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Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and economic burden. Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics (PK) and pharmacodynamics (PD), genetic diversity explains only a limited proportion of IVDR. The role of gut microbiota, also known as the second genome, and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies. Consequently, the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs. This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases, including cancer, cardiovascular diseases (CVDs), endocrine diseases, and others. We summarise how microbiota, directly and indirectly, modify the absorption, distribution, metabolism, and excretion (ADME) of drugs. Conversely, drugs can also modulate the composition and function of gut microbiota, leading to changes in microbial metabolism and immune response. We also discuss the practical challenges, strategies, and opportunities in this field, emphasizing the critical need to develop an innovative approach to multi-omics, integrate various data types, including human and microbiota genomic data, as well as translate lab data into clinical practice. To sum up, pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes, and further research in this field is imperative to unlock its full potential for precision medicine.

Aiming at the problems of low efficiency and high cost in determining the phenotypic parameters of Cymbidium seedlings by artificial approaches, this study proposed a fully automated measurement scheme for some phenotypic parameters based on point cloud. The key point or difficulty is to design a segmentation method for individual tillers according to the morphology-specific structure. After determining the branch points, two rounds of segmentation schemes were designed. The non-overlapping part of each tiller and the overlapping parts of each ramet are separated in the first round based on the edge point cloud-based segmentation, while in the second round, the overlapping part was sliced along the horizontal direction according to the weight ratio of the tillers above, to obtain the complete point cloud of all tillers. The core superiority of the algorithm is that the segmentation fits the tiller growth direction well, and the extracted skeleton points of tillers are close to the actual growth direction, significantly improving the prediction accuracy of the subsequent phenotypic parameters. Five phenotypic parameters, plant height, leaf number, leaf length, leaf width and leaf area, were automatically calculated. Through experiments, the accuracy of the five parameters reached 98.6%, 100%, 92.2%, 89.1%, and 82.3%, respectively, which reach the needs of various phenotypic applications.

Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), are involved in mediating fundamental innate antimicrobial immunity by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. Accumulating evidence suggests that the activation of the cGAS-STING axis is critical for antitumor immunity. The downstream cytokines regulated by cGAS-STING, especially type I IFNs, serve as bridges connecting innate immunity with adaptive immunity. Accordingly, a growing number of studies have focused on the synthesis and screening of STING pathway agonists. However, chronic STING activation may lead to a protumor phenotype in certain malignancies. Hence, the cGAS-STING signaling pathway must be orchestrated properly when STING agonists are used alone or in combination. In this review, we discuss the dichotomous roles of the cGAS-STING pathway in tumor development and the latest advances in the use of STING agonists.

Background This study explored the diagnostic power of preoperative circulating tumor cells (CTCs) for the presence of microvascular invasion (MVI) and the relationship between dynamic changes in postoperative CTCs and prognosis. Methods A total of 137 patients were recruited for the study. Preoperative blood samples were collected from all patients to detect CTCs. The time points for blood collection were before the operation, during the operation, and at 1 week, 1 month, 2 months, 3 months, 6 months, and 1 year after surgery. The predictive power of CTC count for the presence of MVI was analyzed by receiver operating characteristic (ROC) curve analysis. According to recurrence status, 137 patients were divided into three groups: no recurrence, early recurrence, and non-early recurrence groups. Results A threshold CTC count of 5 showed the most significant power for predicting the existence of MVI. In multivariate analysis, the parameters of preoperative CTC count, alpha-fetoprotein (AFP) and tumor diameter were independent predictors of MVI ( P  <  0.05). A CTC count greater than or equal to 5 had better predictive value than AFP > 400 μg/L and tumor diameter > 5 cm. The number of intraoperative CTCs in the three groups did not increase compared to that before surgery ( P  > 0.05). The number of CTCs in the nonrecurrence group and the non-early recurrence group decreased significantly 1 week after surgery compared with the intraoperative values ( P  <  0.001), although there was no significant difference in the early recurrence group ( P  = 0.95). Patients with mean CTC count ≥5 had significantly worse long-term outcomes than those with mean CTC count < 5 ( P  <  0.001). Conclusion The preoperative CTC counts in the peripheral blood of patients with HCC are closely correlated with MVI. The intraoperative manipulation of the lesion by the surgeon does not increase the number of CTCs in peripheral blood. Surgical removal of the tumor decreases the number of CTCs. The persistence of CTCs at a high level (≥ 5) after surgery suggests a risk of early recurrence. Clinical trial registration Registration number is ChiCTR-OOC-16010183 , date of registration is 2016-12-18.

Proinsulin translation and folding is crucial for glucose homeostasis. However, islet β-cell control of Proinsulin translation remains incompletely understood. Here, we identify OSGEP, an enzyme responsible for t 6 A 37 modification of tRNA NNU that tunes glucose metabolism in β-cells. Global Osgep deletion causes glucose intolerance, while β-cell-specific deletion induces hyperglycemia and glucose intolerance due to impaired insulin activity. Transcriptomics and proteomics reveal activation of the unfolded protein response (UPR) and apoptosis signaling pathways in Osgep-deficient islets, linked to an increase in misfolded Proinsulin from reduced t 6 A 37 modification. Osgep overexpression in pancreas rescues insulin secretion and mitigates diabetes in high-fat diet mice. Osgep enhances translational fidelity and alleviates UPR signaling, highlighting its potential as a therapeutic target for diabetes. Individuals carrying the C allele at rs74512655, which promotes OSGEP transcription, may show reduced susceptibility to T2DM. These findings show OSGEP is essential for islet β-cells and a potential diabetes therapy target. Pancreatic islet β cells produce insulin, so their protein quality control mechanisms are critical for human health. Here, the authors show that loss of OSGEP, an enzyme known to add the t6A modification on tRNA, disrupts proinsulin translation and causes ER stress in β cells.

Background Hepatocellular carcinoma (HCC), derived from hepatocytes, is the main histological subtype of primary liver cancer and poses a serious threat to human health due to the high incidence and poor prognosis . This study aimed to establish a multigene prognostic model to predict the prognosis of patients with HCC. Results Gene expression datasets (GSE121248, GSE40873, GSE62232) were used to identify differentially expressed genes (DEGs) between tumor and adjacent or normal tissues, and then hub genes were screened by protein–protein interaction (PPI) network and Cytoscape software. Seventeen genes among hub genes were significantly associated with prognosis and used to construct a prognostic model through COX hazard regression analysis. The predictive performance of this model was evaluated with TCGA data and was further validated with independent dataset GSE14520. Six genes ( CDKN3, ZWINT, KIF20A, NUSAP1, HMMR, DLGAP5 ) were involved in the prognostic model, which separated HCC patients from TCGA dataset into high- and low-risk groups. Kaplan–Meier (KM) survival analysis and risk score analysis demonstrated that low-risk group represented a survival advantage. Univariate and multivariate regression analysis showed risk score could be an independent prognostic factor. The receiver operating characteristic (ROC) curve showed there was a better predictive power of the risk score than that of other clinical indicators. At last, the results from GSE14520 demonstrated the reliability of this prognostic model in some extent. Conclusion This prognostic model represented significance for prognosis of HCC, and the risk score according to this model may be a better prognostic factor than other traditional clinical indicators.

RationaleSecond-generation antipsychotics are the first-line medications prescribed for schizophrenic patients; however, some of them, such as olanzapine and risperidone, may induce metabolic dysfunctions during short-term treatment. Metformin is an effective adjuvant that attenuates antipsychotic-induced metabolic dysfunctions (AIMD) in clinical practice. Whether metformin can reverse AIMD and whether metformin affects the therapeutic effects of antipsychotics in animal models of schizophrenia are questions that still need to be investigated.MethodsIn this study, an animal model of schizophrenia was established by consecutive injections of MK801 during the neurodevelopmental period. In adulthood, different dosages of olanzapine or risperidone treatment were administered to the schizophrenia model animals for 14 days. Both therapeutic effects and metabolic adverse effects were measured by behavioral tests, histopathological tests, and biochemical tests. The coadministration of different doses of metformin with olanzapine or risperidone was used to evaluate the effects of metformin on both AIMD and the therapeutic effect of those antipsychotics.ResultsThe MK801-treated rats showed schizophrenia-like behavior and variations in the shape and volume of the hippocampus. Both olanzapine and risperidone reversed the MK801-induced behavioral abnormalities as the dosage increased; however, they degenerated the hepatocytes in the liver and influenced the blood lipid levels and blood glucose levels. The coadministration of metformin did not affect the therapeutic effects of olanzapine or risperidone on behavioral abnormalities but attenuated the metabolic dysfunctions induced by those antipsychotics.ConclusionMetformin attenuated the olanzapine- and risperidone-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats without reducing the therapeutic effects of the antipsychotics.

Cancer stem cells (CSCs) are a major cause of tumor treatment resistance, relapse and metastasis. Cancer cells exhibit reprogrammed metabolism characterized by aerobic glycolysis, which is also critical for sustaining cancer stemness. However, regulation of cancer cell metabolism rewiring and stemness is not completely understood. Here, we report that ETV4 is a key transcription factor in regulating glycolytic gene expression. ETV4 loss significantly inhibits the expression of HK2, LDHA as well as other glycolytic enzymes, reduces glucose uptake and lactate release in breast cancer cells. In human breast cancer and hepatocellular carcinoma tissues, ETV4 expression is positively correlated with glycolytic signaling. Moreover, we confirm that breast CSCs (BCSCs) are glycolysis-dependent and show that ETV4 is required for BCSC maintenance. ETV4 is enriched in BCSCs, its knockdown and overexpression suppresses and promotes breast cancer cell stem-like traits, respectively. Mechanistically, on the one hand, we find that ETV4 may enhance glycolysis activity to facilitate breast cancer stemness; on the other, ETV4 activates Sonic Hedgehog signaling by transcriptionally promoting CXCR4 expression. A xenograft assay validates the tumor growth-impeding effect and inhibition of CXCR4/SHH/GLI1 signaling cascade after ETV4 depletion. Together, our study highlights the potential roles of ETV4 in promoting cancer cell glycolytic shift and BCSC maintenance and reveals the molecular basis.

Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including the Notch1 pathway in HCC. In this study, we found that Notch1 was highly expressed in HCC, especially in large HCCs. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 cells than that in HepG2 cells. HBx activated the Notch1 pathway in HepG2.2.15 cells. Suppression of HBx and the Notch1 pathway attenuated the growth of HepG2.2.15 cells. Notch1, ERK, and AKT pathways were inhibited after γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were upregulated after γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 suppressed the promoters of DUSP1 and PTEN genes, which was reversed by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we found a link among HBx, the Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC treatment.

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy mainly due to its extensive metastasis. Cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3), a newly discovered splice variant of solute carrier organic anion transporter family member 1B3 (SLCO1B3) , has been reported to be overexpressed in several types of cancer. However, the biological function of Ct-OATP1B3 remains largely unknown. Here, we reveal that Ct-OATP1B3 is overexpressed in HGSOC and promotes the metastasis of HGSOC in vivo and in vitro. Mechanically, Ct-OATP1B3 directly interacts with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an RNA-binding protein, which results in enhancement of the mRNA stability and expression of carnitine palmitoyltransferase 1A (CPT1A) and NADH:Ubiquinone Oxidoreductase Subunit A2 (NDUFA2), leading to increased mitochondrial fatty acid beta-oxidation (FAO) and oxidative phosphorylation (OXPHOS) activities. The increased FAO and OXPHOS activities further facilitate adenosine triphosphate (ATP) production and cellular lamellipodia formation, which is the initial step in the processes of tumor cell migration and invasion. Taken together, our study provides an insight into the function and underlying mechanism of Ct-OATP1B3 in HGSOC metastasis, and highlights Ct-OATP1B3 as a novel prognostic marker as well as therapeutic target in HGSOC.