Natural compound screening predicts novel GSK-3 isoform-specific inhibitors.

Glycogen synthase kinase-3 (GSK-3) plays important roles in the pathogenesis of cardiovascular, metabolic, neurological disorders and cancer. Isoform-specific loss of either GSK-3α or GSK-3ß often provides cytoprotective effects under such clinical conditions. However, available synthetic small molecule inhibitors are relatively non-specific, and their chronic use may lead to adverse effects. Therefore, screening for natural compound inhibitors to identify the isoform-specific inhibitors may provide improved clinical utility. Here, we screened 70 natural compounds to identify novel natural GSK-3 inhibitors employing comprehensive in silico and biochemical approaches. Molecular docking and pharmacokinetics analysis identified two natural compounds Psoralidin and Rosmarinic acid as potential GSK-3 inhibitors. Specifically, Psoralidin and Rosmarinic acid exhibited the highest binding affinities for GSK-3α and GSK-3ß, respectively. Consistent with in silico findings, the kinase assay-driven IC50 revealed superior inhibitory effects of Psoralidin against GSK-3α (IC50 = 2.26 µM) vs. GSK-3ß (IC50 = 4.23 µM) while Rosmarinic acid was found to be more potent against GSK-3ß (IC50 = 2.24 µM) than GSK-3α (IC50 = 5.14 µM). Taken together, these studies show that the identified natural compounds may serve as GSK-3 inhibitors with Psoralidin serving as a better inhibitor for GSK-3α and Rosmarinic for GSK-3ß isoform, respectively. Further characterization employing in vitro and preclinical models will be required to test the utility of these compounds as GSK-3 inhibitors for cardiometabolic and neurological disorders and cancers.

Lipid-Lowering Medications are Associated with Reduced Sarcopenia-Related Quality of Life in Older Adults with Hyperlipidemia.

PURPOSE: Statins medications negatively affect age-associated loss of muscle mass and strength, termed sarcopenia, and neuromuscular junction (NMJ) integrity. However, their association with the sarcopenia-related-quality-of-life (SarQoL) is unknown. METHODS: In this cross-sectional, case control study, we recruited male nonusers (n = 75 and age 75.2 ± 5.9 years) and users (n = 77 and age 77.1 ± 6.2 years) of statins to evaluate SarQoL and handgrip strength (HGS). We also measured plasma C-terminal agrin fragment-22 (CAF22) as a marker of NMJ degradation. RESULTS: Statin users had higher CAF22, and lower HGS, and cumulative SarQoL scores than non-users (all p < 0.05). Plasma CAF22 exhibited negative correlations with SarQoL scores for physical and mental health, locomotion, functionality, activities-of-daily-living, and cumulative SarQoL in statins users and non-users (all p < 0.05). Lastly, the cumulative SarQoL scores exhibited positive associations with HGS and gait speed in the study participants (all p < 0.05). CONCLUSIONS: Collectively, statin usage was associated with NMJ degradation and reduced SarQoL. Statins should be cautiously prescribed in patients with sarcopenia with reduced QoL.

Plasma levels of Neurofilament light chain correlate with handgrip strength and sarcopenia in patients with chronic obstructive pulmonary disease.

BACKGROUND: Age-associated muscle decline, termed sarcopenia, is a common systemic effect of chronic obstructive pulmonary disease (COPD). Circulating Neurofilament light chain (NfL) levels reflect neuronal degradation and may be relevant to sarcopenia phenotype. However, such an association in COPD patients remains elusive. METHODS: We investigated male, 60-76 years old controls (n = 50) and COPD patients (n = 139) for plasma NfL levels in relation to sarcopenia and physical capacity markers. We measured handgrip strength (HGS), body composition, and short physical performance battery (SPPB) to evaluate sarcopenia and physical capacity. RESULTS: COPD patients had higher plasma NfL and lower HGS and SPPB performance than controls. Plasma NfL levels demonstrated negative associations with HGS and gait speed in COPD patients (all p < 0.05). Further, NfL levels were negatively associated with total SPPB scores in controls and patients with advanced COPD (p < 0.05). Plasma NfL also demonstrated an acceptable accuracy in diagnosing sarcopenia in controls (AUC = 0.757, p < 0.05) and COPD (AUC = 0.806, p < 0.05) patients. CONCLUSION: Collectively, plasma NfL may be helpful in evaluating sarcopenia phenotype and physical capacity in geriatric patients with COPD.

Probiotics Supplements Improve the Sarcopenia-Related Quality of Life in Older Adults with Age-Related Muscle Decline.

A pathological increase in intestinal leak is implicated in age-associated muscle loss, termed sarcopenia, and reduced sarcopenia-related quality-of-life (SarQoL). However, the potential therapies remain elusive. We investigated the effects of probiotic supplementation on sarcopenia and SarQoL in geriatric older adults. We randomized sarcopenic men into placebo (age = 71.4 ± 3.9 years, n = 63) and probiotic (age = 73 ± 4.1 years, n = 60) groups for 16 weeks. The probiotic used was one capsule daily of Vivomix 112 billion for 16 weeks. We measured sarcopenia parameters of handgrip strength (HGS) and skeletal mass index (SMI), plasma zonulin (marker of the intestinal leak), and SarQoL using a targeted questionnaire. Probiotics improved the SarQoL scores for locomotion, functionality, and activities of daily living and prevented a decline in cumulative SarQoL observed in the placebo group (all p < 0.05). Probiotic supplementation also reduced plasma zonulin and marker of systemic bacterial load. These changes were accompanied by an increase in HGS and maintenance of gait speed in the probiotic group compared to the placebo group. Correlation analysis revealed significant associations of cumulative SarQoL scores with plasma zonulin and HGS in the probiotic group. Collectively, probiotics improved SarQoL and HGS by repairing pathological intestinal leak. Future studies may further dissect the relation between intestinal leak and SarQoL in older adults taking probiotics.

Metformin Improves Sarcopenia-Related Quality of Life in Geriatric Adults: A Randomized Controlled Trial.

OBJECTIVES: Metformin protects against age-related muscle decline, termed sarcopenia. However, the effects on sarcopenia quality-of-life (SarQoL) are unknown. We investigated the effects of metformin on SarQoL and associated mechanisms in older adults. METHOD: This double-blind randomized, placebo-controlled trial included geriatric adult men, divided into non-sarcopenic controls (age = 72.2 ± 4.3 years, n = 52) and two groups of patients with sarcopenia randomized into placebo (age at baseline = 74.4 ± 5.7 years, n = 54) and metformin (age at baseline = 71.2 ± 3.9 years, n = 47) groups. Patients in the metformin group received 1.7 grams twice daily for four months. We evaluated SarQoL, handgrip strength (HGS), plasma zonulin, c-reactive protein (CRP), and 8-isoprostanes. RESULTS: Patients with sarcopenia had lower HGS and SarQoL than controls (both p <0.05). Metformin improved the HGS and the SarQoL domains related to physical and mental health, locomotion, and leisure activities, as well as cumulative SarQoL scores (all p <0.05). Metformin also prevented the decline in the SarQoL domains for functionality and fear. Among plasma biomarkers, metformin reduced the levels of zonulin, CRP, 8-isoprostanes, and creatine kinase. We also found a significant correlation of plasma zonulin with cumulative SarQoL in patients with sarcopenia taking metformin, suggesting a role for intestinal repair in improving SarQoL. Finally, metformin did not affect body composition and gait speed. CONCLUSION: Overall, metformin improved HGS and SarQoL by repairing intestinal leakage. Our data have clinical relevance for improving the quality of life in older adults with sarcopenia.

Applications of Strain-Specific Probiotics in the Management of Cardiovascular Diseases: A Systemic Review.

Cardiovascular diseases (CVDs) are a leading cause of global mortality and novel approaches for prevention and management are needed. The human gastrointestinal tract hosts a diverse microbiota that is crucial in maintaining metabolic homeostasis. The formulation of effective probiotics, alone or in combination, has been under discussion due to their impact on cardiovascular and metabolic diseases. Probiotics have been shown to impact cardiovascular health positively. An imbalance in the presence of Firmicutes and Bacteroidetes has been linked to the progression of CVDs due to their impact on bile acid and cholesterol metabolism. The probiotics primarily help in the reduction of plasma low-density lipoprotein levels and attenuation of the proinflammatory markers. These beneficial microorganisms contribute to lowering cholesterol levels and produce essential short-chain fatty acids. The impact of lipid-regulating probiotic strains on human health is quite significant. However, only a few have been tested for potential beneficial efficacy, and ambiguity exists regarding strain dosages, interactions with confounding factors, and potential adverse effects. Hence, more comprehensive studies and randomized trials are needed to understand the mechanisms of probiotics on CVDs and to ensure human health. This review assesses the evidence and highlights the roles of strain-specific probiotics in the management of CVDs.

Biomarkers of Physical and Mental Health for Prediction of Parkinson's Disease: A Population-Based Study from 15 European Countries.

OBJECTIVES: Early diagnosis of Parkinson's disease (PD) is critical for optimal treatment. However, the predictive potential of physical and mental health in PD is poorly characterized. METHODS: We evaluated the potential of multiple demographic, physical, and mental factors in predicting the future onset of PD in older adults aged 50 years or older from 15 European countries. Individual study participants were followed over four waves of the Survey of Health, Ageing, and Retirement in Europe (SHARE) from 2013-2020. RESULTS: Of 57,980 study participants, 442 developed PD during the study period. We identified male sex and advancing age from the sixth decade of life onward as significant predictors of future PD. Among physical factors, a low handgrip strength (HGS; men <27 kg, women <16 kg), being bothered by frailty, and recent falls were significantly associated with future PD. Among mental factors, a higher depression (Euro-D depression score >6) emerged as an independent predictor of future PD. Finally, the presence of hypertension or Alzheimer's disease (AD) increases the risk of future PD. CONCLUSIONS: Altogether, male sex, advancing age, low HGS, frailty, depression, hypertension, and AD were identified as critical risk factors for future PD. Our results may be useful in the early identification and treatment of populations at risk for PD.

A leaky gut contributes to reduced sarcopenia-related quality of life (SarQoL) in geriatric older adults.

PURPOSE: The sarcopenia quality-of-life (SarQoL) questionnaire is designed to evaluate the quality of life of sarcopenic patients. A pathological increase in intestinal permeability leads to several systemic diseases, but its contribution to SarQoL is unknown. METHODS: We recruited controls (n = 84, age = 74.6 ± 4.9 years) and sarcopenic (n = 55, age = 76.1 ± 4.2 years) men for validating and adapting a Pashto version of SarQoL. We measured the scores for seven domains of SarQoL, body composition, and handgrip strength (HGS). We also measured plasma zonulin as a marker of increased intestinal permeability. RESULTS: The Pashto SarQoL exhibited adequate discriminative ability, construct validity, internal consistency, and test-retest reliability, without exhibiting the floor and ceiling effect. Sarcopenic patients had higher plasma zonulin and lower scores on SarQoL domains for physical and mental health, locomotion, body composition, functionality, activities of daily living, leisure, and fear, and cumulative SarQoL scores than controls. Plasma zonulin exhibited significant coefficients of determination with Pashto SarQoL domains for locomotion (r2 = 0.217), functionality (r2 = 0.101), activities of daily living (r2 = 0.302), and cumulative SarQoL scores (r2 = 0.168). We also found high efficacies of zonulin in diagnosing low scores for functionality (AUC = 0.785, 95% C.I = 0.708-0.863), activities of daily living (AUC = 0.785, 95% C.I = 0.708-0.863), and cumulative SarQoL scores (AUC = 0.821, 95% C.I = 0.751-0.891). CONCLUSION: Altogether, SarQoL appears reliable in measuring the quality of life in sarcopenic patients. A leaky gut has a potential contribution to reduced SarQoL in sarcopenia.

Butyrate supplementation reduces sarcopenia by repairing neuromuscular junction in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with an intestinal leak and neuromuscular junction (NMJ) degradation, which contributes to physical compromise and accelerated age-related muscle loss, called sarcopenia. However, the relevant interventions partly remain ineffective. We investigated the effects of exogenous butyrate on sarcopenia and physical capacity with relevance to intestinal permeability and NMJ integrity in COPD patients. METHODS: COPD patients were randomized into placebo (n = 67) and butyrate (n = 64) groups in a double-blind manner. The patients in the butyrate group received one 300 mg capsule a day for 12 weeks. We measured circulating markers of intestinal leak (zonulin), systemic bacterial load (LBP), and NMJ loss (CAF22), along with handgrip strength (HGS), and short physical performance battery (SPPB) at baseline and 12 weeks. RESULTS: Butyrate supplementation improved HGS and gait speed in COPD patients. Among SPPB indices, butyrate improved the ability to maintain postural balance and walking and prevented a decline in the ability to rise from a chair. Butyrate also reduced the plasma levels of zonulin, LBP, and CAF22 levels in COPD patients (all p < 0.05). Regression analysis revealed significant associations of plasma zonulin and CAF22 with HGS, gait speed, and cumulative SPPB scores in butyrate group. These changes were associated with reduced markers of inflammation and muscle damage. CONCLUSION: Butyrate may provide a therapeutic approach to sarcopenia and physical dependency in COPD by repairing intestinal leak and NMJ loss.

Time-related changes in the knowledge of HIV/AIDS among followers of various religions in India.

Background: The public knowledge levels about Human Immunodeficiency-Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) have been assessed in previous studies; however, time-related trends in association with socio-demographic standards among the followers of major religions in India are not known. Objectives: We assessed the 2005-06, 2015-16, and 2019-21 demographic and health survey (DHS) data from India to investigate trends in the levels of knowledge of HIV/AIDS among Hindus, Muslims, and Christians in relation to standard socio-demographic variables over a period of 16 years. Methods: The age range of the population was 15-54 years (n=611,821). The HIV/AIDS-related knowledge was assessed by developing a composite index based on ten questions about several aspects of HIV/AIDS, such as the mode of spread. We applied Chi-square and Kruskal-Wallis tests to investigate whether people had heard about HIV/AIDS and their overall HIV knowledge in relation to several socio-demographic standards. Results: Generally, a higher increase in knowledge level was found between the first and second DHS surveys (2006-2016) as compared to between the second and third DHS surveys (2016-2021). We found the highest increase in the level of HIV/AIDS knowledge among Christian women followed by Hindus, whereas Muslims had the least increase over 16 years. Being a female, uneducated, poor, previously married, or having rural residence were associated with the highest increase in the knowledge of HIV/AIDS. Conclusion: Christian women had the highest increase in HIV/AIDS-related knowledge then came Christian men and followers of other religions. We also found the highest increase in HIV/AIDS-related knowledge among the poorest, uneducated, and rural residents. Our findings may help formulate public health strategies targeting various less knowledgeable groups to reduce the incidence of HIV/AIDS.

Depolarized Mitochondrial Membrane Potential and Elevated Calcium in Platelets of Sickle Cell Disease.

Hemolysis, a crucial feature of Sickle cell disease (SCD), is a key player for cellular activation leading to various complications including thrombosis. In response to hemolysis, platelets get activated and release components that are necessary for further platelet activation and aggregation. Thus, it is believed that platelets contribute to the development of thrombotic complications. Platelets in SCD are expected to be affected due to common cause of hemolysis. To measure the surface markers of platelets including P-Selectin, Phosphatidyl Serine and integrin αIIbß3 in SCD patients and healthy controls in order to understand the status of the platelets in SCD. To measure the surface markers of activated platelets using flow cytometry. Since mitochondria and calcium play an important role in cellular functions, the mitochondrial membrane potential and calcium content of platelets in SCD were also evaluated using flow cytometry. In the present study, we have observed significant increase of calcium level in SCD platelets. Further, the loss of mitochondrial membrane potential in SCD platelets was found to be significantly higher when compared to platelets of healthy controls. Though the surface markers of activated platelets in SCD remain unchanged, increased level of calcium and mitochondrial membrane potential loss suggest that the platelets in SCD are more prone to become activated. In order to understand the status of the platelets in SCD, apart from the surface markers, it is also important to assess the calcium levels and mitochondrial membrane potential of platelets.

Circulating H-FABP as a biomarker of frailty in patients with chronic heart failure.

Increased vulnerability to physiologic stressors, termed frailty, is a common occurrence in patients with chronic heart failure (CHF). However, the definite biomarkers to assess frailty in CHF patients are not known. Here, we assessed the frailty phenotype and its potential association with heart failure (HF) markers in CHF patients. We categorized controls (n = 59) and CHF patients (n = 80), the participants, into robust, pre-frail, and frail based on the cardiovascular health study (CHS) frailty index. The plasma levels of HF markers, including tumorigenicity 2 (s-ST2), galectin-3, and heart-type fatty acid binding protein (H-FABP), were measured and correlated with frailty phenotype and cardiac function. The levels of plasma s-ST2, galectin-3, and H-FABP were profoundly elevated in CHF patients. Conversely, the frailty index scores were significantly lower in ischemic and non-ischemic CHF patients versus controls. Of the assessed HF markers, only H-FABP was positively correlated (r2 = 0.07, P = 0.02) with the frailty score in CHF patients. Collectively, these observations suggest that circulating H-FABP may serve as a biomarker of frailty in CHF patients.

A leaky gut contributes to postural dysfunction in patients with Alzheimer's disease.

Background: Postural dysfunction is a common problem in patients with Alzheimer's disease (AD) and may lead to functional dependency and increasing morbidity and mortality. However, the pathophysiology of postural dysfunction in AD patients remains poorly understood. Objectives: Elevated intestinal permeability is an underlying contributor to multiple diseases, including AD. We aimed to investigate the association of elevated intestinal permeability with postural dysfunction in AD patients. Design Setting Participants Measurements: We conducted a cross-sectional, observational study on older adults, including controls and AD patients. We investigated the associations of postural balance with plasma zonulin, a marker of elevated intestinal permeability in geriatric controls (n = 74) and patients with mild (n = 71) and moderate (n = 66) AD. We used a standardized physical performance battery to measure balance in supine, tandem, and semi-tandem positions. We also measured handgrip strength (HGS), and gait speed as markers of physical capacity. Results: AD patients exhibited lower balance scores, HGS, and gait speed and higher plasma zonulin than in controls (all p < 0.05). Plasma zonulin levels demonstrated significant areas under the curves in diagnosing poor balance in AD patients (all p < 0.05). Moderate AD was associated with lower balance and physical capacity, and higher zonulin than mild AD (ALL P < 0.05). Poor scores on balance scale were associated with higher expressions of markers of inflammation, oxidative stress, and muscle damage providing a mechanistic link between increased intestinal permeability and postural dysfunction in AD patients. Conclusion: The results of our study show that plasma zonulin measurement may be used to diagnose postural dysfunction in AD patients. The study is relevant to non-ambulant and/or comatose AD patients with postural dysfunction. Our findings also highlight the therapeutic potential of repairing the intestinal leak to improve postural control and reduce the risk of falls in AD patients.

Angiotensin Receptor Blockers Restore Skeletal Muscle in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Age-related muscle decline, called sarcopenia, and hypertension are commonly observed in patients with chronic obstructive pulmonary disease (COPD). Angiotensin receptor blockers (ARBs) are common antihypertensive medications with muscle protective effects. However, the anti-sarcopenic potential and associated mechanisms of ARBs in hypertensive patients with COPD are unknown. OBJECTIVES: We aimed to investigate the potential contribution of neuromuscular junction (NMJ) stability as a driving mechanism of ARBs-induced muscle protection. METHODS: We categorized 236 patients with COPD into normotensive (n = 79) and hypertensive, based on treatment with ARB (n = 82), and other antihypertensive drugs (n = 75). Hypertensive patients with COPD were evaluated at two time points one year apart. Handgrip strength (HGS), body composition, short physical performance battery (SPPB), and plasma c-terminal agrin fragment-22 (CAF22) as a marker of NMJ degradation were measured. RESULTS: Patients with COPD exhibited reduced HGS and SPPB scores, and higher levels of CAF22 than controls, regardless of hypertension status. ARBs treatment improved HGS and gait speed and reduced plasma CAF22 levels in hypertensive patients with COPD (all p <0.05). ARBs also prevented the decline in SPPB components, including maintaining balance, gait speed, and the ability to rise from a chair in hypertensive patients with COPD (all p <0.05). We also found dynamic associations of plasma CAF22 with HGS, gait speed, and SPPB scores in hypertensive patients with COPD. CONCLUSIONS: Altogether, ARB treatment preserves skeletal muscle health and functional capacity in hypertensive patients with COPD by reducing plasma CAF22 and possibly repairing NMJs.

GSK-3α aggravates inflammation, metabolic derangement, and cardiac injury post-ischemia/reperfusion.

Reperfusion after acute myocardial infarction further exaggerates cardiac injury and adverse remodeling. Irrespective of cardiac cell types, loss of specifically the α isoform of the protein kinase GSK-3 is protective in chronic cardiac diseases. However, the role of GSK-3α in clinically relevant ischemia/reperfusion (I/R)-induced cardiac injury is unknown. Here, we challenged cardiomyocyte-specific conditional GSK-3α knockout (cKO) and littermate control mice with I/R injury and investigated the underlying molecular mechanism using an in vitro GSK-3α gain-of-function model in AC16 cardiomyocytes post-hypoxia/reoxygenation (H/R). Analysis revealed a significantly lower percentage of infarct area in the cKO vs. control hearts post-I/R. Consistent with in vivo findings, GSK-3α overexpression promoted AC16 cardiomyocyte death post-H/R which was accompanied by an induction of reactive oxygen species (ROS) generation. Consistently, GSK-3α gain-of-function caused mitochondrial dysfunction by significantly suppressing mitochondrial membrane potential. Transcriptomic analysis of GSK-3α overexpressing cardiomyocytes challenged with hypoxia or H/R revealed that NOD-like receptor (NLR), TNF, NF-κB, IL-17, and mitogen-activated protein kinase (MAPK) signaling pathways were among the most upregulated pathways. Glutathione and fatty acid metabolism were among the top downregulated pathways post-H/R. Together, these observations suggest that loss of cardiomyocyte-GSK-3α attenuates cardiac injury post-I/R potentially through limiting the myocardial inflammation, mitochondrial dysfunction, and metabolic derangement. Therefore, selective inhibition of GSK-3α may provide beneficial effects in I/R-induced cardiac injury and remodeling. KEY MESSAGES: GSK-3α promotes cardiac injury post-ischemia/reperfusion (I/R). GSK-3α regulates inflammatory and metabolic pathways post-hypoxia/reoxygenation (H/R). GSK-3α overexpression upregulates NOD-like receptor (NLR), TNF, NF-kB, IL-17, and MAPK signaling pathways in cardiomyocytes post-H/R. GSK-3α downregulates glutathione and fatty acid metabolic pathways in cardiomyocytes post-H/R.

The quality of life in Alzheimer's disease is not associated with handgrip strength but with activities of daily living-a composite study from 28 European countries.

OBJECTIVES: The relationship between handgrip strength (HGS) and quality of life is inconsistent. The purpose of this study was to investigate the potential association between HGS and quality of life in the settings of ageing and Alzheimer's disease (AD). METHODS: We investigated the HGS, CASP-12 (control, autonomy, self-realization, and pleasure) measure of quality of life, and physical capacity in European adults above 50, including controls (n = 38,628) and AD subjects (n = 460) using the survey of health, ageing, and retirement in Europe (SHARE; 2022). RESULTS: AD subjects exhibited lower HGS and CASP-12 scores than controls (both p < 0.05). Participants with higher CASP-12 quartiles had higher HGS in controls but not in AD subjects. A linear positive relation was found between HGS and CASP-12 in controls (0.0842, p < 0.05) but not in AD subjects (0.0636, p = 0.091). There was no effect of gender on this finding. Lastly, we found significant negative associations of difficulties walking, rising from chair, climbing stairs, and fatigue with CASP-12 scores in controls and AD subjects (all p < 0.05). CONCLUSIONS: Altogether, HGS was not associated with quality of life in individuals with AD. Conversely, difficulties in activities of daily living seem to be negatively associated with quality of life; thus, strategies are recommended to improve physical capacity.

Suppression of endoplasmic reticulum stress reverses hindlimb unloading-induced hepatic cellular processes in mice.

BACKGROUND: The Hindlimb unloaded mouse, an animal model of simulated microgravity demonstrates significant metabolic and hepatic derangements. However, cellular and molecular mechanisms driving liver dysfunction in Hindlimb unloaded mice are poorly characterized. METHODS: We investigated the possible contribution of dysregulated protein homeostasis by endoplasmic reticulum, endoplasmic reticulum stress, to liver dysfunction during HU. C57BL/6j male mice were grouped into ground-based controls or Hindlimb unloaded groups treated daily with vehicle or 4-phenylbutyrate (4-PBA), a potent inhibitor of endoplasmic reticulum stress. Following three weeks of HU, mice were sacrificed, and liver tissues were dissected for further analysis. RESULTS: Hindlimb unloaded was associated with hepatic atrophy and elevated endoplasmic reticulum stress, which was restored by 4-PBA treatment. The Gene Ontology analysis revealed the downregulation of genes primarily involved in liver metabolic and Wingless-related integration site (WNT) signaling pathways, while those related to cytochrome P450, and liver fibrosis were upregulated. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed downregulation of several genes involved in metabolic pathways following treatment with 4-PBA, induced by HU. CONCLUSIONS: We report several differential and uniquely expressed genes associated with microgravity-induced elevated ER stress and liver injury. Our data has translational potential in unraveling novel molecular targets for pharmaceutical therapies of liver diseases. GENERAL SIGNIFICANCE: Our novel findings show a pathogenic role for elevated ER stress in liver injury in microgravity conditions.

ACE Inhibitors Improve Skeletal Muscle by Preserving Neuromuscular Junctions in Patients with Alzheimer's Disease.

BACKGROUND: Hypertension and skeletal muscle decline are common findings in patients with Alzheimer's disease (AD). Angiotensin-converting enzyme (ACE) inhibitors preserve skeletal muscle and physical capacity; however, the driving mechanisms are poorly understood. OBJECTIVE: We investigated the effects of ACE inhibitors on the neuromuscular junction (NMJ) with relevance to skeletal muscle and physical capacity in AD patients and age-matched controls. METHODS: We evaluated controls (n = 59) and three groups of AD patients, including normotensive (n = 51) and patients with hypertension taking ACE inhibitors (n = 53) or other anti-hypertensive medications (n = 49) at baseline and one year later. We measure plasma c-terminal agrin fragment-22 (CAF22) as a marker of NMJ degradation, handgrip strength (HGS), and Short Physical Performance Battery (SPPB) as markers of physical capacity. RESULTS: At baseline AD patients demonstrated lower HGS and SPPB scores and higher CAF22 levels than controls, irrespective of the hypertension status (all p < 0.05). The use of ACE inhibitors was associated with higher HGS and relative maintenance of SPPB scores, gait speed, and plasma CAF22 levels. Conversely, other anti-hypertensive medications were associated with an unaltered HGS, reduced SPPB scores and elevated plasma CAF22 levels (both p < 0.05). We also found dynamic associations of CAF22 with HGS, gait speed, and SPPB in AD patients taking ACE inhibitors (all p < 0.05). These changes were associated with reduced oxidative stress in AD patients taking ACE inhibitors (p < 0.05). CONCLUSION: Altogether, ACE inhibitors are associated with higher HGS, preserved physical capacity, and the prevention of NMJ degradation in hypertensive AD patients.