Latest ArticlesBerberine is a naturally occurring benzylisoquinoline alkaloid with a wide range of pharmacological activities, such as antibacterial, anticancer, hypolipidemic, antidiabetic and antidiarrheal. Although berberine has a wide range of curative effects, the extremely low bioavailability (< 1%) limits its clinical application. Pure berberine preparations have not yet been approved for any specific disease. The low oral bioavailability of berberine is mainly due to poor solubility caused by self-aggregation under acidic conditions, low permeability, P-glycoprotein (P-gp)-mediated efflux, and liver and intestine metabolism. To improve the oral bioavailability of berberine, researchers have adopted a variety of strategies, including the application of various nano-delivery systems, penetration enhancers and P-gp inhibitors, structural modifications, and development of berberine derivatives. Improving the oral bioavailability of berberine can improve the pharmacological activity of berberine, reduce the dosage, and then reduce the toxic and side effects. This review summarized the various pharmacological activities, metabolism progress and pharmacokinetic characteristics of berberine, the newly discovered berberine target intestinal microbiota and focused on the strategies to improve the oral bioavailability of berberine by improving solubility and permeability, inhibiting P-gp efflux, and structural modification. The research on berberine was prospected, which provided guidance for the in-depth study of berberine.
Colorectal cancer is a common malignant tumor of digestive tract, and the risk of inflammatory bowel disease developing into colorectal cancer is significantly increased. Immune signaling pathways NF-κB, IL-6/STAT3, COX-2/PGE2, IL-23/Th17 and TLRs have been confirmed to promote the transformation from colitis to colorectal cancer. NOD2 and intestinal microbes also participate in the regulation of inflammation mediated carcinogenesis. Chronic inflammation is a potential risk for colorectal cancer, and anti-inflammatory drugs may play a chemical preventive role. In this review, we summarize the signaling pathways involved in inflammation-associated colon carcinogenesis and evaluate the chemoprophylaxis of colon cancer.
Inflammatory bowel disease (IBD) is a chronic, repeated intestinal inflammatory disease. Clinically commonly used therapeutic drugs have some disadvantages, such as poor efficacy and many adverse reactions after long-term application. Although new biological therapies such as anti-tumor necrosis factor agents, overcome common adverse reactions, also have problems such as high price, difficult storage, drug resistance and recurrence after application. In recent years, many new therapeutic methods for inflammatory bowel disease have emerged, for example, modulators that inhibit lymphocyte migration (integrin inhibitors and sphingosine 1-phosphate receptor agonists) have been introduced into the clinical treatment of inflammatory bowel disease, inflammatory cytokine inhibitors (interleukin-23 inhibitors, Janus kinase inhibitors, phosphodiesterase inhibitors, etc.) and inhibitors targeting fibrosis and intestinal tissue degradation and remodeling (matrix metalloproteinase inhibitors) are also being evaluated in clinical trials of IBD. Based on the mechanisms of action, this paper intends to outline the current mainstream IBD therapies and some emerging drugs, and briefly introduce their targets to provide reference for IBD drug design and development.
Virus infection is a serious threat to human health and social development. The increase in pandemics caused by emerging and re-emerging viruses highlights the urgent need for broad-spectrum antivirals. In this perspective, we highlight recent case studies and summarize the universal strategies and methodologies in broad-spectrum antiviral drug discovery from common targets, common steps in viral life cycle, universal strategies, and broad-spectrum molecules, hoping to provide valuable guidance for the current and future development of antiviral drugs.
As one of the most serious hereditary neuromuscular disease, spinal muscular atrophy (SMA) is caused by the loss or mutation of survival motor neuron 1 (SMN1) gene. It leads to a decrease in the level of SMN protein and a consequent loss of alpha neurons and progressive muscle atrophy resulting in the progressive muscle weakness, the significant disability and the shortened lifespan. Up till now, only three drugs have been approved for SMA, including the gene therapy drug onasemnogene abeparvovec. The antisense oligonucleotide drug nusinersen and and the small molecule chemical drug risdiplam were briefly introduced. Some representative samples of the small molecule chemical drugs and antisense oligonucleotide drugs targeting SMN2 in the clinical trial or preclinical research phases were also reviewed.
The amorphous solid dispersion is one of the most effective formulation approaches to enhance the oral bioavailability of poorly water-soluble drugs. However, the amorphous drugs tend to crystallize during storage or dissolution due to inadequate formulations, preparation techniques, storage and dissolution conditions, thus negating their advantages. Meanwhile, it is often difficult to establish in vitro-in vivo correlation for amorphous solid dispersions owing to the difference between dissolution media and physiological environments and between the apparent concentration and membrane transport flux, the dynamic process of the in vivo absorption, which put great challenges to the development of amorphous solid dispersion products. This review covers the recent progress on the mechanistic study of the in vitro dissolution and in vivo absorption of amorphous solid dispersions, aiming to provide guidance for the formulation development of poorly soluble drugs.
Flavonoids is one of the biggest families of the plant-derived secondary metabolites with structural diversity. Until now, over 10 000 kinds of flavonoids with distinct structures have been purified and identified from plants, and some of them possess a range of important pharmacological effects, such as anticancer, anti-inflammatory and so on. So far, a number of genes and enzymes responsible for the biosynthesis of flavonoids have been reported, especially, a great of progress has been achieved in the synthetic biology of flavonoids in the recent years. Herein, based upon a brief introduction on the biosynthesis of flavonoids, this review summarizes the research advances in synthetic biology of flavonoids in the past two decades (2001-2021), highlighting the cell factories construction of the representative flavonoids. And, a brief discussion and prospects of the relevant metabolic bottlenecks and optimizing strategies are proposed.
Preliminary research in our laboratory found that compound YZG-330 can reduce mouse body temperature, which could be blocked by adenosine A1 receptor (A1R) antagonist DPCPX. Based on the downstream signaling pathway of the A1R, the mechanism by which YZG-330 lowers body temperature was further studied. The pharmacodynamics of YZG-330 was evaluated by measuring the rectal temperature; expression of the transient receptor potential (TRP) ion channel, the P38 protein and its phosphorylated form in mouse hypothalamic homogenate were detected by Western blotting. A Ca2+ fluorescent probe, Fluo-3AM, was added to cells to detect the effect of YZG-330 on the Ca2+ content of mouse hypothalamic cells. YZG-330 dose-dependently reduced the body temperature in mice, and the selective P38 inhibitor SB-203580 (20 mg·kg-1, i.p.) significantly inhibited the hypothermic effect of YZG-330. A TRPM8 antagonist 2 (0.1 μg per mouse, i.c.v.) markedly attenuated the hypothermic effect of YZG-330 (0.25 or 1 mg·kg-1, i.p.). YZG-330 (2 mg·kg-1, i.p.) significantly increased the phosphorylation of P38, an effect that could be attenuated by the A1R antagonist DPCPX (5 mg·kg-1, i.g.) in mouse hypothalamus. In addition, YZG-330 also prominently enhanced the expression of TRPM8, which could be blocked by SB-203580; YZG-330 (0.1-10 μmol·L-1) increased intracellular Ca2+ concetration in mouse hypothalamic cells in a dose-dependent manner, and was inhibited by the A1R inhibitor DPCPX (0.5 and 1 μmol·L-1) and TRPM8 antagonist 2 (1 μmol·L-1). In conclusion, YZG-330 exerts its hypothermic effect by activating the A1R to promote the phosphorylation of P38 protein and thereby up-regulating the expression and activity of the TRPM8 ion channel, resulting in increased intracellular Ca2+ concentration to stimulate mouse hypothalamus cells to down-regulate body temperature. All animal experiments were approved by the Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences.
Hepatocellular carcinoma (HCC) is a common malignant tumor worldwise. The incidence rate of HCC is high and is easy to metastasis and recurrence, which seriously affects human health. Traditional chemical drugs have some challenges such as toxicity, side effects, and multidrug resistance, thus it is urgent to find new drugs and effective targets. Here we synthesized a novel chemical, protonic bis-phenanthroline (H-BP), and the antitumor effect was investigated in the study. The results showed that H-BP could selectively inhibit the proliferation of tumor cells and cause HCC apoptosis. And also, in HCC tumor-bearing mice, H-BP could effectively prevent the growth of tumor mass, even completely eliminate the tumor at medium dose (5 mg·kg-1) and high dose (10 mg·kg-1), and meanwhile H-BP has no significant effect on the body weight of mice. The experimental protocol was approved by the Animal Ethics Committee of Southwest University, and the experimental operation was strictly carried out in accordance with the ethical principles of animal use and care. Mechanism studies showed that H-BP induced HCC apoptosis was related to down-regulation the expression of pleomorphic adenoma gene like-2 (PLAGL2), a oncogene transcription factor, resulting in the down-regulation of PLAGL2 downstream proteins hypoxia inducible factor and β-catenin. This study not only introduces the dimerization method to form novel compounds that will provide a new approach for drug design, but also suggests that PLAGL2 may be an effective target in tumor therapy.
This study investigated the effect of puerarin on human umbilical vein endothelial cells (HUVEC) injured with hydrogen peroxide (H2O2). HUVEC were divided into three groups: a control group, a model group (H2O2 400 μmol·L-1) and a puerarin-treated group (3, 10, 30 and 100 μmol·L-1). HUVEC were cultured with varied concentration of puerarin for 2 h and treated with H2O2 for another 24 h. Cell proliferation was detected by a CCK-8 assay. The mitochondrial membrane potential was measured by a JC-1 fluorescent probe. A transwell chamber assay was adopted to observe cell migration ability. Mitochondrial respiratory function was measured in a two-chamber titration injection respirometer (Oxygraph-2k). The expression of interleukin-1β (IL-1β), interleukin-18 (IL-18) and tumor necrosis factor-α (TNF-α) was detected by quantitative real-time PCR. The expression of pyroptosis-mediated proteins, including cleaved-cysteinyl aspartate-specific proteinase-1 (caspase-1), N-gasdermin D (N-GSDMD), NOD-like receptor protein 3 (NLRP3) and purinergic ligand-gated ion channel 7 receptor (P2X7R) was detected by Western blot. The results show that 400 μmol·L-1 H2O2 treatment for 24 h causes obvious damage to HUVEC. Compared with the model group, puerarin protected against cellular injury in a dose-dependent manner, with the greatest effect at a dose of 30 and 100 μmol·L-1. Puerarin significantly decreased the mitochondrial membrane potential and improved mitochondrial function. Puerarin inhibited cell migration induced by H2O2, suppressed the expression of IL-1β, IL-18 and TNF-α, and down-regulated the pyroptosis-mediated protein. These changes are statistically significant (P < 0.05). These findings demonstrate that puerarin has a protective effect against H2O2-induced oxidative damage of HUVEC by inhibiting the migration of HUVEC cells. The mechanism may be related to improved mitochondrial respiratory function and inhibition of pyroptosis.
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