In order to achieve rapid proliferation and adapt to the complex microenvironment, tumor cells have dominant characteristics such as unique metabolic patterns and the ability to escape from immunoregulation. Tumor cells reprogram multiple metabolic pathways to promote immune escape, which impacts tumor diagnosis, treatment and prognosis. Based on the effect of metabolic changes on tumor immune escape and its molecular mechanism, metabolic regulation provides new approaches to enhance immunotherapy. We review recent advances in tumor immuno-escape and immunotherapy based on metabolic regulation. Cutting-edge analytical techniques and methods for tumor metabolism research such as metabolomics, mass spectrometry imaging-based spatially-resolved metabolomics and metabolic flow analysis are also discussed.

In recent years the role of sphingosine kinase 2 (SphK2), a key enzyme in the sphingolipid pathway, in the process of tumorigenesis has gradually been elucidated. Recent research has shown that SphK2 inhibitors can be used as anticancer drugs alone or in combination with existing drugs to increase the therapeutic sensitivity of drug-resistant tumors. Among them, one selective SphK2 inhibitor, ABC294640, shows excellent oral bioavailability and biodistribution in vivo and has now entered Phase Ⅱ clinical research. Therefore, developing innovative drugs based on SphK2 is of great interest. Herein, we discuss progress in understanding the role of SphK2 in tumorigenesis and review the recent development of inhibitors of SphK2.

This research explored the synergistic effects and the mechanism of parthenolide (PTL) and vorinostat (suberoylanilide hydroxamic acid, SAHA) on the proliferation of A549 non-small cell lung cancer cells. The combination effect of PTL and SAHA was detected by cell counting kit-8 (CCK-8) and colony formation assays. Scratch test was performed to detect cell migration. Annexin V-fluorescein isothiocyanate isomer/propidium iodide (FITC/PI) flow cytometry and Western blot analyses were used to determine cell apoptosis and its mechanism. The results showed that combination of PTL and SAHA inhibited the proliferation and migration of A549 with a synergistic effect compared to the single-drug groups. The combination of PTL and SAHA had synergistic effect to induce cell apoptosis by regulating p53 and c-myc pathways, and affected the expression levels of poly ADP-ribose polymerase (PARP), cysteinyl aspartate specific proteinase (caspase)-9, and caspase-3. Taken together, this study shows that combination of PTL and SAHA has synergistic effect, induces cell apoptosis and inhibits A549 proliferation, which is likely to be a novel strategy for the treatment of non-small cell lung cancer.

New candidate targets, biological mechanisms as well as small-molecules are significant factors in the research and development of first-in-class drugs, which is a challenging process with a large amount of time and money devoted as well as high risks. A successful first-in-class drug can not only become a new strategy for disease treatment but can also offer innovative research ideas for the design of drugs. The Food and Drug Administration (FDA) approved 48 new drugs to the market in 2019, among which small-molecule drugs still predominated, containing several first-in-class drugs. Brexanolone, for example, is the first positive modulator of GABA_A receptor for the treatment of postpartum depression; Selinexor is the first small-molecule drug to treat recurrent refractory multiple myeloma by inhibiting exportin (XPO1); Tenapanor is the first sodium/proton exchanger type 3 (NHE3) inhibitor that can treat irritable bowel syndrome; Lasmiditan is the first approved agonist with selectivity for 5-HT_1F, treating migraines. The research and development processes of the first-in-class drugs mentioned above are distinctive from each other with uniqueness and innovation. In this review, we briefly analyze the background and process of the research and development of three typical cases as well as their therapeutic applications in an attempt to offer some help for the future development of first-in-class drugs.

Glucagon-like peptide-1 (GLP-1) could increase the level of cyclic adenosine monophosphate (cAMP) in cells to stimulate insulin secretion in β cells of pancreas. So GLP-1 analogues, such as liraglutide, have become new anti-hyperglycemia drugs for type 2 diabetes. In this study, a set of in vitro activity detection method suitable for GLP-1 analogues was established using GLP-1R-GFP (green fluorescent protein, GFP)-HEK293A cells which stably expressing GLP-1 receptor (GLP-1R). After optimizing the detection parameters such as assay sensitivity, cell density, and the incubation condition, the cAMP content level of GLP-1R-GFP-HEK293A cells stimulated by four GLP-1 analogues, such as liraglutide, were detected by homogeneous time-resolved fluorescence (HTRF). The values of concentration for 50% of maximal effect (EC₅₀) of GLP-1 analogues were calculated by cAMP dose-response curve to evaluate the in vitro activity of those drugs. In addition, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction were applied to determine the content of host cell protein and host residual DNA, respectively. This study provides a stable, reliable, and sensitive in vitro activity analysis and host impurity detection method for high-throughput screening of GLP-1 analogues.

The chemical structures of new components of Epimedium were deduced and verified by combining the secondary metabolism of Epimedium flavonoids with high resolution mass spectrometry. Based on the literature of Epimedium chemistry, the biosynthesis pathway of Yinyanghuo was constructed, and the possible metabolites were deduced. This metabolite information was entered into the PeakView software program and the ions meeting the quality error of less than 5 ppm with correct isotope distribution and containing secondary fragments were taken as the target compounds. Through the use of the software Formula Finder, Mass Calculators, online database (ChemSpider, Metlin, HMDB, etc.) and the fragmentation law of secondary fragments, the chemical structures of 22 metabolites were determined. One new component and eight new compounds were identified in 54 batches of Epimedium samples from 15 varieties by high resolution mass spectrometry. This study avoids the long time and tedious steps of phytochemical separation, saves experimental costs, and provides a new method for the analysis and identification of secondary metabolites with pharmacodynamic activity.

Tanshinones and salvianolic acids are important materials in the treatment of coronary heart disease, myocardial infarction, hypertension, hyperlipidemia, stroke and others illnesses. In recent years, with the development of genomics, transcriptome, metabolomics and bioinformatics, many advances have been made in the biosynthesis and transcriptional regulation of tanshinones and salvianolic acids. This paper summarizes these advances and suggests further study on the downstream synthesis pathways and transcriptional regulatory mechanisms to reveal new molecular mechanism of synthesis, transport, regulation and modification. Additionally, we discuss the design and construction of new biological pathways to increase the expression of biosynthesis genes and the production of secondary components, is a newly developing research field.

In recent years therapeutic proteins products including therapeutic antibodies have become a major driving force for the modern biopharmaceutical industry. However, they have complex product quality attributes (PQAs) which limit product development and quality control (QC). Recent advances in high resolution mass spectrometry (MS) have led to the use of an MS-based multi-attribute method (MAM) for quality control testing of therapeutic proteins, which allows for direct measurement of multiple PQAs and identification of impurities. MAM helps to promote the improvement of product quality and QC and a reduction in manufacturing cost. To explore the application of MAM in QC, we discuss generic MAM workflow, the current state of MAM application in product development and QC, identify points to consider for use of MAM as a QC test, and summarize MAM's advantages and challenges in this article. The future application of MAM for therapeutic antibodies and the opportunities for its further development, use, and substitution for conventional methods is presented.

Gut microbiota dysbiosis is closely related to a variety of host diseases. Recently, targeting the metabolic pathways of gut microbiota for the prevention and treatment of host diseases has become a frontier strategy and research hotspot. Inflammatory bowel disease (IBD) is a group of chronic progressive intestinal inflammatory diseases of unknown etiology. The relationship between IBD and gut microbiota disorders and bacterial respiratory/energy metabolism has been confirmed in recent research. This article will introduce the relationship among them, and propose a new treatment strategy to alleviate host gut inflammation by regulating gut microbiota respiration and energy metabolism based on the latest research progress. In the progression of IBD, the gut microbiota homeostasis is disturbed. The main reasons include two aspects:on the one hand, when the intestinal inflammation of the host occurs, with increasing of oxygen concentration in the intestinal cavity, facultative anaerobic bacteria, especially Enterobacteriaceae bacteria would proliferate abnormally; while the growth of absolute anaerobic bacteria such as Firmicutes is inhibited. On the other hand, intestinal inflammation by-products also support the expansion of facultative anaerobic bacteria, which ultimately exacerbates the imbalance of gut microbiota. Dysregulated intestinal flora will further disturb intestinal immune homeostasis and exacerbate intestinal inflammation. The latest research proposed the possibility that IBD can be alleviated by interfering with the respiration of bacteria, inhibiting the abnormal proliferation of bacteria, or increasing the level of "beneficial" metabolites of gut microbiota. The above studies suggest that alleviating host intestinal inflammation can be explored by focusing on the metabolic pathways of gut microbiota and regulating the intestinal bacterial respiration and energy metabolism, which is of great significance for the clinical treatment of IBD and the research of innovative drugs.

The protective effects of cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MPTP), on vascular permeability in sepsis rats were investigated. Cecal ligation and puncture (CLP)-induced sepsis rats were used for in vivo studies, and the effects of CsA (1 and 5 mg·kg^-1) on vascular permeability of lung, kidney, and intestine, mitochondrial respiratory control ratio, and the survival of the sepsis rats were observed. Lipopolysaccharide (LPS) was used for stimulating vascular endothelial cells (VECs) in vitro, and the effects of CsA on leakage of microvascular, immunofluorescence of zonula occludes-1 (ZO-1), and transendothelial electrical resistance (TER) were observed. All the animal welfare and experimental procedures are in accordance with the regulations of the Animal Ethics Committee of the Army Medical University. Compared with sham-operated group, the vascular permeability of lung, kidney, and intestine in sepsis rats increased significantly (P < 0.05). Compared with conventional treatment group, CsA could significantly decrease the vascular permeability of lung, kidney, and intestine (P < 0.05 or P < 0.01), and prolong the survival period. The results of microcirculation also showed that CsA could significantly reduce the permeability of mesenteric venules in sepsis rats. At the cellular level, LPS stimulation significantly increased the permeability of vascular endothelial cells, including the decrease of transmembrane resistance and protein expression of ZO-1 (P < 0.05). CsA can significantly reduce the increase of permeability of vascular endothelial cells induced by LPS stimulation (P < 0.01). The function of mitochondria in the kidneys and intestines of sepsis rats was obviously impaired, and the respiratory control ratio of mitochondria was decreased. LPS significantly increased MPTP opening of VECs, while CsA significantly inhibited MPTP opening and improved mitochondrial function. CsA may protect mitochondrial function by inhibiting the opening of MPTP and play a protective role in the vascular permeability of sepsis rats. This study will provide an insight for the treatment of sepsis vascular leakage.