Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2.

The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.

Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma.

Adenoviral E1A binding protein 300 kDa (p300) and its closely related paralog CREB binding protein (CBP) are promising therapeutic targets for human cancer. Here, we report the first discovery of novel potent small-molecule PROTAC degraders of p300/CBP against hepatocellular carcinoma (HCC), one of the most common solid tumors. Based upon the clinical p300/CBP bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize the linker to generate a series of PROTACs, culminating in the identification of QC-182. This compound effectively induces p300/CBP degradation in the SK-HEP-1 HCC cells in a dose-, time-, and ubiquitin-proteasome system-dependent manner. QC-182 significantly downregulates p300/CBP-associated transcriptome in HCC cells, leading to more potent cell growth inhibition compared to the parental inhibitors and the reported degrader dCBP-1. Notably, QC-182 potently depletes p300/CBP proteins in mouse SK-HEP-1 xenograft tumor tissue. QC-182 is a promising lead compound toward the development of p300/CBP-targeted HCC therapy.

The Role of the Gut Microbiome in the Development of Acute Pancreatitis.

With the explosion research on the gut microbiome in the recent years, much insight has been accumulated in comprehending the crosstalk between the gut microbiota community and host health. Acute pancreatitis (AP) is one of the gastrointestinal diseases associated with significant morbidity and subsequent mortality. Studies have elucidated that gut microbiota are engaged in the pathological process of AP. Herein, we summarize the major roles of the gut microbiome in the development of AP. We then portray the association between dysbiosis of the gut microbiota and the severity of AP. Finally, we illustrate the promises and challenges that arise when seeking to incorporate the microbiome in acute pancreatitis treatment.

Enantioselective Oral Absorption of Molecular Chiral Mesoporous Silica Nanoparticles.

Inspired by the unique pharmacological effects of chiral drugs in the asymmetrical body environments, it is assumed that the chirality of nanocarriers is also a key factor to determine their oral adsorption efficiency, apart from their size, shape, etc. Herein, l/d-tartaric acid modified mesoporous silica nanoparticles (l/d-CMSNs) are fabricated via a one-pot cocondensation method, and focused on whether the oral adsorption of nanocarriers will be benefited from their chirality. It is found that l-CMSN performed better in the sequential oral absorption processes, including mucus permeation, mucosa bio-adhesion, cellular uptake, intestinal transport and gastrointestinal tract (GIT) retention, than those of the d-chiral (d-CMSN), racemic (dl-CMSN), and achiral (MSN) counterparts. The multiple chiral recognition mechanisms are experimentally and theoretically demonstrated following simple differential adsorption on biointerfaces, wherein electrostatic interaction is the dominant energy. During the oral delivery task, l-CMSN, which is proven to be stable, nonirritative, biocompatible, and biodegradable, is efficiently absorbed into the blood (1.72-2.05-fold higher than other nanocarriers), and helps the loaded doxorubicin (DOX) to achieve better intestinal transport (2.32-27.03-times higher than other samples), satisfactory bioavailability (449.73%) and stronger antitumor effect (up to 95.43%). These findings validated the dominant role of chirality in determining the biological fate of nanocarriers.

Altered gut microbiota in the early stage of acute pancreatitis were related to the occurrence of acute respiratory distress syndrome.

Background: Acute respiratory distress syndrome (ARDS) is the most common cause of organ failure in acute pancreatitis (AP) patients, which associated with high mortality. Specific changes in the gut microbiota have been shown to influence progression of acute pancreatitis. We aimed to determine whether early alterations in the gut microbiota is related to and could predict ARDS occurrence in AP patients. Methods: In this study, we performed 16S rRNA sequencing analysis in 65 AP patients and 20 healthy volunteers. The AP patients were further divided into two groups: 26 AP-ARDS patients and 39 AP-nonARDS patients based on ARDS occurrence during hospitalization. Results: Our results showed that the AP-ARDS patients exhibited specific changes in gut microbiota composition and function as compared to subjects of AP-nonARDS group. Higher abundances of Proteobacteria phylum, Enterobacteriaceae family, Escherichia-Shigella genus, and Klebsiella pneumoniae, but lower abundances of Bifidobacterium genus were found in AP-ARDS group compared with AP-nonARDS groups. Random forest modelling analysis revealed that the Escherichia-shigella genus was effective to distinguish AP-ARDS from AP-nonARDS, which could predict ARDS occurrence in AP patients. Conclusions: Our study revealed that alterations of gut microbiota in AP patients on admission were associated with ARDS occurrence after hospitalization, indicating a potential predictive and pathogenic role of gut microbiota in the development of ARDS in AP patients.

Noninvasive preoperative differential diagnosis of gallbladder carcinoma and xanthogranulomatous cholecystitis: A retrospective cohort study of 240 patients.

BACKGROUND: Xanthogranulomatous cholecystitis (XGC) is an extremely rare entity. Due to XGC's clinical and radiological resemblance to gallbladder carcinoma (GBC), intraoperative frozen section during cholecystectomy is often performed to exclude the diagnosis of GBC. Our study is aiming to find a noninvasive indicator of XGC. To our knowledge, this is the largest XGC cohort ever studied. METHODS: This study retrospectively collected clinical characteristics, serological tests, and imaging features of 150 GBC patients and 90 XGC patients. The diagnosis of these 150 GBC patients and 90 XGC patients was based on intraoperative frozen section histopathology. T-test was utilized to compare differences between XGC and GBC. Receiver operating characteristic (ROC) curve was conducted and the area under the curve (AUC) was managed to evaluate the validity. RESULTS: The carcinoembryonic antigen (CEA) level in blood tests was significantly elevated in GBC patients than in XGC patients (p = 0.007). The presence of submucosal hypo-attenuated nodules (80% in XGC, 16% in GBC, p < 0.001), low density border (60% in XGC, 21% in GBC, p = 0.001), and nodular thickening in the bottom of the gallbladder with calcification (70% in XGC, 37% in GBC, p = 0.004) is significantly associated with XGC patients, whereas massive hilar infiltration (0% in XGC, 21% in GBC, p < 0.001), multiple lymph nodes in the hilar area (10% in XGC, 72% in GBC, p = 0.001), and gallbladder mucosal line continuity (50% in XGC, 95% in GBC, p = 0.002) are highly associated with GBC patients. The ROC curve was performed and the gallbladder mucosal line continuity (AUC = 0.708) and the AUC of low density border around the occupation (AUC = 0.654) showed a good prediction of XGC. CONCLUSIONS: Gallbladder mucosal line continuity and low density border around the occupation presented good indication value for the diagnosis of XGC. Our study proposed a noninvasive differential diagnosis method for XGC and GBC.

Impacts of Cigarette Smoking Status on Metabolomic and Gut Microbiota Profile in Male Patients With Coronary Artery Disease: A Multi-Omics Study.

Background: Cigarette smoking has been considered a modifiable risk factor for coronary artery disease (CAD). Changes in gut microbiota and microbe-derived metabolites have been shown to influence atherosclerotic pathogenesis. However, the effect of cigarette smoking on the gut microbiome and serum metabolites in CAD remains unclear. Method: We profiled the gut microbiota and serum metabolites of 113 male participants with diagnosed CAD including 46 current smokers, 34 former smokers, and 33 never smokers by 16S ribosomal RNA (rRNA) gene sequencing and untargeted metabolomics study. A follow-up study was conducted. PICRUSt2 was used for metagenomic functional prediction of important bacterial taxa. Results: In the analysis of the microbial composition, the current smokers were characterized with depleted Bifidobacterium catenulatum, Akkermansia muciniphila, and enriched Enterococcus faecium, Haemophilus parainfluenzae compared with the former and never smokers. In the untargeted serum metabolomic study, we observed and annotated 304 discriminant metabolites, uniquely including ceramides, acyl carnitines, and glycerophospholipids. Pathway analysis revealed a significantly changed sphingolipids metabolism related to cigarette smoking. However, the change of the majority of the discriminant metabolites is possibly reversible after smoking cessation. While performing PICRUSt2 metagenomic prediction, several key enzymes (wbpA, nadM) were identified to possibly explain the cross talk between gut microbiota and metabolomic changes associated with smoking. Moreover, the multi-omics analysis revealed that specific changes in bacterial taxa were associated with disease severity or outcomes by mediating metabolites such as glycerophospholipids. Conclusions: Our results indicated that both the gut microbiota composition and metabolomic profile of current smokers are different from that of never smokers. The present study may provide new insights into understanding the heterogenic influences of cigarette smoking on atherosclerotic pathogenesis by modulating gut microbiota as well as circulating metabolites.

The Effects of Moderate Alcohol Consumption on Circulating Metabolites and Gut Microbiota in Patients With Coronary Artery Disease.

Background: Epidemiological studies confirmed that moderate alcohol consumption was associated with a reduced risk of adverse cardiovascular events. It is increasingly recognized that the composition of gut microbiota and metabolites is involved in modulating the cardiovascular health of the host. However, the association of moderate alcohol consumption with serum metabolites and gut microbiome and its impact on coronary artery disease (CAD) is not fully investigated. Method: Serum untargeted metabolomics analysis and fecal 16S rRNA sequencing were performed on 72 male patients with CAD having various alcohol consumption (36 non-drinkers, 18 moderate drinkers, and 18 heavy drinkers) and 17 matched healthy controls. MetaboAnalyst and PICRUSt2 were utilized to analyze the possible involved metabolic pathways. Multi-omics analysis was achieved by Spearman correlation to reveal the interactions of alcohol consumption with gut microbiome and serum metabolites in patients with CAD. Results: We noted distinct differences between patients with CAD, with varying levels of alcohol consumption and healthy controls in aspects of serum metabolome and the gut microbiome. Moderate alcohol consumption significantly changed the lipidomic profiles, including reductions of sphingolipids and glycerophospholipids in moderate drinkers with CAD when compared with non and heavy drinkers with CAD. Moreover, we also found the reduction of microbial-derived metabolites in moderate drinkers with CAD, such as 2-phenylacetamide and mevalonic acid. To be noted, the gut microbiota of moderate drinkers with CAD tended to resemble that of healthy controls. Compared with non-drinkers, the relative abundance of genus Paraprevotella, Lysinibacillus was significantly elevated in moderate drinkers with CAD, while the genus Bifidobacterium, Megasphaera, and Streptococcus were significantly reduced in moderate drinkers with CAD. Multi-omics analysis revealed that specific metabolites and microbes associated with moderate alcohol consumption were correlated with the severity of CAD. Conclusions: Our study revealed that the impact of moderate alcohol consumption on serum metabolites and gut microbiota in patients with CAD seemed to be separated from that of heavy and non-alcohol consumption. Moderate drinking tended to have more positive effects on metabolic profiles and commensal flora, which may explain its beneficial effects on cardiovascular health. Overall, our study provides a novel insight into the effects of moderate alcohol consumption in patients with CAD.

Variations in Gut Microbiome are Associated with Prognosis of Hypertriglyceridemia-Associated Acute Pancreatitis.

Hypertriglyceridemia-associated acute pancreatitis (HTGAP) is linked with increased severity and morbidity. Intestinal flora plays an important role in the progression of acute pancreatitis (AP). However, pathogenetic association between gut microbiota and HTGAP remains unknown. In this study, we enrolled 30 HTGAP patients and 30 patients with AP that is evoked by other causes. The V3-V4 regions of 16S rRNA sequences of the gut microbiota were analyzed. Clinical characteristics, microbial diversity, taxonomic profile, microbiome composition, microbiological phenotype, and functional pathways were compared between the two groups. Our results showed that the HTGAP group had a higher proportion of severe AP (46.7% vs. 20.0%), organ failure (56.7% vs. 30.0%), and a longer hospital stay (18.0 days vs. 6.5 days). HTGAP group also had poorer microbial diversity, higher abundances of Escherichia/Shigella and Enterococcus, but lower abundances of Dorea longicatena, Blautia wexlerae, and Bacteroides ovatus as compared with non-HTGAP group. Correlation analysis revealed that gut bacterial taxonomic and functional changes were linked with local and systemic complications, ICU admission, and mortality. This study revealed that alterations of gut microbiota were associated with disease severity and poor prognosis in HTGAP patients, indicating a potential pathophysiological link between gut microbiota and hypertriglyceridemia related acute pancreatitis.

Multi-omics study reveals that statin therapy is associated with restoration of gut microbiota homeostasis and improvement in outcomes in patients with acute coronary syndrome.

Rationale: Prior chronic treatment with statins has been shown to be associated with more favorable outcomes in patients with acute coronary syndrome (ACS). Specific changes in the gut microbiota and microbial metabolites have been shown to influence the progression of coronary artery disease. However, the critical microbial and metabolomic changes associated with the cardiovascular protective effects of statins in ACS remain elusive. Methods: In the present study, we performed 16S rRNA sequencing and serum metabolomic analysis in 36 ACS patients who had received chronic statin treatment, 67 ACS patients who had not, and 30 healthy volunteers. A follow-up study was conducted. Metagenomic functional prediction of important bacterial taxa was achieved using PICRUSt2. Results: Statins modulated the gut microbiome of ACS patients towards a healthier status, i.e., reducing potentially pathogenic bacteria such as Parabacteroides merdae but increasing beneficial bacteria such as Bifidobacterium longum subsp. longum, Anaerostipes hadrus and Ruminococcus obeum. Moreover, prior chronic statin therapy was associated with improved outcome in ACS patients. Multi-omics analysis revealed that specific changes in bacterial taxa were associated with disease severity or outcomes either directly or by mediating metabolites such as fatty acids and prenol lipids. Finally, we discovered that important taxa associated with statins were correlated with fatty acid- and isoprenoid-related pathways that were predicted by PICRUSt2. Conclusions: Our study suggests that statin treatment might benefit ACS patients by modulating the composition and function of the gut microbiome, which might result in improved circulating metabolites and reduced metabolic risk. Our findings provide new insights for understanding the heterogenic roles of statins in ACS patients through host gut microbiota metabolic interactions.

Alterations of Gut Microbiome and Serum Metabolome in Coronary Artery Disease Patients Complicated With Non-alcoholic Fatty Liver Disease Are Associated With Adverse Cardiovascular Outcomes.

Rationale: Patients suffering from coronary artery disease (CAD) complicated with nonalcoholic fatty liver disease (NAFLD) present worse cardiovascular outcomes than CAD patients without NAFLD. The progression of CAD is recently reported to be associated with gut microbiota and microbe-derived metabolites. However, it remains unclear how the complication of NAFLD will affect gut microbiota and microbe-derived metabolites in CAD patients, and whether or not this interplay is related to the worse cardiovascular outcomes in CAD-NAFLD patients. Methods: We performed 16S rRNA sequencing and serum metabolomic analysis in 27 CAD patients with NAFLD, 81 CAD patients without NAFLD, and 24 matched healthy volunteers. Predicted functional profiling was achieved using PICRUSt2. The occurrence of cardiovascular events was assessed by a follow-up study. The association of alterations in the gut microbiome and metabolome with adverse cardiovascular events and clinical indicators was revealed by Spearman correlation analysis. Results: We discovered that the complication of NAFLD was associated with worse clinical outcomes in CAD patients and critical serum metabolome shifts. We identified 25 metabolite modules that were correlated with poor clinical outcome in CAD-NAFLD patients compared with non-NAFLD patients, represented by increased cardiac-toxic metabolites including prochloraz, brofaromine, aristolochic acid, triethanolamine, and reduced potentially beneficial metabolites including estradiol, chitotriose, palmitelaidic acid, and moxisylyte. In addition, the gut microbiome of individuals with CAD-NAFLD was changed and characterized by increased abundances of Oscillibacter ruminantium and Dialister invisus, and decreased abundances of Fusicatenibacter saccharivorans, Bacteroides ovatus and Prevotella copri. PICRUSt2 further confirmed an increase of potential pathogenic bacteria in CAD-NAFLD. Moreover, we found that variations of gut microbiota were critically correlated with changed circulating metabolites and clinical outcomes, which revealed that aberrant gut microbiota in CAD-NAFLD patients may sculpt a detrimental metabolome which results in adverse cardiovascular outcomes. Conclusions: Our findings suggest that CAD patients complicated with NAFLD result in worse clinical outcomes possibly by modulating the features of the gut microbiota and circulating metabolites. We introduce "liver-gut microbiota-heart axis" as a possible mechanism underlying this interrelationship. Our study provides new insights on the contribution of gut microbiota heterogeneity to CAD-NAFLD progression and suggests novel strategies for disease therapy.

Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review.

Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease characterized by pulmonary vasculature reconstruction and right ventricular dysfunction. The mortality rate of PAH remains high, although multiple therapeutic strategies have been implemented in clinical practice. These drugs mainly target the endothelin-1, prostacyclin and nitric oxide pathways. Management for PAH treatment includes improving symptoms, enhancing quality of life, and extending survival rate. Existing drugs developed to treat the disease have resulted in enormous economic and healthcare liabilities. The estimated cost for advanced PAH has exceeded $200,000 per year. The pathogenesis of PAH is associated with numerous molecular processes. It mainly includes germline mutation, inflammation, dysfunction of pulmonary arterial endothelial cells, epigenetic modifications, DNA damage, metabolic dysfunction, sex hormone imbalance, and oxidative stress, among others. Findings based on the pathobiology of PAH may have promising therapeutic outcomes. Hence, faced with the challenges of increasing healthcare demands, in this review, we attempted to explore the pathological mechanisms and alternative therapeutic targets, including other auxiliary devices or interventional therapies, in PAH. The article will discuss the potential therapies of PAH in detail, which may require further investigation before implementation.

Eltrombopag is a potential target for drug intervention in SARS-CoV-2 spike protein.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a current global threat for which there is an urgent need to search for an effective therapy. The transmembrane spike (S) glycoprotein of SARS-CoV-2 directly binds to the host angiotensin-converting enzyme 2 (ACE2) and mediates viral entrance, which is therefore considered as a promising drug target. Considering that new drug development is a time-consuming process, drug repositioning may facilitate rapid drug discovery dealing with sudden infectious diseases. Here, we compared the differences between the virtual structural proteins of SARS-CoV-2 and SARS-CoV, and selected a pocket mainly localizing in the fusion cores of S2 domain for drug screening. A virtual drug design algorithm screened the Food and Drug Administration-approved drug library of 1234 compounds, and 13 top scored compounds were obtained through manual screening. Through in vitro molecular interaction experiments, eltrombopag was further verified to possess a high binding affinity to S protein plus human ACE2 and could potentially affect the stability of the ACE2-S protein complex. Hence, it is worth further exploring eltrombopag as a potential drug for the treatment of SARS-CoV-2 infection.