Chronic liver diseases with common causes including viral infections， alcohol abuse， and autoimmune diseases. Alkaloids， as a class of plant-derived compounds， have shown significant potential in regulating chronic liver diseases. Recent studies have shown that alkaloids are able to exert a therapeutic effect on chronic liver diseases through multiple pathways. These compounds have a regulatory effect on key pathological processes such as liver fibrosis， inflammatory response， oxidative stress， and cell apoptosis， and they also regulate the metabolic homeostasis of hepatocytes by modulating multiple signaling pathways， thereby playing a role in regulating chronic liver diseases. This article reviews the role and mechanism of alkaloids in the treatment of chronic liver diseases， in order to provide new ideas and directions for the treatment of chronic liver diseases.

OBJECTIVE To establish a content determination method for multiple components in Sophora flavescens from different origins and to evaluate its quality by combining with chemometrics. METHODS Thirteen batches （No. K1-K13） of S. flavescens from different origins were selected as test samples. A high-performance liquid chromatography-tandem triple quadrupole mass spectrometry （HPLC-MS/MS） method was established to determine the contents of 12 components， including matrine， oxymatrine， betaine， cytisine， N-methylcytisine， sophoridine， genistein， sophoricoside， sophorone， formononetin， sophorolone Ⅰ and norkurarinone in S. flavescens. Chromatographic separation was performed on a Shim-pack GIST-HP C18 column with a mobile phase consisting of methanol （A） and water containing 0.1% formic acid （B）， using gradient elution at a flow rate of 0.25 mL/min， column temperature of 35 ℃， and an injection volume of 3 μL. Mass spectrometry was conducted using an electrospray ionization source with positive and negative ion scanning. Data were collected in segments using the multiple reaction monitoring mode. Technique for order preference by similarity to ideal solution （TOPSIS） and grey relational analysis （GRA）methods were employed to compare and comprehensively evaluate the 13 batches of S. flavescens from different origins. RESULTS The methodological validation for the content determination met the relevant regulatory requirements. The contents of the 12 components were 490.66-1 231.00， 11 088.10- 18 021.50， 7.91-25.38， 903.97-1 713.64， 336.08-1 485.54，1 065.33-2 075.50， 27.52-71.80， 109.36-517.83， 6 034.55-10 632.73， 21.26-145.35， 814.84-1 911.32， 1 040.87-3 446.37 μg/g）， respectively. TOPSIS results showed that the top 7 samples in Euclidean distance ranking were K6， K12， K11， K3， K5， K10， K13. The GRA results showed that the top 7 samples in the relative correlation ranking were K12， K11， K10， K6， K13， K5， K3. CONCLUSIONS The established HPLC-MS/MS method is rapid， accurate， highly sensitive， stable and reliable. Combined with chemometrics methods， it can be used for the quality control and evaluation of S. flavescens. The comprehensive quality of samples K3， K5， K6（ from Hebei）， K10（ from Sichuan）， K11-K13（ from Shanxi）， etc. is relatively superior.

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver injuries, including steatosis to steatohepatitis (MASH), liver fibrosis, cirrhosis, and relevant complications. The liver mainly comprises hepatocytes, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), immune cells (T cells, B cells), and hepatic stellate cells (HSCs). Crosstalk among these different liver cells, endogenous aberrant glycolipid metabolism, and altered gut dysbiosis are involved in the pathophysiology of MASLD. This review systematically examines advances in understanding the molecular pathogenesis of MASLD, with a focus on emerging therapeutic targets and translational clinical trials. We first delineate the crucial regulatory mechanisms involving diverse liver cells and the gut-liver axis in MASLD development. These cell-specific pathogenic insights offer valuable perspectives for advancing precision medicine approaches in MASLD treatment. Furthermore, we evaluate potential therapeutic targets and summarize clinical trials currently underway. By comprehensively updating the MASLD pathophysiology and identifying promising strategies, this review aims to facilitate the development of novel pharmacotherapies for this increasingly prevalent condition.
Humans ; Fatty Liver/therapy* ; Animals ; Liver/pathology* ; Kupffer Cells/metabolism* ; Hepatocytes/metabolism* ; Hepatic Stellate Cells/metabolism*

Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

Metabolic dysfunction-associated fatty liver disease (MAFLD), characterized by fatty acid overload, secondary chronic inflammation, and fibrosis, has become the most prevalent chronic liver disease globally. While no effective pharmacotherapy exists for MAFLD, mitigating inflammatory responses represents a promising approach to preventing the progression from steatosis to severe steatohepatitis. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which detects endogenous danger and stress signals, has emerged as a significant target for inflammatory disease treatment, as transcriptional inactivation of its components demonstrates the therapeutic potential for MAFLD. Natural products targeting NLRP3 inflammasome activation have shown promising efficacy in MAFLD therapy. This review synthesizes the current understanding of NLRP3 inflammasome activation and therapeutic targets for NLRP3 homeostasis. Additionally, natural products reported to inhibit NLRP3 inflammasome for MAFLD improvement are categorized according to their mechanisms of action. The review also addresses limitations and future directions regarding natural products targeting NLRP3 inflammasome in MAFLD treatment. Enhanced understanding of NLRP3 inflammasome activation mechanisms in MAFLD and the identification of novel natural products supported by mechanistic research will significantly advance MAFLD treatment.
Humans ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology* ; Inflammasomes/metabolism* ; Biological Products/therapeutic use* ; Animals ; Fatty Liver/immunology*

BACKGROUND:In recent years,the development of liver organoids has made it a hot spot in the field of international liver disease research,but there is still no article on the bibliometric analysis of liver organoids. OBJECTIVE:To explore the hot trends in liver organoids in the last 20 years based on bibliometrics and visualization analysis. METHODS:We searched the articles about liver organoids in the Web of Science Core Collection from January 1,2002 to November 12,2022.Origin,Office,and CiteSpace software were used for bibliometrics and visualization analysis.We statistically analyzed the number of annually published articles,countries,institutions,authors,journals,and keywords of the articles by generating charts. RESULTS AND CONCLUSION:The number of articles,citation frequency,institutions and personnel involved in the research about liver organoids showed an overall upward trend in the last 20 years,indicating that the field was growing rapidly and attention was increasing.The USA had published the most papers and had the strongest influence in this field.Although it had invested a lot of time and energy,the number of papers published by a single research institution in the USA was not the highest among many research institutions.China was second only to the USA in the number of publications,with the Chinese Academy of Sciences and Fudan University leading the list.Utrecht University in the Netherlands was the institution with the most publications.Clevers H was the author with the highest number of articles.The article with the highest co-citation frequency was"Long-term culture of genome-stable bipotent stem cells from adult human liver".The main fields of study for liver organoids were Molecular Science,Biology,and Immunology.The most frequently occurring keywords were stem cell,in vitro,and culture.The research hotspots in the liver organoids field were mainly focused on in vitro stem cell three-dimensional culture,differentiation and gene expression.

Objective The purpose of this study was to explore a suitable method to model no-reflow phenomenon following ischemic stroke and to evaluate perfusion decrease from multiple perspectives.Methods Laser scatter contrast imaging and two-photon live imaging were used to compare transient middle cerebral artery occlusion in C57BL/6 and BALB/c mice and perfusion alterations in BALB/c mice with 1 or 1.5 h of ischemia.Several imaging techniques including laser scatter contrast imaging,low and higher magnification images of perfused brain slices and two-photon microscopy to monitor erythrocyte flow rate and flux were used to assess in vivo dynamics as well as whole brain sections and microvasculature for decreased cerebral perfusion after transient middle cerebral artery occlusion.Infarct size and behavioral deficits were assessed with microtubule-associated protein 2 staining and behavioral scoring.Results In C57BL/6 mice,most capillaries in the middle cerebral artery region remained flowing during ischemia,whereas most capillaries were blocked in BALB/c mice.In addition,cortical perfusion at 24 h of recanalization was significantly reduced to 76.1%of baseline following 1.5 h of ischemia in BALB/c mice(P=0.046 compared with the sham group),whereas for it was reduced to 79.9%following 1h of ischemia which was not significantly different from the sham group(P=0.299).Transient middle cerebral artery occlusion in BALB/c mice for 1.5 h resulted in a reduction in whole-brain perfusion to 75.1%(P＜0.001 compared with the sham group),and erythrocyte flow rate assessed by two-photon live-imaging of erythrocyte flow on the cortical surface of the middle cerebral artery basin was reduced to 50.3%of baseline levels at 24 h of recanalization(P=0.010 compared with the sham group),and erythrocyte flux decreased to 38.9%of baseline levels(P= 0.010 compared with the sham group);high-magnification imaging of sections assessed an approximately 76%reduction in the length of capillaries with perfusion(P=0.0001 compared with the sham group),and a reduction in the fraction of the total volume occupied by perfused capillaries by an approximately 76%reduction(P＜0.001 compared with the sham-operated group).Microtubule-associated protein 2 staining suggested that transient middle cerebral artery occlusion for 1.5 h in BALB/c mice resulted in infarcts that accounted for approximately 36%of the total cerebral area and behavioral scores elevated to 9,suggesting behavioral deficits.Conclusion Transient ischemia in BALB/c mice for 1.5 h resulted in a significant decrease in cerebral perfusion as well as capillary no-reflow and thus can model the no-reflow phenomenon following ischemic stroke.The combination of laser scatter contrast imaging,low magnification and higher magnification images of perfused brain slices,and two-photon microscopy live imaging allows for a multifaceted assessment of perfusion changes.

Objective:To explore the correlation between the ratio of C-reactive protein (CRP) to albumin (CAR) and the syndrome type of Wei-Qi-Ying-Xue in patients with severe coronavirus disease 2019 (COVID-19).Methods:A case-control study was conducted to select 63 severe patients with COVID-19 admitted to the Dongzhimen Hospital of Beijing University of Chinese Medicine from December 2022 to December 2023, including 50 severe cases and 13 critical cases. The clinical data of the patients were collected. According to the syndrome differentiation of Wei-Qi-Ying-Xue, there were 21 cases of Qi syndrome, 20 cases of Ying syndrome and 22 cases of Xue syndrome. The differences of CRP, ALB and CAR levels in patients with different Wei-Qi-Ying-Xue syndromes were compared. Spearman correlation test was used to test the correlation between CRP, ALB, CAR and the Wei-Qi-Ying-Xue syndrome type, and the receiver operating characteristic (ROC) curve was used to detect the diagnostic efficacy of CRP, ALB and CAR on the Wei-Qi-Ying-Xue syndrome type.Results:There was a statistically significant difference in the clinical classification of Western medicine among the three groups ( P<0.05). The CAR of the Ying group and the Xue group was higher than that of the Qi group ( P<0.05), while there was no statistically significant difference in age and comorbidities (all P>0.05). The CRP of the Xue group was higher than that of the Qi group ( P<0.05), and the ALB of the Ying group and the Xue group was lower than that of the Qi group (all P<0.05). Correlation analysis showed that there was a correlation between the Wei-Qi-Ying-Xue syndrome type and CRP, ALB and CAR ( P<0.05), among which CAR changed most significantly with the change of Wei-Qi-Ying-Xue syndrome type. ROC curve analysis showed that CRP, ALB and CAR had good diagnostic value for Qi syndrome and Xue syndrome ( P<0.05). The critical values of the diagnosis of Qi syndrome were 48.57 mg/L, 34.20 g/L and 2.97. The critical values of the diagnosis of Xue syndrome were 28.30 mg/L, 26.6 g/L and 5.96. Conclusions:CAR ratio is correlated with the Wei-Qi-Ying-Xue syndrome type of severe COVID-19 patients, and its level changes are in line with the evolution law of Wei-Qi-Ying-Xue syndrome. CAR≤2.97 is contributed to the diagnosis of Qi syndrome, and CAR>5.96 is contributed to the diagnosis of Xue syndrome. CAR may be an objective index related to the Wei-Qi-Ying-Xue syndrome type of severe COVID-19 patients.

Objective To investigate the effect of Nutlin-3a,a mouse double minute 2 homolog(MDM2)inhibitor,on lipid metabolism of mouse adipose.Methods High-fat diet-induced obesity(DIO)C57BL/6J mice were randomly divided into a control group injected with DMSO and an experimental group injected with Nutlin-3a.Then we conducted glucose tolerance(GTT)and insulin tolerance(ITT)tests.The epididymal white adipose tissue(eWAT),inguinal white adipose tissue(iWAT)and brown adipose tissue(BAT)of animals were isolated and microscopy of WATs with hematoxylin-eosin(HE)staining was performed to observe the morphological changes of adipocytes.The expression of lipid metabolism related gene cell death-inducing DFF45-like effector C(CIDEC)in eWAT were detected by qPCR and Western blot.Results Compared with the control group,Nutlin-3a was found to promote the body weight(P＜0.001),but no effect on glucose tolerance and insulin sensitivity in DIO mice.Nutlin-3a treatment decreased the size of adipocytes and fat deposition in adipose tissue and downregulated the mRNA and protein levels of CIDEC in eWAT.Conclusions Nutlin-3a inhibits the formation of lipid droplets by downregulating expression of CIDEC in white adipose tissue.

Objective: To clarify the specific mechanisms of action of raw Phellodendron chinense Schneid. (RPC) and saltwater-processed PC (SPC) in the treatment of rats with a kidney-yin deficiency pattern (KYDP). Methods: Healthy rats were administered hydrocortisone to establish a KYDP model. The rats were divided into seven groups: blank control, model, positive control (Liuwei Dihuang pills), high-dose RPC, low-dose RPC, high-dose SPC, and low-dose SPC. Enzyme-linked immunosorbent assay was used to measure the levels of cAMP, cGMP, TRH, TSH, T3, T4, IFN-γ, TNF-α, and testosterone in the serum and the levels of Na+-K+-ATPase and Ca2+-Mg2+-ATPase in the liver. TRH mRNA expression in the rat hypothalamus was measured using RT-PCR. THRα1+2 protein expression in the hypothalamus of rats was measured using Western blot. Immunohistochemistry was performed to determine the expression levels of FAS, FasL, and TSHR. Flow cytometry was used to determine CD4+ and CD8+ T lymphocyte levels. Illumina MiSeq sequencing technology was used to evaluate the diversity of intestinal flora in KYDP rats. Results: The cAMP/cGMP ratio was significantly higher in the model group than in the blank control group (P = .048). Compared with the model group, after administration, the levels of the above-mentioned serum and liver indexes decreased, except that of testosterone. The CD4+/CD8+ ratio also decreased. Compared with the RPC group, the levels of T3, IFN-γ, FAS, FasL, and TSHR in the SPC group decreased whereas that of testosterone increased. Additionally, immune function and intestinal flora diversity improved in the SPC group. SPC proved to be more effective in improving liver energy metabolism in KYDP rats than RPC. Conclusion SPC had a better therapeutic effect on KYDP than RPC. The underlying mechanism of action may be related to improvements in liver energy metabolism, immune function, and intestinal flora diversity.