Shared genetic correlations between kidney diseases and sepsis.

Background: Clinical studies have indicated a comorbidity between sepsis and kidney diseases. Individuals with specific mutations that predispose them to kidney conditions are also at an elevated risk for developing sepsis, and vice versa. This suggests a potential shared genetic etiology that has not been fully elucidated. Methods: Summary statistics data on exposure and outcomes were obtained from genome-wide association meta-analysis studies. We utilized these data to assess genetic correlations, employing a pleiotropy analysis method under the composite null hypothesis to identify pleiotropic loci. After mapping the loci to their corresponding genes, we conducted pathway analysis using Generalized Gene-Set Analysis of GWAS Data (MAGMA). Additionally, we utilized MAGMA gene-test and eQTL information (whole blood tissue) for further determination of gene involvement. Further investigation involved stratified LD score regression, using diverse immune cell data, to study the enrichment of SNP heritability in kidney-related diseases and sepsis. Furthermore, we employed Mendelian Randomization (MR) analysis to investigate the causality between kidney diseases and sepsis. Results: In our genetic correlation analysis, we identified significant correlations among BUN, creatinine, UACR, serum urate, kidney stones, and sepsis. The PLACO analysis method identified 24 pleiotropic loci, pinpointing a total of 28 nearby genes. MAGMA gene-set enrichment analysis revealed a total of 50 pathways, and tissue-specific analysis indicated significant enrichment of five pairs of pleiotropic results in kidney tissue. MAGMA gene test and eQTL information (whole blood tissue) identified 33 and 76 pleiotropic genes, respectively. Notably, genes PPP2R3A for BUN, VAMP8 for UACR, DOCK7 for creatinine, and HIBADH for kidney stones were identified as shared risk genes by all three methods. In a series of immune cell-type-specific enrichment analyses of pleiotropy, we identified a total of 37 immune cells. However, MR analysis did not reveal any causal relationships among them. Conclusions: This study lays the groundwork for shared etiological factors between kidney and sepsis. The confirmed pleiotropic loci, shared pathogenic genes, and enriched pathways and immune cells have enhanced our understanding of the multifaceted relationships among these diseases. This provides insights for early disease intervention and effective treatment, paving the way for further research in this field.

Mouse sarcopenia model reveals sex- and age-specific differences in phenotypic and molecular characteristics.

Our study was to characterize sarcopenia in C57BL/6J mice using a clinically relevant definition to investigate the underlying molecular mechanisms. Aged male (23-32 months old) and female (27-28 months old) C57BL/6J mice were classified as non-, probable-, or sarcopenic based on assessments of grip strength, muscle mass, and treadmill running time, using 2 SDs below the mean of their young counterparts as cutoff points. A 9%-22% prevalence of sarcopenia was identified in 23-26 month-old male mice, with more severe age-related declines in muscle function than mass. Females aged 27-28 months showed fewer sarcopenic but more probable cases compared with the males. As sarcopenia progressed, a decrease in muscle contractility and a trend toward lower type IIB fiber size were observed in males. Mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in males, with pathways linked to mitochondrial metabolism positively correlated with muscle mass. No age- or sarcopenia-related changes were observed in mitochondrial biogenesis, OXPHOS complexes, AMPK signaling, mitophagy, or atrogenes in females. Our results highlight the different trajectories of age-related declines in muscle mass and function, providing insights into sex-dependent molecular changes associated with sarcopenia progression, which may inform the future development of novel therapeutic interventions.

Activated platelet-derived exosomal LRG1 promotes multiple myeloma cell growth.

The hypercoagulable state is a hallmark for patients with multiple myeloma (MM) and is associated with disease progression. Activated platelets secrete exosomes and promote solid tumor growth. However, the role of platelet-derived exosomes in MM is not fully clear. We aim to study the underlying mechanism of how platelet-derived exosomes promote MM cell growth. Flow cytometry, Western blot, proteome analysis, co-immunoprecipitation, immunofluorescence staining, and NOD/SCID mouse subcutaneous transplantation model were performed to investigate the role of exosomal LRG1 on multiple myeloma cell growth. Peripheral blood platelets in MM patients were in a highly activated state, and platelet-rich plasma from MM patients significantly promoted cell proliferation and decreased apoptotic cells in U266 and RPMI8226 cells. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) was significantly enriched in MM platelet-derived exosomes. Blocking LRG1 in recipient cells using LRG1 antibody could significantly eliminate the proliferation-promoting effect of platelet-derived exosomes on MM cells. And high exosomal LRG1 was associated with poor prognosis of patients with MM. Mechanistic studies revealed that LRG1 interacted with Olfactomedin 4 (OLFM4) to accelerate MM progression by activating the epithelial-to-mesenchymal transition (EMT) signaling pathway and promoting angiogenesis. Our results revealed that blocking LRG1 is a promising therapeutic strategy for the treatment of MM.

In utero chronic intermittent nicotine aerosol exposure increases ischemic heart injury in adult offspring via programming of Angiotensin II receptor-derived TGFß/ROS/Akt signaling pathway.

BACKGROUND: In utero cigarette smoking/nicotine exposure during pregnancy significantly affects fetal development and increases the risk of cardiovascular disease late in life. However, the underlying molecular mechanisms remain largely unknown. We tested the hypothesis that fetal nicotine aerosol exposure reprograms ischemia-sensitive gene expressions, resulting in increased heart susceptibility to ischemic injury and cardiac dysfunction in adulthood. METHODS: Pregnant rats were exposed to chronic intermittent nicotine aerosol (CINA) or saline aerosol control from gestational day 4 to day 21. Experiments were performed on 6-month-old adult offspring. RESULTS: CINA exposure increased ischemia-induced cardiac injury and cardiac dysfunction compared to the control group, which was associated with over- expression of angiotensin II receptor (ATR) protein in the left ventricle (LV) of adult offspring. Meanwhile, CINA exposure up-regulated cardiac TGF-ß/SMADs family proteins in the LV. In addition, CINA exposure enhanced cardiac reactive oxygen species (ROS) production and increased the DNA methylation level. The levels of phosphorylated-Akt were upregulated but LC3B-II/I protein abundances were downregulated in the hearts isolated from the CINA-treated group. CONCLUSION: Fetal nicotine aerosol exposure leads to cardiac dysfunction in response to ischemic stimulation in adulthood. Two molecular pathways are implicated. First, fetal CINA exposure elevates cardiac ATR levels, affecting the TGFß-SMADs pathway. Second, heightened Angiotensin II/ATR signaling triggers ROS production, leading to DNA hypermethylation, p-Akt activation, and autophagy deficiency. These molecular shifts in cardiomyocytes result in the development of a heart ischemia-sensitive phenotype and subsequent dysfunction in adult offspring.

Lexical pathway from L2 to L1 activation in intermediate proficient bilinguals: behavioral and ERP evidence.

Numerous studies have demonstrated that second language (L2) comprehension is often accompanied by activations in the first language (L1). Using both behavioral measurement and event-related potential (ERP), this study conducted two experiments to investigate whether a direct activation pathway exists from L2 lexical representation to L1 lexical representation (the lexical pathway) in intermediate proficient bilinguals. In Experiment 1, we designed a vowel letter search task on English word pairs, which enables bilinguals to prevent semantic priming in the first 300 ms processing stage after the words' onset. In Experiment 2, Mandarin-English bilinguals were recruited to complete this task on English word pairs with occasional first character repetition between the Chinese counterparts of a word pair. Results showed a significant main effect within both the P200 and N400 time windows, indicating the activation of bilinguals' L1 lexical representation during these intervals. However, the main effect of semantic relatedness was only significant in the N400 time window. These results suggest that bilinguals can activate their L1 lexical representation directly before engaging in conceptual representation. This finding supported a lexical pathway of activation from L2 lexical representation to L1 lexical representation during visual-word recognition in intermediate proficient bilinguals.

STZ-induced gestational diabetes exposure alters PTEN/AKT/mTOR-mediated autophagy signaling pathway leading to increase the risk of neonatal hypoxic-ischemic encephalopathy.

Exposure to gestational diabetes mellitus (GDM) during pregnancy has significant consequences for the unborn baby and newborn infant. However, whether and how GDM exposure induces the development of neonatal brain hypoxia/ischemia-sensitive phenotype and the underlying molecular mechanisms remain unclear. In this study, we used a late GDM rat model induced by administration of streptozotocin (STZ) on gestational day 12 and investigated its effects of GDM on neonatal brain development. The pregnant rats exhibited increased blood glucose levels in a dose-dependent manner after STZ administration. STZ-induced maternal hyperglycemia led to reduced blood glucose levels in neonatal offspring, resulting in growth restriction and an increased brain to body weight ratio. Importantly, GDM exposure increased susceptibility to hypoxia/ischemia (HI)-induced brain infarct sizes compared to the controls in both male and female neonatal offspring. Further molecular analysis revealed alterations in the PTEN/AKT/mTOR/autophagy signaling pathway in neonatal male offspring brains, along with increased ROS production and autophagy-related proteins (Atg5 and LC3-II). Treatment with the PTEN inhibitor bisperoxovanadate (BPV) eliminated the differences in HI-induced brain infarct sizes between the GDM-exposed and the control groups. These findings provide novel evidence of the development of a brain hypoxia/ischemia-sensitive phenotype in response to GDM exposure and highlight the role of the PTEN/AKT/mTOR/autophagy signaling pathway in this process.

N6-methyladenosine-modified circ_0000337 sustains bortezomib resistance in multiple myeloma by regulating DNA repair.

Studies have shown that bortezomib resistance in multiple myeloma (MM) is mediated by the abnormalities of various molecules and microenvironments. Exploring these resistance mechanisms will improve the therapeutic efficacy of bortezomib. In this study, bone marrow tissues from three patients with MM, both sensitive and resistant to bortezomib, were collected for circRNA high-throughput sequencing analysis. The relationship between circ_0000337, miR-98-5p, and target gene DNA2 was analyzed by luciferase detection and verified by RT-qPCR. We first found that circ_0000337 was significantly upregulated in bortezomib-resistant MM tissues and cells, and overexpression of circ_0000337 could promote bortezomib resistance in MM cells. circ_0000337 may act as a miR-98-5p sponge to upregulate DNA2 expression, regulate DNA damage repair, and induce bortezomib resistance. Furthermore, it was determined that the increased circ_0000337 level in bortezomib-resistant cells was due to an increased N6-methyladenosine (m6A) level, resulting in enhanced RNA stability. In conclusion, the m6A level of circ_0000337 and its regulation may be a new and potential therapeutic target for overcoming bortezomib resistance in MM.

Repression of LSD1/KDM1A activity improves the response of liver cancer cells to the lenvatinib.

BACKGROUND/AIM: Lenvatinib, a multikinase inhibitor, has become a second-line treatment option for unresectable liver cancer, while its monotherapy response rate is limited. Hence, we aim to investigate whether one of the epigenetic inhibitors will be synthetic lethal with Lenvatinib in liver cancer cells. MATERIALS AND METHODS: We performed high-throughput drug screening in combination with Lenvatinib. And we employed CCK-8-based Bliss Synergy Score analysis, colony formation and western blotting to confirm our screening results in both HepG2 and HCCC9810 cells. RESULTS: We identified that LSD1 inhibitor Pulrodemstat in combination with Lenvatinib dramatically suppressed the PI3K-AKT signaling and induced a more significant activation of Caspase3 compared to Lenvatinib monotherapy. CONCLUSION: Pulrodemstat synergized with Lenvatinib based on suppression of PI3K-AKT signaling and activation of apoptotic signaling.

Genetically predicted causality between gut microbiota, blood metabolites, and intracerebral hemorrhage: a bidirectional Mendelian randomization study.

Background: Recent research linked changes in the gut microbiota and serum metabolite concentrations to intracerebral hemorrhage (ICH). However, the potential causal relationship remained unclear. Therefore, the current study aims to estimate the effects of genetically predicted causality between gut microbiota, serum metabolites, and ICH. Methods: Summary data from genome-wide association studies (GWAS) of gut microbiota, serum metabolites, and ICH were obtained separately. Gut microbiota GWAS (N = 18,340) were acquired from the MiBioGen study, serum metabolites GWAS (N = 7,824) from the TwinsUK and KORA studies, and GWAS summary-level data for ICH from the FinnGen R9 (ICH, 3,749 cases; 339,914 controls). A two-sample Mendelian randomization (MR) study was conducted to explore the causal effects between gut microbiota, serum metabolites, and ICH. The random-effects inverse variance-weighted (IVW) MR analyses were performed as the primary results, together with a series of sensitivity analyses to assess the robustness of the results. Besides, a reverse MR was conducted to evaluate the possibility of reverse causation. To validate the relevant findings, we further selected data from the UK Biobank for analysis. Results: MR analysis results revealed a nominal association (p < 0.05) between 17 gut microbial taxa, 31 serum metabolites, and ICH. Among gut microbiota, the higher level of genus Eubacterium xylanophilum (odds ratio (OR): 1.327, 95% confidence interval (CI):1.154-1.526; Bonferroni-corrected p = 7.28 × 10-5) retained a strong causal relationship with a higher risk of ICH after the Bonferroni corrected test. Concurrently, the genus Senegalimassilia (OR: 0.843, 95% CI: 0.778-0.915; Bonferroni-corrected p = 4.10 × 10-5) was associated with lower ICH risk. Moreover, after Bonferroni correction, only two serum metabolites remained out of the initial 31 serum metabolites. One of the serum metabolites, Isovalerate (OR: 7.130, 95% CI: 2.648-19.199; Bonferroni-corrected p = 1.01 × 10-4) showed a very strong causal relationship with a higher risk of ICH, whereas the other metabolite was unidentified and excluded from further analysis. Various sensitivity analyses yielded similar results, with no heterogeneity or directional pleiotropy observed. Conclusion: This two-sample MR study revealed the significant influence of gut microbiota and serum metabolites on the risk of ICH. The specific bacterial taxa and metabolites engaged in ICH development were identified. Further research is required in the future to delve deeper into the mechanisms behind these findings.

Key factors capturing the willingness to use automated vehicles for travel in China.

With the continuous advancement of technology, automated vehicle technology is progressively maturing. It is crucial to comprehend the factors influencing individuals' intention to utilize automated vehicles. This study examined user willingness to adopt automated vehicles. By incorporating age and educational background as random parameters, an ordered Probit model with random parameters was constructed to analyze the influential factors affecting respondents' adoption of automated vehicles. We devised and conducted an online questionnaire survey, yielding 2105 valid questionnaires. The findings reveal significant positive correlations between positive social trust, perceived ease of use, perceived usefulness, low levels of perceived risk, and the acceptance of automated vehicles. Additionally, our study identifies extraversion and openness as strong mediators in shaping individuals' intentions to use automated vehicles. Furthermore, prior experience with assisted driving negatively impacts people's inclination toward embracing automated vehicles. Our research also provides insights for promoting the adoption of automated vehicles: favorable media coverage and a reasonable division of responsibilities can enhance individuals' intentions to adopt this technology.

Prenatal Nicotine Exposure Raises Male Blood Pressure via FTO-Mediated NOX2/ROS Signaling.

BACKGROUND: Cigarette smoking/nicotine exposure in pregnancy shows an increased risk of hypertension in offspring, but the mechanisms are unclear. This study tested the hypothesis that m6A RNA hypomethylation epigenetically regulates vascular NOX (NADPH oxidase) and reactive oxygen species production, contributing to the fetal programming of a hypertensive phenotype in nicotine-exposed offspring. METHODS: Pregnant rats were exposed to episodic chronic intermittent nicotine aerosol (CINA) or saline aerosol control from gestational day 4 to day 21, and experiments were performed in 6-month-old adult offspring. RESULTS: Antenatal CINA exposure augmented Ang II (angiotensin II)-stimulated blood pressure response in male, but not female offspring. Moreover, CINA increased vascular NOX2 expression and superoxide production exclusively in male offspring. Inhibition of NOX2 with gp91ds-tat, both ex vivo and in vivo, mitigated the CINA-induced elevation in superoxide production and blood pressure response. Notably, CINA enhanced the expression of vascular m6A demethylase FTO (fat mass and obesity-associated protein), while reducing the total vascular m6A abundance and specific m6A methylation of the NOX2 gene. Additionally, ex vivo inhibition of FTO with FB23-2 attenuated CINA-induced increases in vascular NOX2 expression. In vitro experiments using human umbilical vein endothelial cells demonstrated that nicotine dose-dependently upregulated FTO and NOX2 protein abundance, which were reversed by treatment with the FTO inhibitor FB23-2 or FTO knockdown using siRNAs. CONCLUSIONS: This study uncovers a new mechanism: m6A demethylase FTO-mediated epigenetic upregulation of vascular NOX2 signaling in CINA-induced hypertensive phenotype. This insight could lead to a therapeutic target for preventing and treating developmental hypertension programming.

DeepGraFT: A novel semantic segmentation auxiliary ROI-based deep learning framework for effective fundus tessellation classification.

Fundus tessellation (FT) is a prevalent clinical feature associated with myopia and has implications in the development of myopic maculopathy, which causes irreversible visual impairment. Accurate classification of FT in color fundus photo can help predict the disease progression and prognosis. However, the lack of precise detection and classification tools has created an unmet medical need, underscoring the importance of exploring the clinical utility of FT. Thus, to address this gap, we introduce an automatic FT grading system (called DeepGraFT) using classification-and-segmentation co-decision models by deep learning. ConvNeXt, utilizing transfer learning from pretrained ImageNet weights, was employed for the classification algorithm, aligning with a region of interest based on the ETDRS grading system to boost performance. A segmentation model was developed to detect FT exits, complementing the classification for improved grading accuracy. The training set of DeepGraFT was from our in-house cohort (MAGIC), and the validation sets consisted of the rest part of in-house cohort and an independent public cohort (UK Biobank). DeepGraFT demonstrated a high performance in the training stage and achieved an impressive accuracy in validation phase (in-house cohort: 86.85 %; public cohort: 81.50 %). Furthermore, our findings demonstrated that DeepGraFT surpasses machine learning-based classification models in FT classification, achieving a 5.57 % increase in accuracy. Ablation analysis revealed that the introduced modules significantly enhanced classification effectiveness and elevated accuracy from 79.85 % to 86.85 %. Further analysis using the results provided by DeepGraFT unveiled a significant negative association between FT and spherical equivalent (SE) in the UK Biobank cohort. In conclusion, DeepGraFT accentuates potential benefits of the deep learning model in automating the grading of FT and allows for potential utility as a clinical-decision support tool for predicting progression of pathological myopia.

Advances in photothermal regulation strategies: from efficient solar heating to daytime passive cooling.

Photothermal regulation concerning solar harvesting and repelling has recently attracted significant interest due to the fast-growing research focus in the areas of solar heating for evaporation, photocatalysis, motion, and electricity generation, as well as passive cooling for cooling textiles and smart buildings. The parallel development of photothermal regulation strategies through both material and system designs has further improved the overall solar utilization efficiency for heating/cooling. In this review, we will review the latest progress in photothermal regulation, including solar heating and passive cooling, and their manipulating strategies. The underlying mechanisms and criteria of highly efficient photothermal regulation in terms of optical absorption/reflection, thermal conversion, transfer, and emission properties corresponding to the extensive catalog of nanostructured materials are discussed. The rational material and structural designs with spectral selectivity for improving the photothermal regulation performance are then highlighted. We finally present the recent significant developments of applications of photothermal regulation in clean energy and environmental areas and give a brief perspective on the current challenges and future development of controlled solar energy utilization.

Fiber Sedimentation and Layer-By-Layer Assembly Strategy for Designing Biomimetic Quasi-Ordered Mullite Fiber Aerogels as Extreme Conditions Thermal Insulators.

Ceramic fiber aerogels are attractive thermal insulating materials. In a thermomechanical coupling environment, however, they often show limited mechanical strength and considerably increased heat transfer which can lead to thermal runaway. In this paper, inspired by bird's nest and nacre, we demonstrate a sample strategy combining fiber sedimentation and layer-by-layer assembly to fabricate ultrastrong mullite fiber aerogels (MFAs) with quasi-ordered structures. The fibrous layers and fiber bridges are constructed in a fiber sedimentation self-assembly process. The fiber sedimentation technique optimizes the structure of the MFAs by regulating the fiber orientation. Owing to the quasi-ordered structure, the fabricated MFAs exhibit the integrated properties of high compression fatigue resistance, temperature-invariant compression resilience from -196 to 1300 °C, and low thermal conductivity (0.034 W·m-1·K-1). By deliberately pressing multilayer MFAs into a thin paper, we substantially enhance the load-bearing capacity of the MFAs and achieve large temperature differences (563 °C) between the cold and hot surfaces by using a thin layer of MFAs (3-5 mm) under the simulated high-temperature (685 °C) and high-pressure (0.9 MPa) environment test. The combination of compression resistance, mechanical flexibility, and excellent thermal insulation provides an appealing material for efficient thermal insulation in extreme environments.

CD38-targeted and erythrocyte membrane camouflaged nanodrug delivery system for photothermal and chemotherapy in multiple myeloma.

Multiple myeloma (MM) is a malignant and incurable disease. Chemotherapy is currently the primary treatment option for MM. However, chemotherapeutic drugs can interrupt treatment because of serious side effects. Therefore, development of novel therapeutics for MM is essential. In this study, we designed and constructed an innovative nanoparticle-based drug delivery system, P-R@Ni3P-BTZ, and investigated its feasibility, effectiveness, and safety both in vitro and in vivo. P-R@Ni3P-BTZ is a nanocomposite that consists of two parts: (1) the drug carrier (Ni3P), which integrates photothermal therapy (PTT) with chemotherapy by loading bortezomib (BTZ); and (2) the shell (P-R), a CD38 targeting peptide P-modified red blood cell membrane nanovesicles. In vitro and in vivo, it was proven that P-R@Ni3P-BTZ exhibits remarkable antitumor effects by actively targeting CD38 + MM cells. P-R@Ni3P-BTZ significantly induces the accumulation of intracellular reactive oxygen species (ROS) and increases the apoptosis of MM cells, which underlies the primary mechanism of its antitumor effects. In addition, P-R@Ni3P exhibits good biocompatibility and biosafety, both in vitro and in vivo. Overall, P-R@Ni3P-BTZ is a specific and efficient MM therapeutic method.

Association of mitochondrial DNA variation with high myopia in a Han Chinese population.

High myopia (HM), which is characterized by oxidative stress, is one of the leading causes of visual impairment and blindness across the world. Family and population genetic studies have uncovered nuclear-genome variants in proteins functioned in the mitochondria. However, whether mitochondrial DNA mutations are involved in HM remains unexplored. Here, we performed the first large-scale whole-mitochondrial genome study in 9613 HM cases and 9606 control subjects of Han Chinese ancestry for identifying HM-associated mitochondrial variants. The single-variant association analysis identified nine novel genetic variants associated with HM reaching the entire mitochondrial wide significance level, including rs370378529 in ND2 with an odds ratio (OR) of 5.25. Interestingly, eight out of nine variants were predominantly located in related sub-haplogroups, i.e. m.5261G > A in B4b1c, m.12280A > G in G2a4, m.7912G > A in D4a3b, m.94G > A in D4e1, m.14857 T > C in D4e3, m.14280A > G in D5a2, m.16272A > G in G2a4, m.8718A > G in M71 and F1a3, indicating that the sub-haplogroup background can increase the susceptible risk for high myopia. The polygenic risk score analysis of the target and validation cohorts indicated a high accuracy for predicting HM with mtDNA variants (AUC = 0.641). Cumulatively, our findings highlight the critical roles of mitochondrial variants in untangling the genetic etiology of HM.

Effect of hydrodynamics on the transformation of nitrogen in river water by regulating the mass transfer performance of dissolved oxygen in biofilm.

Biofilms drive crucial ecosystem processes in rivers. This study provided the basis for overall quantitative calculations about the contribution of biofilms to the nitrogen cycle. At the early stage of biofilm formation, dissolved oxygen (DO) could penetrate the biofilms. As the biofilm grew and the thickness increased, then the mass transfer of DO was restricted. The microaerobic layer firstly appeared in biofilm under the turbulent flow conditions, with the appearance of the microaerobic and anaerobic layer, the nitrification and denitrification reaction could proceed smoothly in biofilm. And the removal efficiency of total nitrogen (TN) increased as the biofilm matured. Under the turbulent flow conditions, mature biofilms had the smallest thickness, but the highest proportion the anaerobic layer to the biofilm thickness, the highest density, and the highest nitrogen removal efficiency. However, the nitrogen removal efficiency of biofilm was the lowest under laminar flow conditions. The difference of layered structure of biofilm and the DO flux in biofilm explained the difference of nitrogen migration and transformation in river water under different hydrodynamic conditions. This study would help control the growth of biofilm and improve the nitrogen removal capacity of biofilm by regulating hydrodynamic conditions.

Potential lipolytic regulators derived from natural products as effective approaches to treat obesity.

Epidemic obesity is contributing to increases in the prevalence of obesity-related metabolic diseases and has, therefore, become an important public health problem. Adipose tissue is a vital energy storage organ that regulates whole-body energy metabolism. Triglyceride degradation in adipocytes is called lipolysis. It is closely tied to obesity and the metabolic disorders associated with it. Various natural products such as flavonoids, alkaloids, and terpenoids regulate lipolysis and can promote weight loss or improve obesity-related metabolic conditions. It is important to identify the specific secondary metabolites that are most effective at reducing weight and the health risks associated with obesity and lipolysis regulation. The aims of this review were to identify, categorize, and clarify the modes of action of a wide diversity of plant secondary metabolites that have demonstrated prophylactic and therapeutic efficacy against obesity by regulating lipolysis. The present review explores the regulatory mechanisms of lipolysis and summarizes the effects and modes of action of various natural products on this process. We propose that the discovery and development of natural product-based lipolysis regulators could diminish the risks associated with obesity and certain metabolic conditions.

Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction.

The mitochondrial dysfunction characteristic of heart failure (HF) is associated with changes in intracellular nicotinamide adenine dinucleotide (NAD+) and NADH levels. Raising NAD+ levels with the NAD+ precursor, nicotinamide riboside (NR), may represent a novel HF treatment. In this 30-participant trial of patients with clinically stable HF with reduced ejection fraction, NR, at a dose of 1,000 mg twice daily, appeared to be safe and well tolerated, and approximately doubled whole blood NAD+ levels. Intraindividual NAD+ increases in response to NR correlated with increases in peripheral blood mononuclear cell basal (R 2 = 0.413, P = 0.003) and maximal (R 2 = 0.434, P = 0.002) respiration, and with decreased NLRP3 expression (R 2 = 0.330, P = 0.020). (Nicotinamide Riboside in Systolic Heart Failure; NCT03423342).

Discovering the main "reinforce kidney to strengthening Yang" active components of salt Morinda officinalis based on the spectrum-effect relationship combined with chemometric methods.

Morinda officinalis, a well-known traditional herbal medicine in China, is used to treat deficiency of kidney-yang syndrome. Although this medicine has the property of "reinforcing kidney to strengthening Yang," the chemical constituents responsible for this effect remain to be elucidated. Here, we aimed to identify the main active compounds responsible for reinforcing kidney to strengthening Yang, based on spectrum-effect relationships combined with chemometrics. We used the UPLC-diode array detection method to establish the chromatography fingerprint of M. officinalis. Hydrocortisone-induced and adenine-induced kidney-yang deficiency patterns were established to evaluate the efficacy of M. officinalis. Serum triiodothyronine, free thyroxine, thyrotropin, testosterone, cortisol, luteinizing hormone, follicle-stimulating hormone, corticotropin-releasing hormone, and adrenocorticotropic hormone levels were determined as pharmacodynamic indices. Analytic hierarchy process was used to determine the weight of each index to the total pharmacodynamic contribution. Lastly, the spectrum-effect between the fingerprint and the pharmacological effects were established using grey relational analysis and partial least squares. Our findings indicated that peaks 1, 2, 3, 5, 6, 7, 8, 9, 11, 13, 15, 17, and 20 might represent the main components that positively correlated to the total effect, of which four were identified by comparison with reference standards. The identified components were monotropein (peak 1), deacetyl asperulosidic acid (peak 3), asperulosidic acid (peak 8), and asperuloside (peak 9). Our results suggest that the "reinforce kidney to strengthening Yang" effects were attributable to the combined effects of the multiple chemical components of M. officinalis and provide a valuable method to identify the active "reinforce kidney to strengthening Yang" components of M. officinalis and establish the quality control of M. officinalis.