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Physiological Reports Jun 2024Although the liver is the largest metabolic organ in the body, it is not alone in functionality and is assisted by "an organ inside an organ," the gut microbiota. This... (Review)
Review
Although the liver is the largest metabolic organ in the body, it is not alone in functionality and is assisted by "an organ inside an organ," the gut microbiota. This review attempts to shed light on the partnership between the liver and the gut microbiota in the metabolism of macronutrients (i.e., proteins, carbohydrates, and lipids). All nutrients absorbed by the small intestines are delivered to the liver for further metabolism. Undigested food that enters the colon is metabolized further by the gut microbiota that produces secondary metabolites, which are absorbed into portal circulation and reach the liver. These microbiota-derived metabolites and co-metabolites include ammonia, hydrogen sulfide, short-chain fatty acids, secondary bile acids, and trimethylamine N-oxide. Further, the liver produces several compounds, such as bile acids that can alter the gut microbial composition, which can in turn influence liver health. This review focuses on the metabolism of these microbiota metabolites and their influence on host physiology. Furthermore, the review briefly delineates the effect of the portosystemic shunt on the gut microbiota-liver axis, and current understanding of the treatments to target the gut microbiota-liver axis.
Topics: Gastrointestinal Microbiome; Humans; Liver; Animals; Nutrients; Bile Acids and Salts
PubMed: 38886098
DOI: 10.14814/phy2.16114 -
Canadian Family Physician Medecin de... Jun 2024To understand how lack of attachment to a regular primary care provider influences patients' outlooks on primary care, ability to address their health care needs, and...
OBJECTIVE
To understand how lack of attachment to a regular primary care provider influences patients' outlooks on primary care, ability to address their health care needs, and confidence in the health care system.
DESIGN
Qualitative descriptive study using semistructured interviews.
SETTING
Canadian provinces of Nova Scotia, Ontario, and Quebec.
PARTICIPANTS
Patients aged 18 years or older who were unattached or had become attached within 1 year of being interviewed and who resided in the province in which they were interviewed.
METHODS
Forty-one semistructured interviews were conducted, during which participants were asked to describe how they had become unattached, their searches to find new primary care providers, their perceptions of and experiences with the centralized waiting list in their province, their experiences seeking care while unattached, and the impact of being unattached on their health and on their perceptions of the health care system. Interviews were transcribed and analyzed using a thematic approach.
MAIN FINDINGS
Two main themes were identified in interviews with unattached or recently attached patients: unmet needs of unattached patients and the impact of being unattached. Patients' perceived benefits of attachment included access to care, longitudinal relationships with health care providers, health history familiarity, and follow-up monitoring and care coordination. Being unattached was associated with negative effects on mental health, poor health outcomes, decreased confidence in the health care system, and greater pre-existing health inequities.
CONCLUSION
Having a regular primary care provider is essential to having access to high-quality care and other health care services. Attachment also promotes health equity and confidence in the public health care system and has broader system-level, social, and policy implications.
Topics: Humans; Qualitative Research; Female; Male; Middle Aged; Adult; Patient Acceptance of Health Care; Primary Health Care; Health Services Accessibility; Canada; Aged; Interviews as Topic; Physician-Patient Relations
PubMed: 38886083
DOI: 10.46747/cfp.7006396 -
International Journal of Spine Surgery Jun 2024We sought to determine which aspect of the upper instrumented vertebrae (UIV)-tilt angle or screw angle-was more strongly associated with: (1) proximal junctional...
Comparing the Upper Instrumented Vertebrae Tilt Angle vs Screw Angle in the Development of Proximal Junction Kyphosis After Adult Spinal Deformity Surgery: Which Matters More?
BACKGROUND
We sought to determine which aspect of the upper instrumented vertebrae (UIV)-tilt angle or screw angle-was more strongly associated with: (1) proximal junctional kyphosis/failure (PJK/F), (2) other mechanical complications and reoperations, and (3) patient-reported outcome measures (PROMs).
METHODS
A single-institution, retrospective cohort study was undertaken for patients undergoing adult spinal deformity (ASD) surgery from 2011 to 2017. Only patients with UIV at T7 or below were included. The primary exposure variables were UIV tilt angle (the angle of the UIV inferior endplate and the horizontal) and UIV screw angle (the angle of the UIV screws and superior endplate). Multivariable logistic regression included age, body mass index, osteopenia/osteoporosis, postoperative sagittal vertical axis, postoperative pelvic-incidence lumbar lordosis mismatch, UIV tilt angle and UIV screw angle.
RESULTS
One hundred and seventeen patients underwent adult spinal deformity surgery with a minimum of 2-year follow-up. A total of 41 patients (35.0%) had PJK and 26 (22.2%) had PJF. (1) UIV tilt angle: 96 (82.1%) had lordotic UIV tilt angles, 6 (5.1%) were neutral, and 15 (12.8%) were kyphotic. (2) UIV screw angle: 38 (32.5%) had cranially directed screws, 4 (3.4%) were neutral, and 75 (64.1%) were caudally directed. Both lordotic-angled UIV endplate (OR = 1.06, 95% CI = 1.01-1.12, and = 0.020) and cranially directed screws (OR = 1.19, 95% CI = 1.07-1.33, and < 0.001) were associated with higher odds of PJK, with a more pronounced effect of UIV screw angle compared with UIV tilt angle (Wald test, 9.40 vs 4.42). Similar results were found for PJF. Neither parameter was associated with other mechanical complications, reoperations, or patient-reported outcome measures.
CONCLUSIONS
UIV screw angle was more strongly associated with development of PJK/F compared with tilt angle. Overall, these modifiable parameters are directly under the surgeon's control and can mitigate the development of PJK/F.
CLINICAL RELEVANCE
Surgeons may consider selecting a UIV with a neutral or kyphotically directed UIV tilt angle when performing ASD surgery with a UIV in the lower thoracic or lumbar region, as well as use UIV screw angles that are caudally directed, for the purprose of decreasing the risk of developing PJK/F.
PubMed: 38886012
DOI: 10.14444/8607 -
PloS One 2024With the escalating demand for energy, there is a growing focus on decentralized, small-scale energy infrastructure. The success of new turbines in this context is...
With the escalating demand for energy, there is a growing focus on decentralized, small-scale energy infrastructure. The success of new turbines in this context is notable. However, many of these turbines do not follow many of the basic ideas established to evaluate their performance, leaving no precise technique or mathematical model. This research developed a Ducted Horizontal-axis Helical Wind Turbine (DHAHWT). The DHAHWT is a duct-mounted helical savonius turbine with a venturi and diffuser to improve flow. Unlike a vertical axis helical savonius turbine, DHAHWT revolves roughly parallel to the wind, making it a horizontal turbine. This complicates mathematical and theoretical analysis. This study created a DHAHWT mathematical model. COMSOL simulations utilizing Menter's Shear Stress Transport model (SST) across an incoming velocity range of 1m/s to 4m/s were used to evaluate the turbine's interaction with the wind. MATLAB was used to train an artificial neural network (ANN) utilizing COMSOL data to obtain greater velocity data. The Mean Average Percentage Error (MAPE) and Root Mean Square Error (RMSE) of ANN data were found to be 3%, indicating high accuracy. Further, using advanced statistical methods the Pearson's correlation coefficient was calculated resulting in a better understanding of the relationship of between incoming velocity and velocity at different sections of the wind turbine. This study will shed light on the aerodynamics and working of DHAHWT.
Topics: Wind; Models, Theoretical; Power Plants; Neural Networks, Computer; Computer Simulation
PubMed: 38885289
DOI: 10.1371/journal.pone.0303526 -
Research Square Jun 2024The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through...
The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is docked at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-β responses. UBXN9 deletion prompts constitutive GLUT4 trafficking, sequestration of RLRs, and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs.
PubMed: 38883790
DOI: 10.21203/rs.3.rs-3373803/v1 -
Research Square Jun 2024Apoptotic vesicles (apoVs) play a vital role in various pathological conditions; however, we have yet to fully understand their precise biological effects in rescuing...
Apoptotic vesicles (apoVs) play a vital role in various pathological conditions; however, we have yet to fully understand their precise biological effects in rescuing impaired mesenchymal stem cells (MSCs) and regulating tissue homeostasis. Here, we proved that systemic infusion of bone marrow MSCs derived from wild-type (WT) mice effectively improved the osteopenia phenotype and hyperimmune state in ovariectomized (OVX) mice. Importantly, the WT MSCs rescued the impairment of OVX MSCs both and , whereas OVX MSCs did not show the same efficacy. Interestingly, treatment with apoVs derived from WT MSCs (WT apoVs) restored the impaired biological function of OVX MSCs and their ability to improve osteoporosis. This effect was not observed with OVX MSCs-derived apoVs (OVX apoVs) treatment. Mechanistically, the reduced miR-145a-5p expression hindered the osteogenic differentiation and immunomodulatory capacity of OVX MSCs by affecting the TGF-β/Smad 2/3-Wnt/β-catenin signaling axis, resulting in the development of osteoporosis. WT apoVs directly transferred miR-145a-5p to OVX MSCs, which were then reused to restore their impaired biological functions. Conversely, treatment with OVX apoVs did not produce significant effects due to their limited expression of miR-145a-5p. Overall, our findings unveil the remarkable potential of apoVs in rescuing the biological function and therapeutic capability of MSCs derived from individuals with diseases. This discovery offers a new avenue for exploring apoVs-based MSC engineering and expands the application scope of stem cell therapy, contributing to the maintenance of bone homeostasis through a previously unrecognized mechanism.
PubMed: 38883762
DOI: 10.21203/rs.3.rs-4416138/v1 -
Frontiers in Endocrinology 2024Postmenopausal osteoporosis is a prevalent disease that affects the bone health of middle-aged and elderly women. The link between gut microbiota and bone health, known...
BACKGROUND
Postmenopausal osteoporosis is a prevalent disease that affects the bone health of middle-aged and elderly women. The link between gut microbiota and bone health, known as the gut-bone axis, has garnered widespread attention.
METHODS
We employed a two-sample Mendelian randomization approach to assess the associations between gut microbiota with osteoclasts and postmenopausal osteoporosis, respectively. Single nucleotide polymorphisms associated with the composition of gut microbiota were used as instrumental variables. By analyzing large-scale multi-ethnic GWAS data from the international MiBioGen consortium, and combining data from the eQTLGen consortium and the GEFOS consortium, we identified microbiota related to osteoclasts and postmenopausal osteoporosis. Key genes were further identified through MAGMA analysis, and validation was performed using single-cell data GSE147287.
RESULTS
The outcomes of this study have uncovered significant associations within the gut microbiome community, particularly with the Burkholderiales order, which correlates with both an increase in osteoclasts and a reduced risk of postmenopausal osteoporosis. with an odds ratio (OR) of 0.400, and a P-value of 0.011. Further analysis using single-cell data allowed us to identify two key genes, FMNL2 and SRBD1, that are closely linked to both osteoclasts and osteoporosis.
CONCLUSION
This study utilizing Mendelian randomization and single-cell data analysis, provides new evidence of a causal relationship between gut microbiota and osteoclasts, as well as postmenopausal osteoporosis. It was discovered that the specific microbial group, the Burkholderiales order, significantly impacts both osteoporosis and osteoclasts. Additionally, key genes FMNL2 and SRBD1 were identified, offering new therapeutic strategies for the treatment of postmenopausal osteoporosis.
Topics: Humans; Mendelian Randomization Analysis; Osteoporosis, Postmenopausal; Female; Osteoclasts; Gastrointestinal Microbiome; Polymorphism, Single Nucleotide; Genome-Wide Association Study; Middle Aged; Bone and Bones; Aged
PubMed: 38883609
DOI: 10.3389/fendo.2024.1419566 -
Frontiers in Endocrinology 2024Diabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients' health and quality of life. Cuproptosis...
Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis.
BACKGROUND
Diabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients' health and quality of life. Cuproptosis is a newly defined type of programmed cell death that is thought to be involved in the pathogenesis and progression of cardiovascular disease, but the molecular mechanisms involved are not well understood. Therefore, we aimed to identify biomarkers associated with cuproptosis in diabetes mellitus-associated heart failure and the potential pathological mechanisms in cardiomyocytes.
MATERIALS
Cuproptosis-associated genes were identified from the previous publication. The GSE26887 dataset was downloaded from the GEO database.
METHODS
The consistency clustering was performed according to the cuproptosis gene expression. Differentially expressed genes were identified using the limma package, key genes were identified using the weighted gene co-expression network analysis(WGCNA) method, and these were subjected to immune infiltration analysis, enrichment analysis, and prediction of the key associated transcription factors. Consistency clustering identified three cuproptosis clusters. The differentially expressed genes for each were identified using limma and the most critical MEantiquewhite4 module was obtained using WGCNA. We then evaluated the intersection of the MEantiquewhite4 output with the three clusters, and obtained the key genes.
RESULTS
There were four key genes: , , , and . , , and were negatively associated with multiple immune factors, while was positively associated, and T-cells accounted for a major proportion of this relationship with the immune system. Four enriched pathways were found to be associated: arachidonic acid metabolism, peroxisomes, fatty acid metabolism, and dorsoventral axis formation, which may be regulated by the transcription factor MECOM, through a change in protein structure.
CONCLUSION
HSDL2, BCO2, CORIN, and SNORA80E may regulate cardiomyocyte cuproptosis in patients with diabetes mellitus-associated heart failure through effects on the immune system. The product of the cuproptosis-associated gene is probably involved in myocardial fibrosis in patients with diabetes, which leads to the development of cardiac insufficiency.
Topics: Myocytes, Cardiac; Humans; Heart Failure; Computational Biology; Gene Expression Profiling; Gene Regulatory Networks; Ferroptosis; Diabetic Cardiomyopathies
PubMed: 38883603
DOI: 10.3389/fendo.2024.1370387 -
Drug Design, Development and Therapy 2024(Fuzi) has been conventionally used to cure a variety of ailments, such as pain, cold sensations, and numbness of limb muscles (Bi Zheng) in China. Our prior...
BACKGROUND
(Fuzi) has been conventionally used to cure a variety of ailments, such as pain, cold sensations, and numbness of limb muscles (Bi Zheng) in China. Our prior investigations identified Benzoylaconine (BAC) as a bioactive alkaloid derived from , with other studies also demonstrating its significant pharmacological potential.
PURPOSE
This study aimed to explore the potential of BAC as a protective agent against skeletal muscle ischemia-reperfusion (I/R) injury and to elucidate the underlying mechanisms.
METHODS
In vivo models involved subjecting Sprague-Dawley rats to I/R through femoral artery ligation followed by reperfusion, while in vitro models utilized C2C12 cells subjected to hypoxia/reoxygenation (H/R). CCK-8 assay was used to assess cell viability. TUNEL staining and flow cytometric analysis were used to measure cell apoptosis. Biochemical assay was used to assess skeletal muscle injury and oxidative stress. Immunofluorescence and Western blot were performed to determine protein levels.
RESULTS
BAC effectively protected muscle tissue from I/R injury, enhancing cell viability (p<0.01), elevating SOD levels (p<0.05), and reducing CK (p<0.01), LDH (p<0.01), ROS (p<0.01), MDA (p<0.01), and apoptosis-related molecules in vivo and in vitro (p<0.05, p<0.01). Mechanistically, BAC increased the expression of IF1, phosphorylated AMPK, facilitated the translocation of nuclear Nrf2, and induced the expression of HO-1 (p<0.01). Notably, AMPK inhibitor Compound C significantly hindered the ability of BAC to ameliorate H/R-induced cell injury (p<0.05), oxidative stress(p<0.01), and apoptosis (p<0.05), as well as promote Nrf2 nuclear translocation (p<0.01). Moreover, silencing of IF1 with siRNA abolished BAC-induced activation of AMPK/Nrf2 axis (p<0.01).
CONCLUSION
Our study provides novel evidence supporting the potential of BAC as a myocyte-protective agent against I/R injury, and we establish a previously unknown mechanism involving the activation of the IF1-dependent AMPK/Nrf2 axis in mediating the protective effects of BAC.
Topics: Animals; NF-E2-Related Factor 2; Rats, Sprague-Dawley; Reperfusion Injury; AMP-Activated Protein Kinases; Rats; Muscle, Skeletal; Male; Cell Survival; Apoptosis; Mice; Oxidative Stress; Structure-Activity Relationship; Protective Agents; Cells, Cultured; Dose-Response Relationship, Drug
PubMed: 38882050
DOI: 10.2147/DDDT.S456699 -
Drug Design, Development and Therapy 2024The Baihe Dihuang decoction (BDD) is a representative traditional Chinese medicinal formula that has been used to treat anxiety disorders for thousands of years. This...
PURPOSE
The Baihe Dihuang decoction (BDD) is a representative traditional Chinese medicinal formula that has been used to treat anxiety disorders for thousands of years. This study aimed to reveal mechanisms of anxiolytic effects of BDD with multidimensional omics.
METHODS
First, 28-day chronic restraint stress (CRS) was used to create a rat model of anxiety, and the open field test and elevated plus maze were used to assess anxiety-like behavior. Enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin staining, and immunofluorescence staining were used to evaluate inflammatory response. Besides, 16S rRNA gene sequencing assessed fecal microbiota composition and differential microbiota. Non-targeted metabolomics analysis of feces was performed to determine fecal biomarkers, and targeted metabolomics was used to observe the levels of hippocampus neurotransmitters. Finally, Pearson correlation analysis was used to examine relationships among gut microbiota, fecal metabolites, and neurotransmitters.
RESULTS
BDD significantly improved anxiety-like behaviors in CRS-induced rats and effectively ameliorated hippocampal neuronal damage and abnormal activation of hippocampal microglia. It also had a profound effect on the diversity of microbiota, as evidenced by significant changes in the abundance of 10 potential microbial biomarkers at the genus level. Additionally, BDD led to significant alterations in 18 fecal metabolites and 12 hippocampal neurotransmitters, with the majority of the metabolites implicated in amino acid metabolism pathways such as D-glutamine and D-glutamate, alanine, arginine and proline, and tryptophan metabolism. Furthermore, Pearson analysis showed a strong link among gut microbiota, metabolites, and neurotransmitters during anxiety and BDD treatment.
CONCLUSION
BDD can effectively improve anxiety-like behaviors by regulating the gut-brain axis, including gut microbiota and metabolite modification, suppression of hippocampal neuronal inflammation, and regulation of neurotransmitters.
Topics: Animals; Rats; Anti-Anxiety Agents; Drugs, Chinese Herbal; Male; Metabolomics; Disease Models, Animal; Rats, Sprague-Dawley; Gastrointestinal Microbiome; Stress, Psychological; Anxiety; Restraint, Physical; Hippocampus
PubMed: 38882046
DOI: 10.2147/DDDT.S458983