Cultivated Enterococcus faecium B6 from children with obesity promotes nonalcoholic fatty liver disease by the bioactive metabolite tyramine.

Gut microbiota plays an essential role in nonalcoholic fatty liver disease (NAFLD). However, the contribution of individual bacterial strains and their metabolites to childhood NAFLD pathogenesis remains poorly understood. Herein, the critical bacteria in children with obesity accompanied by NAFLD were identified by microbiome analysis. Bacteria abundant in the NAFLD group were systematically assessed for their lipogenic effects. The underlying mechanisms and microbial-derived metabolites in NAFLD pathogenesis were investigated using multi-omics and LC-MS/MS analysis. The roles of the crucial metabolite in NAFLD were validated in vitro and in vivo as well as in an additional cohort. The results showed that Enterococcus spp. was enriched in children with obesity and NAFLD. The patient-derived Enterococcus faecium B6 (E. faecium B6) significantly contributed to NAFLD symptoms in mice. E. faecium B6 produced a crucial bioactive metabolite, tyramine, which probably activated PPAR-γ, leading to lipid accumulation, inflammation, and fibrosis in the liver. Moreover, these findings were successfully validated in an additional cohort. This pioneering study elucidated the important functions of cultivated E. faecium B6 and its bioactive metabolite (tyramine) in exacerbating NAFLD. These findings advance the comprehensive understanding of NAFLD pathogenesis and provide new insights for the development of microbe/metabolite-based therapeutic strategies.

Mechanisms of the role of proto-oncogene activation in promoting malignant transformation of mature B cells. / åŽŸç˜¤åŸºå› æ¿€æ´»è¯±å¯¼æˆç†ŸB细胞恶变的作用机制.

Malignant tumors continue to pose a significant threat to human life and safety and their development is primarily due to the activation of proto-oncogenes and the inactivation of suppressor genes. Among these, the activation of proto-oncogenes possesses greater potential to drive the malignant transformation of cells. Targeting oncogenes involved in the malignant transformation of tumor cells has provided a novel approach for the development of current antitumor drugs. Several preclinical and clinical studies have revealed that the development pathway of B cells, and the malignant transformation of mature B cells into tumors have been regulated by oncogenes and their metabolites. Therefore, summarizing the key oncogenes involved in the process of malignant transformation of mature B cells and elucidating the mechanisms of action in tumor development hold significant importance for the clinical treatment of malignant tumors.

Folic acid supplementation prevents high body fat-induced bone loss through TGR5 signaling pathways.

Osteoporosis caused by bone loss is one of the serious global public health problems. Folic acid is a B vitamin with multiple physiological functions such as lipid regulation and antioxidant capacity, and its potential to improve bone loss has attracted our attention. Through NHANES database analysis, we found that folic acid intake was significantly correlated with whole-body bone mineral density (BMD) in people aged 20-60 years, and the association may be mediated by the body fat rate. Male C57Bl/6 mice were fed either a normal diet or a high-fat diet, and folic acid was added to drinking water for supplementation. Our results indicated that mice with high body fat showed bone microstructure damage and bone loss, while folic acid supplementation improved bone quality. At the same time, we found that mice with high body fat exhibited abnormal blood lipids, dysregulation of intestinal flora, and metabolic disorders. Folic acid supplementation improved these phenomena. Through the network analysis of intestinal flora and metabolites, we found that LCA and TGR5 may play important roles. The results showed that folic acid promoted the expression of LCA and TGR5 in mice, increased the phosphorylation of AMPK, and decreased the phosphorylation of NF-κB and ERK, thereby reducing bone loss. In summary, folic acid intake is closely related to BMD, and folic acid supplementation can prevent high body fat-induced bone loss. Our study provides new ideas and an experimental basis for preventing bone loss and osteoporosis.

Discovery of novel harmine derivatives as GSK-3ß/DYRK1A dual inhibitors for Alzheimer's disease treatment.

Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3ß and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK-3ß and DYRK1A in vitro. ZLQH-5 was selected as the best compound due to the most potent inhibitory effect against GSK-3ß and DYRK1A. Molecular docking studies demonstrated that ZLQH-5 could form stable interactions with the ATP binding pocket of GSK-3ß and DYRK1A. In addition, ZLQH-5 showed low cytotoxicity against SH-SY5Y and HL-7702, good blood-brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH-5 also attenuated the tau hyperphosphorylation in the okadaic acid SH-SY5Y cell model. These results indicated that ZLQH-5 could be a promising dual-target drug candidate for the treatment of AD.

Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma.

The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.

Landscape of enhancer disruption and functional screen in melanoma cells.

BACKGROUND: The high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma. RESULTS: Here, we leveraged 297 melanoma whole-genome sequencing samples to prioritize highly recurrent regions. By performing a genome-scale CRISPR interference (CRISPRi) screen on highly recurrent region-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers reveal many known and hidden mechanisms underlying melanoma growth. Utilizing extensive functional validation experiments, we demonstrate that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A, and another distal enhancer is able to sustain PTEN tumor-suppressive potential via long-range interactions. CONCLUSIONS: Our study establishes a catalogue of crucial enhancers and their target genes in melanoma growth and progression, and illuminates the identification of novel mechanisms of dysregulation for melanoma driver genes and new therapeutic targeting strategies.

Lactobacillus fermentum Alleviates the Colorectal Inflammation Induced by Low-Dose Sub-Chronic Microcystin-LR Exposure.

Microcystin-LR (MC-LR) contamination is a worldwide environmental problem that poses a grave threat to the water ecosystem and public health. Exposure to MC-LR has been associated with the development of intestinal injury, but there are no effective treatments for MC-LR-induced intestinal disease. Probiotics are "live microorganisms that are beneficial to the health of the host when administered in sufficient quantities". It has been demonstrated that probiotics can prevent or treat a variety of human diseases; however, their ability to mitigate MC-LR-induced intestinal harm has not yet been investigated. The objective of this study was to determine whether probiotics can mitigate MC-LR-induced intestinal toxicity and its underlying mechanisms. We first evaluated the pathological changes in colorectal tissues using an animal model with sub-chronic exposure to low-dose MC-LR, HE staining to assess colorectal histopathologic changes, qPCR to detect the expression levels of inflammatory factors in colorectal tissues, and WB to detect the alterations on CSF1R signaling pathway proteins in colorectal tissues. Microbial sequencing analysis and screening of fecal microorganisms differential to MC-LR treatment in mice. To investigate the role of microorganisms in MC-LR-induced colorectal injury, an in vitro model of MC-LR co-treatment with microorganisms was developed. Our findings demonstrated that MC-LR treatment induced an inflammatory response in mouse colorectal tissues, promoted the expression of inflammatory factors, activated the CSF1R signaling pathway, and significantly decreased the abundance of Lactobacillus. In a model of co-treatment with MC-LR and Lactobacillus fermentum (L. fermentum), it was discovered that L. fermentum substantially reduced the incidence of the colorectal inflammatory response induced by MC-LR and inhibited the protein expression of the CSF1R signaling pathway. This is the first study to suggest that L. fermentum inhibits the CSF1R signaling pathway to reduce the incidence of MC-LR-induced colorectal inflammation. This research may provide an excellent experimental foundation for the development of strategies for the prevention and treatment of intestinal diseases in MC-LR.

High expression of VARS promotes the growth of multiple myeloma cells by causing imbalance in valine metabolism. / VARSé«˜è¡¨è¾¾è‡´ç¼¬æ°¨é ¸ä»£è°¢å¤±è¡¡ä¿ƒè¿›å¤šå‘æ€§éª¨é«“ç˜¤ç»†èƒžç”Ÿé•¿.

OBJECTIVES: Multiple myeloma (MM) is a plasma cell malignancy occurring in middle and old age. MM is still an incurable disease due to its frequent recurrence and drug resistance. However, its pathogenesis is still unclear. Abnormal amino acid metabolism is one of the important characteristics of MM, and the important metabolic pathway of amino acids participates in protein synthesis as basic raw materials. Aminoacyl transfer ribonucleic acid synthetase (ARS) gene is a key regulatory gene in protein synthesis. This study aims to explore the molecular mechanism for ARS, a key factor of amino acid metabolism, in regulating amino acid metabolism in MM and affecting MM growth. METHODS: The corresponding gene number was combined with the gene expression profile GSE5900 dataset and GSE2658 dataset in Gene Expression Omnibus (GEO) database to standardize the gene expression data of ARS. GSEA_4.2.0 software was used to analyze the difference of gene enrichment between healthy donors (HD) and MM patients in GEO database. GraphPad Prism 7 was used to draw heat maps and perform data analysis. Kaplan-Meier and Cox regression model were used to analyze the expression of ARS gene and the prognosis of MM patients, respectively. Bone marrow samples from 7 newly diagnosed MM patients were collected, CD138+ and CD138- cells were obtained by using CD138 antibody magnetic beads, and the expression of ARS in MM clinical samples was analyzed by real-time RT-PCR. Human B lymphocyte GM12878 cells and human MM cell lines ARP1, NCI-H929, OCI-MY5, U266, RPMI 8266, OPM-2, JJN-3, KMS11, MM1.s cells were selected as the study objects. The expression of ARS in MM cell lines was analyzed by real-time RT-PCR and Western blotting. Short hairpin RNA (shRNA) lentiviruses were used to construct gene knock-out plasmids (VARS-sh group). No-load plasmids (scramble group) and gene knock-out plasmids (VARS-sh group) were transfected into HEK 293T cells with for virus packaging, respectively. Stable expression cell lines were established by infecting ARP1 and OCI-MY5 cells, and the effects of knockout valyl-tRNA synthetase (VARS) gene on proliferation and apoptosis of MM cells were detected by cell counting and flow cytometry, respectively. GEO data were divided into a high expression group and a low expression group according to the expression of VARS. Bioinformatics analysis was performed to explore the downstream pathways affected by VARS. Gas chromatography time-of-flight mass spectrometry (GC-TOF/MS) and high performance liquid chromatography (HPLC) were used to detect the valine content in CD138+ cells and ARP1, OCI-MY5 cells and supernatant of knockdown VARS gene in bone marrow samples from patients, respectively. RESULTS: Gene enrichment analysis showed that tRNA processing related genes were significantly enriched in MM compared with HD (P<0.0001). Further screening of tRNA processing-pathway related subsets revealed that cytoplasmic aminoacyl tRNA synthetase family genes were significantly enriched in MM (P<0.0001). The results of gene expression heat map showed that the ARS family genes except alanyl-tRNA synthetase (AARS), arginyl-tRNA synthetase (RARS), seryl-tRNA synthetase (SARS) in GEO data were highly expressed in MM (all P<0.01). With the development of monoclonal gammopathy of undetermined significance (MGUS) to MM, the gene expression level was increased gradually. Kaplan-Meier univariate analysis of survival results showed that there were significant differences in the prognosis of MM patients in methionyl-tRNA synthetase (MARS), asparaginyl-tRNA synthetase (NARS) and VARS between the high expression group and the low expression group (all P<0.05). Cox regression model multivariate analysis showed that the high expression of VARS was associated with abnormal overall survival time of MM (HR=1.83, 95% CI 1.10 to 3.06, P=0.021). The high expression of NARS (HR=0.90, 95% CI 0.34 to 2.38) and MARS (HR=1.59, 95% CI 0.73 to 3.50) had no effect on the overall survival time of MM patients (both P>0.05). Real-time RT-PCR and Western blotting showed that VARS, MARS and NARS were highly expressed in CD138+ MM cells and MM cell lines of clinical patients (all P<0.05). Cell counting and flow cytometry results showed that the proliferation of MM cells by knockout VARS was significantly inhibited (P<0.01), the proportion of apoptosis was significantly increased (P<0.05). Bioinformatics analysis showed that in addition to several pathways including the cell cycle regulated by VARS, the valine, leucine and isoleucine catabolic pathways were upregulated. Non-targeted metabolomics data showed reduced valine content in CD138+ tumor cells in MM patients compared to HD (P<0.05). HPLC results showed that compared with the scramble group, the intracellular and medium supernatant content of ARP1 cells and the medium supernatant of OCI-MY5 in the VARS-shRNA group was increased (all P<0.05). CONCLUSIONS: MM patients with abnormal high expression of VARS have a poor prognosis. VARS promotes the malignant growth of MM cells by affecting the regulation of valine metabolism.

Multimetallic nanoparticles decorated metal-organic framework for boosting peroxidase-like catalytic activity and its application in point-of-care testing.

Metal-organic frameworks (MOFs) are a sort of promising peroxidase-like nanozyme but face the challenge that the inorganic nodes in most of the MOF structures are generally blocked by the organic linkers. Further enhancement or activation of their peroxidase-like activity plays an important role in developing MOF-based nanozymes. Herein, a multimetallic nanoparticle (NP) decorated-MOF, Cu/Au/Pt NP decorated-Cu-TCPP(Fe) nanozyme (CuAuPt/Cu-TCPP(Fe)) was synthesized in situ and served as a peroxidase-like nanozyme. The peroxidase-like activity of this stable CuAuPt/Cu-TCPP(Fe) nanozyme was enhanced due to the decreased potential barriers for *OH generation in the catalytic process. Owing to the remarkable peroxidase-like activity, a CuAuPt/Cu-TCPP(Fe)-based colorimetric assay was established for the sensitive determination of H2O2 and glucose with the limit of detection (LOD) of 9.3 µM and 4.0 µM, respectively. In addition, a visual point-of-care testing (POCT) device was developed by integrating the CuAuPt/Cu-TCPP(Fe)-based test strips with a smartphone and was employed for a portable test of 20 clinical serum glucose samples. The results determined by this method agree well with the values deduced by clinical automatic biochemical analysis. This work not only represents an inspiration for the usage of MNP/MOF composite as a novel nanozyme for POCT diagnosis, but also provides a deeper insight and understanding into the enhanced enzyme-mimic effect of MNP-hybrid MOF composites, which in turn will guide the engineering of MOF-based functional nanomaterials. Graphical Abstract.

Dynamic changes of enhancer and super enhancer landscape in degenerated nucleus pulposus cells.

Inflammatory cascade and extracellular matrix remodeling have been identified as pivotal pathological factors in the progression of intervertebral disc degeneration (IDD), but the mechanisms underlying the aberrant activation of transcription during nucleus pulposus (NP) cell degeneration remain elusive. Super-enhancers (SEs) are large clusters of adjacent lone enhancers, which control expression modes of cellular fate and pathogenic genes. Here, we showed that SEs underwent tremendous remodeling during NP cell degeneration and that SE-related transcripts were most abundant in inflammatory cascade and extracellular matrix remodeling processes. Inhibition of cyclin-dependent kinase 7, a transcriptional kinase-mediated transcriptional initiation in trans-acting SE complex, constricted the transcription of inflammatory cascades, and extracellular matrix remodeling-related genes such as IL1ß and MMP3 in NP cells, meanwhile, also restrained the transcription of Mmp16, Tnfrsf21, and Il11ra1 to retard IDD in rats. In summary, our findings clarify SEs control the transcription of genes associated with inflammatory cascade and extracellular matrix remodeling during NP cell degeneration and identify inhibition of the cyclin-dependent kinase 7, required for SE-mediated transcriptional activation, as a therapeutic option for IDD.

Excessive serine from the bone marrow microenvironment impairs megakaryopoiesis and thrombopoiesis in Multiple Myeloma.

Thrombocytopenia is a major complication in a subset of patients with multiple myeloma (MM). However, little is known about its development and significance during MM. Here, we show thrombocytopenia is linked to poor prognosis in MM. In addition, we identify serine, which is released from MM cells into the bone marrow microenvironment, as a key metabolic factor that suppresses megakaryopoiesis and thrombopoiesis. The impact of excessive serine on thrombocytopenia is mainly mediated through the suppression of megakaryocyte (MK) differentiation. Extrinsic serine is transported into MKs through SLC38A1 and downregulates SVIL via SAM-mediated tri-methylation of H3K9, ultimately leading to the impairment of megakaryopoiesis. Inhibition of serine utilization or treatment with TPO enhances megakaryopoiesis and thrombopoiesis and suppresses MM progression. Together, we identify serine as a key metabolic regulator of thrombocytopenia, unveil molecular mechanisms governing MM progression, and provide potential therapeutic strategies for treating MM patients by targeting thrombocytopenia.

An autoimmune pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping.

Genetic sharing is extensively observed for autoimmune diseases, but the causal variants and their underlying molecular mechanisms remain largely unknown. Through systematic investigation of autoimmune disease pleiotropic loci, we found most of these shared genetic effects are transmitted from regulatory code. We used an evidence-based strategy to functionally prioritize causal pleiotropic variants and identify their target genes. A top-ranked pleiotropic variant, rs4728142, yielded many lines of evidence as being causal. Mechanistically, the rs4728142-containing region interacts with the IRF5 alternative promoter in an allele-specific manner and orchestrates its upstream enhancer to regulate IRF5 alternative promoter usage through chromatin looping. A putative structural regulator, ZBTB3, mediates the allele-specific loop to promote IRF5-short transcript expression at the rs4728142 risk allele, resulting in IRF5 overactivation and M1 macrophage polarization. Together, our findings establish a causal mechanism between the regulatory variant and fine-scale molecular phenotype underlying the dysfunction of pleiotropic genes in human autoimmunity.

Proline promotes proliferation and drug resistance of multiple myeloma by downregulation of proline dehydrogenase.

Amino acids in the bone marrow microenvironment (BMME) are a critical factor for multiple myeloma (MM) progression. Here, we have determined that proline is elevated in BMME of MM patients and links to poor prognosis in MM. Moreover, exogenous proline regulates MM cell proliferation and drug resistance. Elevated proline in BMME is due to bone collagen degradation and abnormal expression of the key enzyme of proline catabolism, proline dehydrogenase (PRODH). PRODH is downregulated in MM patients, mainly as a result of promoter hypermethylation with high expression of DNMT3b. Thus, overexpression of PRODH suppresses cell proliferation and drug resistance of MM and exhibits therapeutic potential for treatment of MM. Altogether, we identify proline as a key metabolic regulator of MM, unveil PRODH governing MM progression and provide a promising therapeutic strategy for MM treatment.

QTLbase2: an enhanced catalog of human quantitative trait loci on extensive molecular phenotypes.

Deciphering the fine-scale molecular mechanisms that shape the genetic effects at disease-associated loci from genome-wide association studies (GWAS) remains challenging. The key avenue is to identify the essential molecular phenotypes that mediate the causal variant and disease under particular biological conditions. Therefore, integrating GWAS signals with context-specific quantitative trait loci (QTLs) (such as different tissue/cell types, disease states, and perturbations) from extensive molecular phenotypes would present important strategies for full understanding of disease genetics. Via persistent curation and systematic data processing of large-scale human molecular trait QTLs (xQTLs), we updated our previous QTLbase database (now QTLbase2, http://mulinlab.org/qtlbase) to comprehensively analyze and visualize context-specific QTLs across 22 molecular phenotypes and over 95 tissue/cell types. Overall, the resource features the following major updates and novel functions: (i) 960 more genome-wide QTL summary statistics from 146 independent studies; (ii) new data for 10 previously uncompiled QTL types; (iii) variant query scope expanded to fit 195 QTL datasets based on whole-genome sequencing; (iv) supports filtering and comparison of QTLs for different biological conditions, such as stimulation types and disease states; (v) a new linkage disequilibrium viewer to facilitate variant prioritization across tissue/cell types and QTL types.

A validated UHPLC-MS/MS assay for rapid and sensitive determination of crisaborale in human plasma and its clinico-pharmacokinetic application.

Crisaborole ointment, 2%, is a non-steroidal, topical anti-inflammatory phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. To date, a specific analytic method of crisaborole in plasma has not been reported. The aim of this study was to develop a rapid, sensitive and robust UHPLC-MS/MS method for the quantitative detection of crisaborole in human plasma by using deuterated crisaborole-d4 as the internal standard (IS). The analyte was well extracted from human plasma with acetonitrile and subsequently eluted with gradient acetonitrile and water in short run time of 3.3 min. Negative electrospray ionization in multiple reaction monitoring mode was employed to acquire the quantification ion pairs of m/z 250.0→118.0 for crisaborole and m/z 254.0→121.9 for IS. The assay met the regulations of the US Food and Drug Administration and the European Medicines Agency for assay validation with a good linearity in the calibration range of 0.20-80 ng/mL. Intra-day and inter-day precision was less than 9.17% and the accuracy was - 2.29%-6.33% across all the quality control samples. The average extraction recovery of analyte and IS was 84.61% and 91.43%, respectively, and consistent over different quality control samples. The fully validated method was successfully used for the drug level measurement in ten healthy Chinese subjects receiving crisaborole ointment. Our novel UPLC-MS/MS assay for the quantification of plasma crisaborole concentrations in human samples may be easily used in clinical practice and help to reveal the pharmacokinetic profiles of crisaborole in Chinese population.

MC-LR Aggravates Liver Lipid Metabolism Disorders in Obese Mice Fed a High-Fat Diet via PI3K/AKT/mTOR/SREBP1 Signaling Pathway.

Obesity, a metabolic disease caused by excessive fat accumulation in the body, has attracted worldwide attention. Microcystin-LR (MC-LR) is a hepatotoxic cyanotoxin which has been reportedly to cause lipid metabolism disorder. In this study, C57BL/6J mice were fed a high-fat diet (HFD) for eight weeks to build obese an animal model, and subsequently, the obese mice were fed MC-LR for another eight weeks, and we aimed to determine how MC-LR exposure affects the liver lipid metabolism in high-fat-diet-induced obese mice. The results show that MC-LR increased the obese mice serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), indicating damaged liver function. The lipid parameters include serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and liver TG, which were all increased, whilst the high-density lipoprotein cholesterol (HDL-c) was decreased. Furthermore, after MC-LR treatment, histopathological observation revealed that the number of red lipid droplets increased, and that steatosis was more severe in the obese mice. In addition, the lipid synthesis-related genes were increased and the fatty acid ß-oxidation-related genes were decreased in the obese mice after MC-LR exposure. Meanwhile, the protein expression levels of phosphorylation phosphatidylinositol 3-kinase (p-PI3K), phosphorylation protein kinase B (p-AKT), phosphorylation mammalian target of rapamycin (p-mTOR), and sterol regulatory element binding protein 1c (SREBP1-c) were increased; similarly, the p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and SREBP1/ß-actin were significantly up-regulated in obese mice after being exposed to MC-LR, and the activated PI3K/AKT/mTOR/SREBP1 signaling pathway. In addition, MC-LR exposure reduced the activity of superoxide dismutase (SOD) and increased the level of malondialdehyde (MDA) in the obese mice's serum. In summary, the MC-LR could aggravate the HFD-induced obese mice liver lipid metabolism disorder by activating the PI3K/AKT/mTOR/SREBP1 signaling pathway to hepatocytes, increasing the SREBP1-c-regulated key enzymes for lipid synthesis, and blocking fatty acid ß-oxidation.

Development and structure-activity relationship of tacrine derivatives as highly potent CDK2/9 inhibitors for the treatment of cancer.

CDK2/9 are members of the CDKs family, which play key roles in the occurrence and development of many cancers by regulating cell cycle and transcriptional prolongation, respectively. To further optimize and discuss the structure-activity relationships (SARs), a series of tacrine-based compounds were designed and synthesized from the compound ZLWT-37, which was studied by our group previously but no detailed SARs study was conducted on CDK2/9. Among this series, compounds ZLMT-12 (35) exhibited the most potent antiproliferative activity (GI50 = 0.006 µM for HCT116) and superior CDK2/9 inhibitory properties (CDK2: IC50 = 0.011 µM, CDK9: IC50 = 0.002 µM). Meanwhile, ZLMT-12 showed a weak inhibitory effect on acetylcholinesterase (AChE, IC50 = 19.023 µM) and butyrylcholinesterase (BuChE, IC50 = 2.768 µM). In addition, ZLMT-12 can suppress colony formation and migration in HCT116 cells, as well as induce the apoptosis and arrest the cell cycle in the S phase and G2/M phase. In vivo investigations revealed that ZLMT-12 inhibits tumor growth in the HCT116 xenograft tumor model at a low dose of 10 mg/kg without causing hepatotoxicity. The acute toxicity test showed low toxicity with a median lethal dosage (LD50) of 104.417 mg/kg. These findings showed that ZLMT-12 might be used as a drug candidate by targeting CDK2/9.

Intestinal Klebsiella pneumoniae Contributes to Pneumonia by Synthesizing Glutamine in Multiple Myeloma.

Pneumonia accounts for a significant cause of morbidity and mortality in multiple myeloma (MM) patients. It has been previously shown that intestinal Klebsiella pneumonia (K. pneumonia) enriches in MM and promotes MM progression. However, what role the altered gut microbiota plays in MM with pneumonia remains unknown. Here, we show that intestinal K. pneumonia is significantly enriched in MM with pneumonia. This enriched intestinal K. pneumonia links to the incidence of pneumonia in MM, and intestinal colonization of K. pneumonia contributes to pneumonia in a 5TGM1 MM mice model. Further targeted metabolomic assays reveal the elevated level of glutamine, which is consistently increased with the enrichment of K. pneumonia in MM mice and patients, is synthesized by K. pneumonia, and leads to the elevated secretion of TNF-α in the lung normal fibroblast cells for the higher incidence of pneumonia. Inhibiting glutamine synthesis by establishing glnA-mutated K. pneumonia alleviates the incidence of pneumonia in the 5TGM1 MM mice model. Overall, our work proposes that intestinal K. pneumonia indirectly contributes to pneumonia in MM by synthesizing glutamine. Altogether, we unveil a gut-lung axis in MM with pneumonia and establish a novel mechanism and a possible intervention strategy for MM with pneumonia.