from traditional stir-frying techniques. This eco-friendly approach facilitates the preparation of HCD, emphasizing the role of sugar compounds as the primary carbon source in their formation. In vitro assays demonstrate that HCD possess potent anti-inflammatory and antioxidant properties, which are crucial in combating the oxidative stress and inflammation associated with obesity. We further investigate the impact of HCD intervention in a high-fat diet (HFD)-induced obesity mouse model, employing both post-modeling and simultaneous modeling administration strategies. Our findings reveal that HCD treatment significantly reduces body weight and hepatic lipid accumulation in HFD mice, concurrently enhancing glucose tolerance and alleviating insulin resistance. Moreover, antibiotic perturbation experiments, complemented by bioinformatics analysis of colon microbiota, indicate that HCD substantially modulate gut microbiota composition. This modulation is associated with the amelioration of obesity-related conditions, suggesting that HCD may exert their beneficial effects through the regulation of gut microbiota, in addition to their anti-inflammatory and antioxidant activities. These multimodal mechanisms of action position HCD as a promising candidate for the prevention and treatment of obesity, offering a novel therapeutic strategy that targets the complex interplay of factors involved in this metabolic disorder.

Biomimetic Fe3O4 Nanozymes Promote Apoptosis in Breast Cancer Cell Lines via Free Radical Scavenging and Inhibition of RelA/p65.

Iron oxide nanozyme was synthesized from the fruit peel extract of pomegranate, which served as a reducing agent during the green synthesis. The scavenging of reactive oxygen species is often accompanied by immunomodulation following antiproliferative effects due to the crosstalk between the proteins involved in the inter-related signaling pathways. In the current study, the green synthesized nanozyme was studied for its ability to induce apoptosis in breast cancer cell lines. The free radical scavenging effect of the nanozyme was reflected as an extension of its intrinsic endogenous enzyme-mimicking property. The cell cycle analysis revealed that the cell death induced by nanozyme mainly affected the G0/G1 phase. The expression of RelA/p65 and the inflammatory mediators affected by the nanozyme established the role of the Fe3O4 nanozyme in immunomodulation along with its antiproliferative activity. This is the first report on the antiproliferative and immunomodulatory activities expressed by the biomimetic iron oxide nanozyme.

Exploring the role of the TLR4/NF-B signaling pathway in diabetic retinopathy

Abstract. Diabetes mellitus (DM) is a major cause of blindness and the neurodegenerative and microvascular disease known as diabetic retinopathy (DR). Diabetes-related retinal neurodegeneration (DRN) is thought to be a potential therapeutic target for primary or secondary prevention of traditional DR while the exact nature of the link between DRN and diabetic retinal vasculopathy (DRV) is still unknown. Therefore, compared with the DRV, in-depth study of DRN may provide a better understanding of this important cause of blindness. Immunoinflammatory mechanisms are currently believed to play crucial role in the occurrence and development of DR. Interrelated molecular pathways, such as the formation of glycosylation end products and oxidative stress (OS) in late diabetes, contribute to the inflammatory response. Furthermore, blocking the TLR4/NF-B signaling pathway has been shown to be an effective way to reduce DR, as demonstrated by a number of studies. This paper examines the function of the inflammatory response and TLR4/NF-B signaling pathway in the pathophysiology of DRN, which may offer fresh perspectives on DR therapy.

Phosphatidylserine: A Novel Target for Ischemic Stroke Treatment.

Over the past 40 years, research has heavily emphasized stroke treatments that directly target ischemic cascades after stroke onset. Much attention has focused on studying neuroprotective drugs targeting one aspect of the ischemic cascade. However, the single-target therapeutic approach resulted in minimal clinical benefit and poor outcomes in patients. Considering the ischemic cascade is a multifaceted and complex pathophysiological process with many interrelated pathways, the spotlight is now shifting towards the development of neuroprotective drugs that affect multiple aspects of the ischemic cascade. Phosphatidylserine (PS), known as the "eat-me" signal, is a promising candidate. PS is involved in many pathophysiological changes in the central nervous system after stroke onset, including apoptosis, inflammation, coagulation, and neuronal regeneration. Moreover, PS might also exert various roles in different phases after stroke onset. In this review, we describe the synthesis, regulation, and function of PS under physiological conditions. Furthermore, we also summarize the different roles of PS after stroke onset. More importantly, we also discuss several treatment strategies that target PS. We aim to advocate a novel stroke care strategy by targeting PS through a translational perspective.

Interplay among IL1R1, gut microbiota, and bile acids in metabolic dysfunction-associated steatotic liver disease: a comprehensive review.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder characterized by hepatic steatosis associated with metabolic abnormalities. Recent research has shed light on the intricate interplay among interleukin-1 receptor 1 (IL1R1), gut microbiota, and bile acids in the pathogenesis of MASLD. This review aims to provide a comprehensive overview of the current understanding of the role of IL1R1, gut microbiota, and bile acids in MASLD, exploring their interrelationships and potential mechanisms. We summarize the evidence supporting the involvement of IL1R1 in inflammation, discuss the influence of gut microbiota on bile acid metabolism and its influence on liver health, and elucidate the bidirectional interactions among IL1R1 signaling, gut microbiota composition, and bile acid homeostasis in MASLD. Furthermore, we highlight emerging therapeutic strategies targeting these interrelated pathways for the management of MASLD.

Ammonia-induced stress response in liver disease progression and hepatic encephalopathy.

Ammonia levels are orchestrated by a series of complex interrelated pathways in which the urea cycle has a central role. Liver dysfunction leads to an accumulation of ammonia, which is toxic and is strongly associated with disruption of potassium homeostasis, mitochondrial dysfunction, oxidative stress, inflammation, hypoxaemia and dysregulation of neurotransmission. Hyperammonaemia is a hallmark of hepatic encephalopathy and has been strongly associated with liver-related outcomes in patients with cirrhosis and liver failure. In addition to the established role of ammonia as a neurotoxin in the pathogenesis of hepatic encephalopathy, an increasing number of studies suggest that it can lead to hepatic fibrosis progression, sarcopenia, immune dysfunction and cancer. However, elevated systemic ammonia levels are uncommon in patients with metabolic dysfunction-associated steatotic liver disease. A clear causal relationship between ammonia-induced immune dysfunction and risk of infection has not yet been definitively proven. In this Review, we discuss the mechanisms by which ammonia produces its diverse deleterious effects and their clinical relevance in liver diseases, the importance of measuring ammonia levels for the diagnosis of hepatic encephalopathy, the prognosis of patients with cirrhosis and liver failure, and how our knowledge of inter-organ ammonia metabolism is leading to the development of novel therapeutic approaches.

Proteomic and phosphoproteomic analysis of a Haematococcus pluvialis (Chlorophyceae) mutant with a higher heterotrophic cell division rate reveals altered pathways involved in cell proliferation and nutrient partitioning.

Haematococcus pluvialis has been used to produce the ketocarotenoid antioxidant, astaxanthin. Currently, heterotrophic cultivation of H. pluvialis is limited by slow growth rates. This work aimed to address this challenge by exploring the mechanisms of acetate metabolism in Haematococcus. Chemical mutagenesis and screening identified H. pluvialis strain KREMS 23D-3 that achieved up to a 34.9% higher cell density than the wild type when grown heterotrophically on acetate. An integrative proteomics and phosphoproteomics approach was employed to quantify 4955 proteins and 5099 phosphorylation sites from 2505 phosphoproteins in the wild-type and mutant strains of H. pluvialis. Among them, 12 proteins were significantly upregulated and 22 significantly downregulated in the mutant while phosphoproteomic analysis identified 143 significantly upregulated phosphorylation sites on 106 proteins and 130 downregulated phosphorylation sites on 114 proteins. Upregulation of anaphase-promoting complex phosphoproteins and downregulation of a putative cell cycle division 20 phosphoprotein in the mutant suggests rapid mitotic progression, coinciding with higher cell division rates. Upregulated coproporphyrinogen oxidase and phosphorylated magnesium chelatase in the mutant demonstrated altered nitrogen partitioning toward chlorophyll biosynthesis. The large proportion of differentially expressed phosphoproteins suggests phosphorylation is a key regulator for protein expression and activity in Haematococcus. Taken together, this study reveals the regulation of interrelated acetate metabolic pathways in H. pluvialis and provides protein targets that may guide future strain engineering work.

Exploring the versatility of miRNA-128: a comprehensive review on its role as a biomarker and therapeutic target in clinical pathways.

MicroRNAs (miRNAs/ miRs) are short, noncoding RNAs, usually consisting of 18 to 24 nucleotides, that control gene expression after the process of transcription and have crucial roles in several clinical processes. This article seeks to provide an in-depth review and evaluation of the many activities of miR-128, accentuating its potential as a versatile biomarker and target for therapy; The circulating miR-128 has garnered interest because of its substantial influence on gene regulation and its simplicity in extraction. Several miRNAs, such as miR-128, have been extracted from circulating blood cells, cerebrospinal fluid, and plasma/serum. The miR-128 molecule can specifically target a diverse range of genes, enabling it to have intricate physiological impacts by concurrently regulating many interrelated pathways. It has a vital function in several biological processes, such as modulating the immune system, regulating brain plasticity, organizing the cytoskeleton, and inducing neuronal death. In addition, miR-128 modulates genes associated with cell proliferation, the cell cycle, apoptosis, plasma LDL levels, and gene expression regulation in cardiac development. The dysregulation of miR-128 expression and activity is associated with the development of immunological responses, changes in neural plasticity, programmed cell death, cholesterol metabolism, and heightened vulnerability to autoimmune illnesses, neuroimmune disorders, cancer, and cardiac problems; The paper highlights the importance of studying the consequences of miR-128 dysregulation in these specific locations. By examining the implications of miRNA-128 dysregulation in these areas, the article underscores its significance in diagnosis and treatment, providing a foundation for research and clinical applications.

The prognostic and predictive value of homologous recombination deficiency status in patients with advanced stage epithelial ovarian carcinoma after first-line platinum-based chemotherapy.

Homologous recombination (HR) comprises series of interrelated pathways that repair double-stranded DNA breaks and inter-strand crosslinks. It provides support for DNA replication to recover stalled or broken replication forks. Compared with homologous recombination proficiency (HRP), cancers with homologous recombination deficiency (HRD) are more likely to undergo cell death when treated with DNA-damaging agents, such as platinum agents, and have better disease control. Patients diagnosed with stage III/IV ovarian cancer, early stages with recurrence, who received adjuvant chemotherapy after debulking surgery, and who also had known HR status were eligible. Forty-four patients were included, with 21 in the HRD group (including 8 with germline mutations) and 23 in the HRP group. The HRD group was composed predominantly of serous carcinoma (95.2%), while mucinous (n=3) and clear cell (n=1) cases were all found in the HRP group. Stage III/IV disease was 66.7% and 91.3% in HRD and HRP groups, respectively (p=0.064). Patients who were optimally debulked to no residual disease was 90.0% and 72.7% (p=0.243), respectively. Late line use of PARP inhibitors was 33.3% and 17.4% (p=0.303). Median PFS was 22.5 months (95% CI, 18.5 - 66.6) and 21.5 months (95% CI, 18.3-39.5) (p=0.49) in HRD and HRP respectively. Median platinum free interval (PFI) was 15.8 months (95% CI 12.4-60.4) and 15.9 months (95% CI 8.3-34.1) (p=0.24), respectively. Median OS was 88.2 months (95% CI 71.2-NA) and 49.7 months (95% CI 35.1-NA) (p=0.21). The PFS of the patients with germline BRCA mutations (n=5) was 54.3 months (95% CI 23.1-NA) and 21.5 months (95% CI 18.3-39.5) in the HRP group (p=0.095); the PFI difference was 47.7 months (95% CI 17.6-NA) in the BRCA mutation group, and 15.9 months (95% CI 12.4-60.4) in HRP, showing statistical significance (p=0.039); while the median OS was NA and 49.7 months (95% CI 35.1-NA) respectively (p=0.051). When adding two additional patients with somatic BRCA mutations to the germline BRCA mutation carriers, the median OS is NA (95% CI 73, NA) versus 49.7 months (95% CI 35.1, NA) for HRP (p=0.045). HRD status was not associated with longer PFS or PFI in advanced ovarian cancer who received first line adjuvant platinum-based chemotherapy. Its role as a prognostic marker for overall survival is suggested, particularly in the subgroup with germline and somatic BRCA mutations.

Inflammasomes Are Influenced by Epigenetic and Autophagy Mechanisms in Colorectal Cancer Signaling.

Inflammasomes contribute to colorectal cancer signaling by primarily inducing inflammation in the surrounding tumor microenvironment. Its role in inflammation is receiving increasing attention, as inflammation has a protumor effect in addition to inducing tissue damage. The inflammasome's function is complex and controlled by several layers of regulation. Epigenetic processes impact the functioning or manifestation of genes that are involved in the control of inflammasomes or the subsequent signaling cascades. Researchers have intensively studied the significance of epigenetic mechanisms in regulation, as they encompass several potential therapeutic targets. The regulatory interactions between the inflammasome and autophagy are intricate, exhibiting both advantageous and harmful consequences. The regulatory aspects between the two entities also encompass several therapeutic targets. The relationship between the activation of the inflammasome, autophagy, and epigenetic alterations in CRC is complex and involves several interrelated pathways. This article provides a brief summary of the newest studies on how epigenetics and autophagy control the inflammasome, with a special focus on their role in colorectal cancer. Based on the latest findings, we also provide an overview of the latest therapeutic ideas for this complex network.

A transformative shift in urban ecology toward a more active and relevant future for the field and for cities

This paper builds on the expansion of urban ecology from a biologically based discipline—ecology in the city—to an increasingly interdisciplinary field—ecology of the city—to a transdisciplinary, knowledge to action endeavor—an ecology for and with the city. We build on this “prepositional journey” by proposing a transformative shift in urban ecology, and we present a framework for how the field may continue this shift. We conceptualize that urban ecology is in a state of flux, and that this shift is needed to transform urban ecology into a more engaged and action based field, and one that includes a diversity of actors willing to participate in the future of their cities. In this transformative shift, these actors will engage, collaborate, and participate in a continuous spiral of knowledge → action → knowledge spiral and back to knowledge loop, with the goal of co producing sustainable and resilient solutions to myriad urban challenges. Our framework for this transformative shift includes three pathways: (1) a repeating knowledge → action → knowledge spiral of ideas, information, and solutions produced by a diverse community of agents of urban change working together in an “urban sandbox”; (2) incorporation of a social–ecological–technological systems framework in this spiral and expanding the spiral temporally to include the “deep future,” where future scenarios are based on a visioning of seemingly unimaginable or plausible future states of cities that are sustainable and resilient; and (3) the expansion of the spiral in space, to include rural areas and places that are not yet cities. The three interrelated pathways that define the transformative shift demonstrate the power of an urban ecology that has moved beyond urban systems science and into a realm where collaborations among diverse knowledges and voices are working together to understand cities and what is urban while producing sustainable solutions to contemporary challenges and envisioning futures of socially, ecologically, and technologically resilient cities. We present case study examples of each of the three pathways that make up this transformative shift in urban ecology and discuss both limitations and opportunities for future research and action with this transdisciplinary broadening of the field.

Ethics of early detection of disease risk factors: A scoping review

BackgroundScientific and technological advancements in mapping and understanding the interrelated pathways through which biological and environmental exposures affect disease development create new possibilities for detecting disease risk factors. Early detection of such risk factors may help prevent disease onset or moderate the disease course, thereby decreasing associated disease burden, morbidity, and mortality. However, the ethical implications of screening for disease risk factors are unclear and the current literature provides a fragmented and case-by-case picture.MethodsTo identify key ethical considerations arising from the early detection of disease risk factors, we performed a systematic scoping review. The Scopus, Embase, and Philosopher’s Index databases were searched for peer-reviewed, academic records, which were included if they were written in English or Dutch and concerned the ethics of (1) early detection of (2) disease risk factors for (3) disease caused by environmental factors or gene-environment interactions. All records were reviewed independently by at least two researchers.ResultsAfter screening 2034 titles and abstracts, and 112 full papers, 55 articles were included in the thematic synthesis of the results. We identified eight common ethical themes: (1) Reliability and uncertainty in early detection, (2) autonomy, (3) privacy, (4) beneficence and non-maleficence, (5) downstream burdens on others, (6) responsibility, (7) justice, and (8) medicalization and conceptual disruption. We identified several gaps in the literature, including a relative scarcity of research on ethical considerations associated with environmental preventive health interventions, a dearth of practical suggestions on how to address expressed concerns about overestimating health capacities, and a lack of insights into preventing undue attribution of health responsibility to individuals.ConclusionsThe ethical concerns arising with the early detection of risk factors are often interrelated and complex. Comprehensive ethical analyses are needed that are better embedded in normative frameworks and also assess and weigh the expected benefits of early risk factor detection. Such research is necessary for developing and implementing responsible and fair preventive health policies.

Regulation of tricarboxylate transport and metabolism in Acinetobacter baylyi ADP1.

Despite the significant presence of plant-derived tricarboxylic acids in some environments, few studies detail the bacterial metabolism of trans-aconitic acid (Taa) and tricarballylic acid (Tcb). In a soil bacterium, Acinetobacter baylyi ADP1, we discovered interrelated pathways for the consumption of Taa and Tcb. An intricate regulatory scheme tightly controls the transport and catabolism of both compounds and may reflect that they can be toxic inhibitors of the tricarboxylic acid cycle. The genes encoding two similar LysR-type transcriptional regulators, TcuR and TclR, were clustered on the chromosome with tcuA and tcuB, genes required for Tcb consumption. The genetic organization differed from that in Salmonella enterica serovar Typhimurium, in which tcuA and tcuB form an operon with a transporter gene, tcuC. In A. baylyi, tcuC was not cotranscribed with tcuAB. Rather, tcuC was cotranscribed with a gene, designated pacI, encoding an isomerase needed for Taa consumption. TcuC appears to transport Tcb and cis-aconitic acid (Caa), the presumed product of PacI-mediated periplasmic isomerization of Taa. Two operons, tcuC-pacI and tcuAB, were transcriptionally controlled by both TcuR and TclR, which have overlapping functions. We investigated the roles of the two regulators in activating transcription of both operons in response to multiple effector compounds, including Taa, Tcb, and Caa.IMPORTANCEIngestion of Taa and Tcb by grazing livestock can cause a serious metabolic disorder called grass tetany. The disorder, which results from Tcb absorption by ruminants, focuses attention on the metabolism of tricarboxylic acids. Additional interest stems from efforts to produce tricarboxylic acids as commodity chemicals. Improved understanding of bacterial enzymes and pathways for tricarboxylic acid metabolism may contribute to new biomanufacturing strategies.

SGLT2 inhibitors, intrarenal hypoxia and the diabetic kidney: insights into pathophysiological concepts and current evidence.

Approximately 20-40% of all diabetic patients experience chronic kidney disease, which is related to higher mortality (cardiovascular and all-cause). A large body of evidence suggests that renal hypoxia is one of the main forces that drives diabetic kidney disease, both in its early and advanced stages. It promotes inflammation, generation of intrarenal collagen, capillary rarefaction and eventually accumulation of extracellular matrix that destroys normal renal architecture. SGLT2 inhibitors are unquestionably a practice-changing drug class and a valuable weapon for patients with type 2 diabetes and chronic kidney disease. They have achieved several beneficial kidney effects after targeting multiple and interrelated signaling pathways, including renal hypoxia, independent of their antihyperglycemic activities. This manuscript discusses the pathophysiological concepts that underly their possible effects on modulating renal hypoxia. It also comprehensively investigates both preclinical and clinical studies that explored the possible role of SGLT2 inhibitors in this setting, so as to achieve long-term renoprotective benefits.

Multi-omics analysis to reveal the synergistic mechanism underlying the multiple ingredients of Stephania tetrandra extract on rheumatoid arthritis through the PI3K/Akt signaling pathway.

Background: Stephania tetrandra has been used for treating rheumatic diseases for thousands of years in rural areas of China. Several studies have found that tetrandrine and fangchinoline can inactivate the PI3K/Akt signaling pathway by reducing the expression and phosphorylation of AKT. However, the mechanism underlying the therapeutic actions of S. tetrandra on RA is not well known. Methods: In this study, we determined the molecular mechanism of the therapeutic effects of the multiple ingredients of S. tetrandra extract (STE) on collagen-induced arthritic (CIA) rats by integrating pharmacometabolomics, proteomics, and PTMomics. Results: In the multi-omics joint analysis, first, the expression signatures of proteins, PTMs, metabolites, and STE ingredients were profiled in CIA rats PBMCs that underwent STE treatment. Bioinformatics analysis were subsequently probed that STE mainly regulated tryptophan metabolism, inflammatory response, and cell adhesion pathways in CIA rats. The interrelated pathways were further constructed, and the findings revealed that STE attenuated the inflammatory response and proliferation of PBMCs in CIA rats by mediating the key targets of the PI3K/Akt pathway, including Hint1, ACP1, FGR, HSP90@157W + dioxidation, and Prkca@220N + 845.4540Da. The rheumatic functions of Hint1 and ACP1 were further confirmed by applying a transcriptomic data of RA patients who clinically received abatacept therapy. Furthermore, a cross-ome correlation analysis was performed and major in vivo ingredients of STE, including coclaurine-N-glucuronide, Me,coclaurine-O-glc, N-gluA-schefferine, corydamine, corypamine, tetrandrine, and fangchiniline, were found to act on these targerts to inactivate the PI3K/Akt pathway. Conclusion: These results elucidated the molecular mechanism by which the ingredients of STE mediate the expression of the key targets in the PI3K/Akt pathway, leading to anti-rheumatic functions. The findings of this study provided new insights into the synergistic effect of STE against arthritis in rats.

An Integrative Multi‐Omics Approach Reveals Molecular Signatures Associated with Age and High‐Fat Diet in Mouse Models of Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is a complex, multifactorial pathology with high heterogeneity in biological alterations. Our understanding of cellular and molecular mechanisms from disease risk variants to various phenotypes is still limited. Therefore, it is required to integrate the information from multiple data modalities for thorough exploration of endophenotype networks, biological interactions related to disease and thus accelerate our understanding of heterogeneity in Alzheimer’s disease.MethodIn this study, we performed multi‐level omics in a cohort of mouse models expressing humanized Abeta and two genetic risk factors (APOE4 and Trem2*R47H) at multiple ages for both sexes. Data from multiple omics platforms (transcriptomics, proteomics, and metabolomics) were analyzed at single‐omic level as well as integrated in an unbiased fashion, considering interaction between modalities using multi‐omics factor analysis (MOFA). We also systematically aligned multimodal mouse data to relevant human studies cohort.ResultMulti‐omics integration identified major components of heterogeneity explaining the variance within the cohort and differentially associated with age, sex, and high fat diet. Enrichment analysis of genes and protein associated with these components were significantly enriched for multiple AD‐related processes. Specifically, components associated with age and diet related heterogeneity exhibited overrepresentation of immune response and metabolic processes as well as increased levels of long‐chain acylcarnitine’s and reduced levels of spermidine in aged and high‐fat diet fed AD mouse models, similar to human AD. In addition, we observed weak correspondence between change in protein and RNA expression in mouse models compared to controls, similar to recent results from the ROSMAP cohort, which reported weak correlation between protein and RNA expression. We also identified a negative correlation for the change in RNA expression between male and female mice.ConclusionWe identified axes of variation within a cohort of LOAD mouse models using integrative multi‐omics approach. Our analysis revealed multiple interaction between distinct multi‐omics molecular signatures associated with Alzheimer’s disease. We determined that mRNA profiling alone provides an incomplete picture of molecular mechanism of AD. In this study, we highlighted that assembling multi‐omics measurements reveal interrelated pathway alterations in AD and the ability to identify biomarkers combinations that may inform clinical practice.

SGLT2 Inhibitors and Diabetic Kidney Disease: Targeting Multiple and Interrelated Signaling Pathways for Renal Protection.

Almost 20-40% of all patients suffering from diabetes mellitus experience chronic kidney disease, which is related to higher mortality (cardiovascular and all-cause). The implication of several pathophysiological mechanisms (hemodynamic, tubular, metabolic and inflammatory) in the pathogenesis of diabetic kidney disease generates an urgent need to develop multitarget therapeutic strategies to face its development and progression. SGLT2 inhibitors are undoubtedly a practice-changing drug class for individuals who experience type 2 diabetes and diabetic kidney disease. In vitro studies, exploratory research, sub-analyses of large randomized controlled trials, and investigation of several biomarkers have demonstrated that SGLT2 inhibitors achieved multiple beneficial activities, targeting several renal cellular and molecular pathways independent of their antihyperglycemic activity. These mainly include the reduction in intraglomerular pressure through the restoration of TGF, impacts on the renin-angiotensin-aldosterone system, improvement of renal hypoxia, adaptive metabolic alterations in substrate use/energy expenditure, improvement of mitochondrial dysfunction, and reduction of inflammation, oxidative stress and fibrosis. This manuscript thoroughly investigates the possible mechanisms that underlie their salutary renal effects in patients with diabetes, focusing on several pathways involved and the interplay between them. It also explores their upcoming role in ameliorating the evolution of chronic kidney disease in patients with diabetes.

Are there causal mucosal drivers in the preclinical development of rheumatoid arthritis?

BackgroundThe causal pathways which drive the development of seropositive rheumatoid arthritis (RA) are incompletely understood, especially in the period of time prior to the first development of signs and symptoms of joint involvement. That asymptomatic period, designated herein as pre-RA, is characterized by the presence of RA-related autoantibodies for many years and is the subject of an increasing number of studies as well as a focus of efforts to prevent the onset of clinically apparent arthritis. ObjectivesTo review the potential causal pathways in pre-RA by examining results of studies which evaluate the systemic peripheral blood and mucosal alterations that have been identified in individuals who are genetically at-risk, and/or who elaborate RA-related autoantibodies, and are defined as in a pre-RA period. MethodsPublished studies by the author and his colleagues, as well as publications by other groups, which describe the presence of biomarkers at mucosal sites and in the blood were reviewed. From these studies, a hypothesis related to the presence of pre-RA causal drivers was constructed. ResultsThe author and his colleagues, as well as other groups, have shown that there are multiple mucosal sites, primarily gut, lung and oral/peridontial, which appear in subsets of individuals in the pre-RA to exhibit inflammation and/or the presence of local production of IgA and IgG RA-related autoantibodies, including anti-citrullinated protein antibodies (ACPA). These findings are reviewed herein. There remain a large number of unanswered questions, though, related to the immune mechanisms that are operative at each site, as well as how these local findings evolve to causal systemic autoimmunity and eventually inflammatory arthritis. Author's ConclusionsComprehensive natural history studies are required to understand how multiple mucosal sites which appear to be involved in pre-RA are causally involved in the development of arthritis. Questions remain as to whether there are independent, serially involved, or inter-related causal immune pathways originating from these sites. In addition, the microbiota which may be involved in local immune inflammation and autoantibody production should be identified and characterized.

Network based approach to identify interactions between Type 2 diabetes and cancer comorbidities

High blood sugar and insulin insensitivity causes the lifelong chronic metabolic disease called Type 2 diabetes (T2D) which has a higher chance of developing different malignancies. T2D with comorbidities like Cancers can make normal medications for those disorders more difficult. There may be a significant correlation between comorbidities and have an impact on one another's health. These associations may be due to a number of direct and indirect mechanisms. Such molecular mechanisms that underpin T2D and cancer are yet unknown. However, the large volumes of data available on these diseases allowed us to use analytical tools for uncovering their interrelated pathways. Here, we tried to present a system for investigating potential comorbidity relationships between T2D and Cancer disease by looking at the molecular processes involved, analyzing a huge number of freely accessible transcriptomic datasets of various disorders using bioinformatics. Using semantic similarity and gene set enrichment analysis, we created an informatics pipeline that evaluates and integrates Gene Ontology (GO), expression of genes, and biological process data. We discovered genes that are common in T2D and Cancer along with molecular pathways and GOs. We compared the top 200 Differentially Expressed Genes (DEGs) from each selected T2D and cancer dataset and found the most significant common genes. Among all the common genes 13 genes were found most frequent. We also found 4 common GO terms: GO:0000003, GO:0000122, GO:0000165, and GO:0000278 among all the common GO terms between T2d and different cancers. Using these genes and GO term semantic similarity, we calculated the distance between these two diseases. The semantic similarity results of our study showed a higher association of Liver Cancer (LiC), Breast Cancer (BreC), Colorectal Cancer (CC), and Bladder Cancer (BlaC) with T2D. Furthermore we found KIF4A, NUSAP1, CENPF, CCNB1, TOP2A, CCNB2, RRM2, HMMR, NDC80, NCAPG, and IGFBP5 common hub proteins among different cancers correlated to T2D. AGE-RAGE signaling pathway in diabetic complications, Osteoclast differentiation, TNF signaling pathway, IL-17 signaling pathway, p53 signaling pathway, MAPK signaling pathway, Human T-cell leukemia virus 1 infection, and Non-alcoholic fatty liver disease are the 8 most significant pathways found among 18 common pathways between T2D and selected cancers. As a result of our technique, we now know more about disease pathways that are critical between T2D and cancer.