A promising therapy for fatty liver disease: PCSK9 inhibitors.

BACKGROUND: Fatty liver disease (FLD) poses a significant global health concern worldwide, with its classification into nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) contingent upon the presence or absence of chronic and excessive alcohol consumption. The absence of specific therapeutic interventions tailored to FLD at various stages of the disease renders its treatment exceptionally arduous. Despite the fact that FLD and hyperlipidemia are intimately associated, there is still debate over how lipid-lowering medications affect FLD. Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) is a serine protease predominantly synthesized in the liver, which has a crucial impact on cholesterol homeostasis. Research has confirmed that PCSK9 inhibitors have prominent lipid-lowering properties and substantial clinical effectiveness, thereby justifying the need for additional exploration of their potential role in FLD. PURPOSE: Through a comprehensive literature search, this review is to identify the relationship and related mechanisms between PCSK9, lipid metabolism and FLD. Additionally, it will assess the pharmacological mechanism and applicability of PCSK9 inhibitors (including naturally occurring PCSK9 inhibitors, such as conventional herbal medicines) for the treatment of FLD and serve as a guide for updating the treatment protocol for such conditions. METHODS: A comprehensive literature search was conducted using several electronic databases, including Pubmed, Medline, Embase, CNKI, Wanfang database and ClinicalTrials.gov, from the inception of the database to 30 Jan 2024. Key words used in the literature search were "fatty liver", "hepatic steatosis", "PCSK9", "traditional Chinese medicine", "herb medicine", "botanical medicine", "clinical trial", "vivo", "vitro", linked with AND/OR. Most of the included studies were within five years. RESULTS: PCSK9 participates in the regulation of circulating lipids via both LDLR dependent and independent pathways, and there is a potential association with de novo lipogenesis. Major clinical studies have demonstrated a positive correlation between circulating PCSK9 levels and the severity of NAFLD, with elevated levels of circulating PCSK9 observed in individuals exposed to chronic alcohol. Numerous studies have demonstrated the potential of PCSK9 inhibitors to ameliorate non-alcoholic steatohepatitis (NASH), potentially completely alleviate liver steatosis, and diminish liver impairment. In animal experiments, PCSK9 inhibitors have exhibited efficacy in alleviating alcoholic induced liver lipid accumulation and hepatitis. Traditional Chinese medicine such as berberine, curcumin, resveratrol, piceatannol, sauchinone, lupin, quercetin, salidroside, ginkgolide, tanshinone, lunasin, Capsella bursa-pastoris, gypenosides, and Morus alba leaves are the main natural PCS9 inhibitors. Excitingly, by inhibiting transcription, reducing secretion, direct targeting and other pathways, traditional Chinese medicine exert inhibitory effects on PCSK9, thereby exerting potential FLD therapeutic effects. CONCLUSION: PCSK9 plays an important role in the development of FLD, and PCSK9 inhibitors have demonstrated beneficial effects on lipid regulation and FLD in both preclinical and clinical studies. In addition, some traditional Chinese medicines have improved the disease progression of FLD by inhibiting PCSK9 and anti-inflammatory and antioxidant effects. Consequently, the inhibition of PCSK9 appears to be a promising therapeutic strategy for FLD.

Ganoderma lucidum: Current advancements of characteristic components and experimental progress in anti-liver fibrosis.

Ganoderma lucidum (G. lucidum, Lingzhi) is a well-known herbal medicine with a variety of pharmacological effects. Studies have found that G. lucidum has pharmacological effects such as antioxidant, antitumor, anti-aging, anti-liver fibrosis, and immunomodulation. The main active components of G. lucidum include triterpenoids, polysaccharides, sterols, peptides and other bioactive components. Among them, the triterpenoids and polysaccharide components of G. lucidum have a wide range of anti-liver fibrotic effects. Currently, there have been more reviews and studies on the antioxidant, antitumor, and anti-aging properties of G. lucidum. Based on the current trend of increasing number of liver fibrosis patients in the world, we summarized the role of G.lucidum extract in anti-liver fibrosis and the effect of G. lucidum extract on liver fibrosis induced by different pathogenesis, which were discussed and analyzed. Research and development ideas and references are provided for the subsequent application of G. lucidum extracts in anti-liver fibrosis treatment.

Antidiabetic Potential of Flavonoids from Traditional Chinese Medicine: A Review.

Diabetes mellitus (DM) is a group of metabolic disorders in which high blood sugar levels occur over a prolonged period. Approximately 4% of the global population is affected by DM. Western medical treatment methods for diabetes including injection or oral hypoglycemic drugs have some toxic or side effects, economic pressures, and so on. Many researchers turn to discover new drugs from natural products or Traditional Chinese Medicine (TCM). Flavonoids are widely distributed in plants, and many studies have shown that flavonoids possess antidiabetic properties, exhibiting not only well-recognized antidiabetic and hypoglycemic activities but also activity in the treatment of diabetic complications. In this review, we systematically summarized anti-diabetic flavonoid compounds based on structure classification by examining the PubMed, Springer Link, Web of Science, and CNKI databases. There are 13 flavonoid compounds listed which have been studied extensively and have antidiabetic features respectively. Apigenin, baicalein, and catechin mainly reduces blood glucose via anti-oxidation; hesperidin is good for diabetic neuropathy; glycyrrhiza flavonoids have a significant effect on gestational DM; quercetin takes advantage of crossing the blood-brain barrier and improving renal function. Some compounds have protective and preventive effects on diabetic complications, such as kaempferol and puerarin which are beneficial to cardiomyopathy; myricetin has therapeutic potential in the treatment of DN; dihydromyricetin might improve CI. It is a pity or might be a pointcut that most studies remain in the animal experimental stage, and further investigation should be carried out.

The p300/YY1/miR-500a-5p/HDAC2 signalling axis regulates cell proliferation in human colorectal cancer.

The biological role of miR-500a-5p has not yet been reported in the context of colorectal cancer (CRC). Here, we show that miR-500a-5p expression is decreased in CRC tissues compared with adjacent normal tissues. Low miR-500a-5p expression is associated with malignant progression. Moreover, transfection of CRC cells with miR-500a-5p induces G0/G1 cell cycle arrest and inhibits their growth and migration. Mechanistically, miR-500a-5p directly targets HDAC2 and inhibits HDAC2-mediated proliferation in CRC in nude mice. Furthermore, YY1 binds to the promoter of miR-500a-5p and negatively regulates its transcription. Restoration of miR-500a-5p expression is up-regulated via the p300/YY1/HDAC2 complex. Besides, therapeutic delivery of miR-500a-5p significantly suppresses tumour development in a xenograft tumour model and a HDAC2 inhibitor FK228-treated CRC model. Our studies demonstrate that miR-500a-5p functions as a tumour suppressor in CRC by targeting the p300/YY1/HDAC2 axis, which contributes to the development of and provides new potential candidates for CRC therapy.

Polysaccharides from Chinese herbal medicine for anti-diabetes recent advances.

Diabetes mellitus (DM) is a chronic disease occurring when the body no longer produces adequate insulin or when it cannot use the produced insulin effectively. In recent years, more and more studies have revealed that Chinese materia medica polysaccharides are the key bioactive components of Chinese herbal medicine and have significant anti-diabetic effects with almost no side effects. In this review, we summarize 10 kinds of polysaccharides from Chinese herbal medicine which have effective anti-diabetes activities and the mechanism since 2014 to now. And it is hoped that this will provide an enlightenment for our researchers to design, research and development of polysaccharides.

[Effect of folate in modulating the expression of DNA methyltransferase 1 and methyl-CpG-binding protein 2 in cervical cancer cell lines].

OBJECTIVE: To explore the effects of folate on the expression of DNA methyltransferase 1 (DNMT1) and methyl-CpG-binding protein 2 (MeCP2) in cervical cancer cell lines. METHODS: Experimental study was carried out in vitro. Human cervical cancer cell lines, including C33A cell with HPV negative and Caski cell with HPV16 positive, were treated with different concentration of folate. The expression of DNMT1 and MeCP2 protein (by Western blot) and mRNA (by real-time PCR) were then detected in the two cell lines. RESULTS: It was found that supplement of folate was able to reduce the cell proliferation in C33A cell (r = 0.984, P < 0.001) and Caski cell (r = 0.978, P = 0.002), as well as induced the cell apoptosis (C33A: r = 0.989, P < 0.001; Caski: r = 0.994, P < 0.001). RESULTS: showed that the expression levels of DNMT1 protein (C33A: r = -0.914, P < 0.001; Caski: r = -0.859, P = 0.003) and MeCP2 protein (C33A: r = -0.830, P = 0.005; Caski: r = -0.981, P < 0.001) decreased gradually with the increase of folate concentrations, but the expression of DNMT1 and MeCP2 mRNA was not observed in Caski or C33A cell. When at the same levels of folate, the expression of DNMT1 protein or mRNA was higher in Caski cell than in C33A cell. However, the expression of MeCP2 protein or mRNA was higher in C33A cell than in Caski cell. CONCLUSION: Our finding indicated that adequate folate could effectively inhibit the proliferation of cervical cancer cells and facilitate their apoptosis in vitro, thus would reverse the aberration protein expression of DNMT1 and MeCP2. That there might be a synergistic action between HPV16 infection and parafunction of DNMT1 in cervical cancer, being noticed.

[Study of cytochrome P450 1A1 gene 3'-UTR 6235T-C polymorphism and susceptibility to breast cancer with Uighur medicine].

OBJECTIVE: To explore the association between polymorphism of cytochrome P450 1A1 Gene 3'-UTR (3'-untranslated region) 6235T-C and breast cancer with abnormal Hilit in Chinese Han population of Xinjiang. METHODS: The breast cancer patients were divided into four body fluids according to Uighur medical theories. And the technique of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed to detect the genotypic and allelic frequencies of 6235T-C polymorphism situated in 3'-untranslated region of CYP1A1 gene in 137 breast cancer patients with abnormal Hilit and 148 normal control subjects in Han population of Xinjiang province. RESULTS: (1) Significant differences in the genotypic and allelic distribution frequencies of CYP1A1 gene 3'-UTR6235T-C were found between breast cancer patients with abnormal Sapra Hilit and controls (χ(2) = 8.790, P = 0.012; χ(2) = 7.102, P = 0.008). The frequencies of CC genotype and C allele were significantly higher in breast cancer patients with abnormal Sapra Hilit (16.4% vs 39.8%) than in controls (4.7% vs 25.7%). (2) Significant differences in the genotypes and allelic distribution frequencies of CYP1A1 gene 3'-UTR6235T-C were found between breast cancer patients with abnormal Savda Hilit and controls (χ(2) = 6.638, P = 0.036; χ(2) = 5.824, P = 0.016). And the frequencies of TC, CC genotypes and C allele were significantly higher in breast cancer patients with abnormal Savda Hilit (56.9%, 9.8%, 39.2%) than those of the controls (41.9%, 4.7%, 25.7%). CONCLUSION: The CC genotype and C allele of 6235T-C polymorphism of CYP1A1 may be linked with breast cancer with abnormal Sapra Hilit and abnormal savda Hilit in Chinese Han population of Xinjiang province. But they are not correlated with the susceptibility to breast cancer with abnormal Balgham Hilit.