Single cell study of cellular diversity and mutual communication in chronic heart failure and drug repositioning.

Non-cardiomyocytes (non-CMs) play an important role in the process of cardiac remodeling of chronic heart failure. The mechanism of non-CMs transit and interact with each other remains largely unknown. Here, we try to characterize the cellular landscape of non-CMs in mice with chronic heart failure by using single-cell RNA sequencing (scRNA-seq) and provide potential therapeutic hunts. Cellular and molecular analysis revealed that the most affected cellular types are mainly fibroblasts and endothelial cells. Specially, Fib_0 cluster, the most abundant cluster in fibroblasts, was the only increased one, enriched for collagen synthesis genes such as Adamts4 and Crem, which might be responsible for the fibrosis in cardiac remodeling. End_0 cluster in endothelial cells was also the most abundant and only increased one, which has an effect of blood vessel morphogenesis. Cell communication further confirmed that fibroblasts and endothelial cells are the driving hubs in chronic heart failure. Furthermore, using fibroblasts and endothelial cells as the entry point of CMap technology, histone deacetylation (HDAC) inhibitors and HSP inhibitors were identified as potential anti-heart failure new drugs, which should be evaluated in the future. The combined application of scRNA-seq and CMap might be an effective way to achieve drug repositioning.

Kinetic Resolution of ß-Alkyl Phenylethylamine Derivatives through Palladium-Catalyzed, Nosylamide-Directed C-H Olefination.

Palladium-catalyzed C-H activation reactions have attracted the attention of organic researchers due to their unique high selectivity, broad functional group tolerance, and high efficiency, and they are widely used in natural products and asymmetric synthesis. Here, we report an example of enantioselective C-H alkenylation between ß-alkyl phenylethylamine compounds and styrenes with Boc-L-lle-OH as the ligand and nosylamide as the directing group. This reaction is applicable to styrene containing various electron-deficient and electron-donating substitutions and may be utilized for the synthesis of benzoazepine compounds.

Emerging Biopharmaceuticals from Pimpinella Genus.

Evolved over eons to encode biological assays, plants-derived natural products are still the first dawn of drugs. Most researchers have focused on natural compounds derived from commonly used Pimpinella species, such as P. anisum, P. thellungiana, P. saxifrage, and P. brachycarpa, to investigate their antioxidant, antibacterial, and anti-inflammatory properties. Ethnopharmacological studies demonstrated that the genus Pimpinella has the homology characteristics of medicine and food and mainly in the therapy of gastrointestinal dysfunction, respiratory diseases, deworming, and diuresis. The natural product investigation of Pimpinella spp. revealed numerous natural products containing phenylpropanoids, terpenoids, flavonoids, coumarins, sterols, and organic acids. These natural products have the potential to provide future drugs against crucial diseases, such as cancer, hypertension, microbial and insectile infections, and severe inflammations. It is an upcoming field of research to probe a novel and pharmaceutically clinical value on compounds from the genus Pimpinella. In this review, we attempt to summarize the present knowledge on the traditional applications, phytochemistry, and pharmacology of more than twenty-five species of the genus Pimpinella.

LncRNA Meg3 knockdown reduces corneal neovascularization and VEGF-induced vascular endothelial angiogenesis via SDF-1/CXCR4 and Smad2/3 pathway.

The crucial effect of vascular endothelial growth factor (VEGF)-induced vascular angiogenesis has been well known in corneal neovascularization (CNV). This research aimed to determine the underlying value and mechanism of Meg3 on CNV in vivo and in vitro. In an alkali-burned mouse model, length and area of new vessels were increased along with thinning of corneal epithelium, accompanied by the overexpression of Meg3. Notably, subconjunctival injection of shMeg3 suppressed the degree of injury in cornea, causing expression of the angiogenesis markers--VEGF-A and CD31 decreased. In VEGF-induced human umbilical vein endothelial cells (HUVECs), knockdown of Meg3 antagonized the enhancement of viability, proliferation, wound healing ability and angiogenesis by VEGF. The proteins expression of VEGF-A, CD31, SDF-1/CXCR4 as well as phosphoraylation-Smad2/3 pathways, which were related to angiogenesis, were reduced with Meg3 deficiency. Overall, knockdown of Meg3 alleviated formation of neovascularization in alkali-burned corneas and reduced VEGF-induced angiogenesis by inhibiting SDF-1/CXCR4 and Smad2/3 signaling in vitro.

Network pharmacological investigation into the mechanism of Kaixinsan powder for the treatment of depression.

Kaixinsan powder (KXS), a classic prescription of traditional Chinese Medicine (TCM), is widely used in the treatment of depression, but its mechanism remains unclear. The network pharmacology method was used to constructe the "herb-component-target" network, and elucidated KXS potential mechanisms of action in the treatment of depression. Moreover, molecular docking was applied to valid the important interactions between the ingredients and the target protein. The "herb-component-target" network indicated that the ingredients of Girinimbin, Gomisin B and Asarone, and the protein targets of ESR, AR and NR3C1 mostly contribute to the antidepressant effect of KXS. KEGG pathway analysis highlighted the most significant pathways associated with depression treatment, including neuroactive ligand-receptor interaction pathway, serotonergic synapse pathway, PI3K-Akt signaling pathway and MAPK signaling pathway. Go enrichment analysis indicated that the mechanism of KXS in treating depression was involved in the biological process of GPCR signal transduction, hormone metabolism and nerve cell apoptosis. Moreover, molecular docking results showed that Polygalaxanthone III, Girinimbine and Pachymic acid performed greater binding ability with key antidepressant target 5-HTR. In conclusion, this study preliminarily revealed key active components in KXS, including Gomisin B, Asarone, Ginsenoside Rg1, Polygalaxanthone III and Pachymic acid, could interact with multiple targets (5-HTR, DR, ADRA, AR, ESR, NR3C1) and modulate the activation of multiple pathways (Neuroactive ligand -receptor interaction pathway, serotonergic synapse pathway, PI3K-Akt signaling pathway and MAPK signaling pathway).

A Comprehensive In Silico Exploration of Pharmacological Properties, Bioactivities, Molecular Docking, and Anticancer Potential of Vieloplain F from Xylopia vielana Targeting B-Raf Kinase.

Compounds derived from plants have several anticancer properties. In the current study, one guaiane-type sesquiterpene dimer, vieloplain F, isolated from Xylopia vielana species, was tested against B-Raf kinase protein (PDB: 3OG7), a potent target for melanoma. A comprehensive in silico analysis was conducted in this research to understand the pharmacological properties of a compound encompassing absorption, distribution, metabolism, excretion, and toxicity (ADMET), bioactivity score predictions, and molecular docking. During ADMET estimations, the FDA-approved medicine vemurafenib was hepatotoxic, cytochrome-inhibiting, and non-cardiotoxic compared to the vieloplain F. The bioactivity scores of vieloplain F were active for nuclear receptor ligand and enzyme inhibitor. During molecular docking experiments, the compound vieloplain F has displayed a higher binding potential with -11.8 kcal/mol energy than control vemurafenib -10.2 kcal/mol. It was shown that intermolecular interaction with the B-Raf complex and the enzyme's active gorge through hydrogen bonding and hydrophobic contacts was very accurate for the compound vieloplain F, which was then examined for MD simulations. In addition, simulations using MM-GBSA showed that vieloplain F had the greatest propensity to bind to active site residues. The vieloplain F has predominantly represented a more robust profile compared to control vemurafenib, and these results opened the road for vieloplain F for its utilization as a plausible anti-melanoma agent and anticancer drug in the next era.

[A new isoflavone from Dalbergia odorifera and inhibitory activity of its tyrosinase].

Twelve flavonoids were isolated and purified from the ethyl acetate fraction of 95% ethanol extract of Dalbergia odorifera by heat reflux extraction, solvent extraction, recrystallization, normal phase silica gel, Sephadex LH-20, MCI gel and HPLC methods. The structures were identified with multiple spectroscopic methods, including 1 D-NMR, 2 D-NMR and MS. The compounds were identified as 6,7,8-trimethoxy-5,4'-dihydroxy isoflavone(1), medicarpin(2), 7,2'-dihydroxy-4'-methoxy-isoflavanol(3), biochanin A(4), prunetin(5), genistein(6), pratensein(7), 3-(4-hydroxyphenyl)-6-isopentenyl-7-methoxy-4H-chromen-4-one(8), tectorigenin(9), irisolidone(10), vestitol(11), and formononetin(12). Compound 1 was a new isoflavone, and compound 8 was isolated from D. odorifera for the first time. The results showed that compounds 1-3 had inhibitory effects on tyrosinase, with inhibition rates of 35.58%, 38.63% and 51.34% at the concentration of 1.0 mmol·L~(-1), respectively.

Stress Driven Discovery of Natural Products From Actinobacteria with Anti-Oxidant and Cytotoxic Activities Including Docking and ADMET Properties.

Elicitation through abiotic stress, including chemical elicitors like heavy metals, is a new technique for drug discovery. In this research, the effect of heavy metals on actinobacteria Streptomyces sp. SH-1312 for secondary metabolite production, with strong pharmacological activity, along with pharmacokinetics profile, was firstly investigated. The optimum metal stress conditions consisted of actinobacteria strain Streptomyces sp. SH-1312 with addition of mix metals (Co2+ + Zn2+) ions at 0.5 mM in Gause's medium. Under these conditions, the stress metabolite anhydromevalonolactone (MVL) was produced, which was absent in the normal culture of strain and other metals combinations. Furthermore, the stress metabolite was also evaluated for its anti-oxidant and cytotoxic activities. The compound exhibited remarkable anti-oxidant activities, recording the IC50 value of 19.65 ± 5.7 µg/mL in DPPH, IC50 of 15.49 ± 4.8 against NO free radicals, the IC50 value of 19.65 ± 5.22 µg/mL against scavenging ability, and IC50 value of 19.38 ± 7.11 µg/mL for iron chelation capacity and the cytotoxic activities against PC3 cell lines were recorded with IC50 values of 35.81 ± 4.2 µg/mL after 24 h, 23.29 ± 3.8 µg/mL at 48 h, and 16.25 ± 6.5 µg/mL after 72 h. Further mechanistic studies have revealed that the compound MVL has shown its pharmacological efficacy by upregulation of P53 and BAX while downregulation of BCL-2 expression, indicating that MVL is following apoptosis in varying degrees. To better understand the pharmacological properties of MVL, in this work, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) were also evaluated. During ADMET predictions, MVL has displayed a safer profile in case of hepatotoxicity, cytochrome inhibition and also displayed as non-cardiotoxic. The compound MVL showed good binding energy in the molecular docking studies, and the results revealed that MVL bind in the active region of the target protein of P53 and BAX. This work triumphantly announced a prodigious effect of heavy metals on actinobacteria with fringe benefits as a key tool of MVL production with a strong pharmacological and pharmacokinetic profile.

Vieloplains A-G, seven new guaiane-type sesquiterpenoid dimers from Xylopia vielana.

Seven new guaiane-type sesquiterpene dimers vieloplains A-G, connecting patterns through three different direct CC bonds compounds 1-5 (C-3 to C-3', C-4 to C-1'), compound 6 (C-2 to C-3', C-4 to C-2') and compound 7 (C-2 to C-1', C-4 to C-2') were isolated from the roots of Xylopia vielana. Their absolute configurations were established by NOESY analysis, the Cu Kα X-ray crystallographic the experiment circular dichroism (ECD) and the calculated ECD. Among them, only compound 6 showed a considerable cytotoxicity against DU145 cells with IC50 values of 9.5 µM. Flow cytometry analysis confirmed that 6 caused death of DU145 cells via apoptosis induction.

Xylopsides A-D, four rare guaiane dimers with two unique bridged pentacyclic skeletons from Xylopia vielana.

Four unprecedented guaiane dimers, xylopsides A-D (1-4), were isolated and identified from the roots of Xylopia vielana. The structures of 1-4 were elucidated by spectroscopic analysis, Cu Kα X-ray crystallography and CD spectra. 1-4 showed two bridged pentacyclic skeletons between two guaiane-type sesquiterpenes, which were characterized as two different bridged ring systems. Among these compounds, 4 exhibited a moderate inhibitory activity against the production of nitric oxide with an IC50 value of 25.7 µM in RAW264.7 cells stimulated by LPS.

Chemical Constituents from Campylotropis hirtella.

A phytochemical investigation on the roots of Campylotropis hirtella afforded nine new isoflavones (3-9, 12, 15), two new isoflavans (10 and 11), one new coumestan (1), and three new prenylated benzoic acid derivatives (2, 13, 14), together with twenty-four known compounds. Their structures were established by spectroscopic analysis and circular dichroism data. The isolated compounds were also evaluated for their antibacterial activities against Enterococcus faecalis, Salmonella gallinarum, Streptococcus suis, Streptococcus agalactiae, Aeromonas hydrophila, Pseudomonas aeruginosa, Bacillus subtilis, Riemerella anatipestifer, and Vibrio alginolyticus.

A new phenyldilactone from Lespedeza cuneata.

A new phenyldilactone, maysedilactone B (1), together with twenty known compounds, were isolated from the aerial parts of Lespedeza cuneata. The structural elucidation of the isolated compounds was primarily based on HR-ESI-MS, IR and 1D and 2D NMR analyses. Compounds 1-8 and 15-21 were tested for cytotoxicity against four human tumor cell lines (A549, HCT116, SKOV3, and HepG2) using MTT method in vitro, while no significant activities were observed for the evaluated compounds.

[Research progress in mechanism of intestinal microorganisms in human diseases].

The international cooperated research projects of the Human Microbiome Project (HMP) and Metagenomics of The Human Intestinal Tract (MetaHIT) were officially launched in 2007, which indicated the era of metagenomics research of microorganisms in human gastrointestinal tract had been coming. Each human body is a superorganism which is composed of 90% commensal microorganisms, especially the intestinal microorganisms. The intestinal microorganisms play an important role on health maintenance since they are involved in the absorption and metabolism of nutrients in the human bodies. Herein, we review the research progress in the mechanism of intestinal microorganisms in human diseases. Our purpose is to provide novel ideas on human health and therapeutic targets of diseases.

Pharmacokinetic study of five ginsenosides using a sensitive and rapid liquid chromatography-tandem mass spectrometry method following single and multiple oral administration of Shexiang Baoxin pills to rats.

Shexiang Baoxin pills (SBP) are a traditional Chinese medicine that are used for treating coronary heart disease. Ginsenosides are the main effective components of SBP, but a comprehensive and deep pharmacokinetic study of ginsenosides in SBP, including multiple dosing and linear or nonlinear properties, is lacking. This study was designed to investigate and compare the pharmacokinetic characteristics of ginsenosides in SBP at a single dose and in multiple doses. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of the ginsenosides Rg1, Re, Rb3, Rc and Rb1 in rat plasma. Rats were randomly assigned to receive a single dose of 4, 8 or 12 g/kg and multiple doses (4 g/kg) of SBP for 8, 15 or 22 consecutive days. The results revealed that ginsenosides, following a single oral dose of 4 or 8 g/kg, were absorbed rapidly, with a Tmax ranging from 0.250 to 1.08 h. The AUC0-t and Cmax of the ppd-type ginsenosides Rb3, Rc and Rb1 were greater than those of the ppt-type ginsenosides Rg1 and Re. Nondose-dependent exposure was observed at doses of 4-12 g/kg for all of the ginsenosides. After multiple dosing, the plasma levels of the ppt-type ginsenosides decreased, whereas those of the ppd-type ginsenosides did not change significantly. In conclusion, the LC-MS/MS method was successfully applied to investigate the pharmacokinetics of ginsenosides after single and multiple oral administrations of SBP. The ginsenosides did not accumulate after multiple dosing. The ppd-type ginsenosides displayed more favorable pharmacokinetic properties compared with the ppt-type ginsenosides.

Neuroprotective effects of Anshen Bunao Syrup on cognitive dysfunction in Alzheimer's disease rat models.

Alzheimer's disease (AD) presents a significant challenge due to its prevalence and lack of cure, driving the quest for effective treatments. Anshen Bunao Syrup, a traditional Chinese medicine known for its neuroprotective properties, shows promise in addressing this need. However, understanding its precise mechanisms in AD remains elusive. This study aimed to investigate Anshen Bunao Syrup's therapeutic potential in AD treatment using a scopolamine-induced AD rat model. Assessments included novel-object recognition and Morris water maze tasks to evaluate spatial learning and memory, alongside Nissl staining and ELISA analyses for neuronal damage and biomarker levels. Results demonstrated that Anshen Bunao Syrup effectively mitigated cognitive dysfunction by inhibiting amyloid-ß and phosphorylation Tau aggregation, thereby reducing neuronal damage. Metabolomics profiling of rats cortex revealed alterations in key metabolites implicated in tryptophan and fatty acid metabolism pathways, suggesting a role in the therapeutic effects of Anshen Bunao Syrup. Additionally, ELISA and correlation analyses indicated attenuation of oxidative stress and immune response through metabolic remodeling. In conclusion, this study provides compelling evidence for the neuroprotective effects of Anshen Bunao Syrup in AD models, shedding light on its potential as a therapeutic agent for AD prevention and treatment.

Identification and structural characterization of dimeric sesquiterpene lactones in Inula japonica Thunb. by high-performance liquid chromatography/electrospray ionization with multi-stage mass spectrometry.

RATIONALE: Dimeric sesquiterpene lactones (DSLs) exhibit more 'biological friendly' and 'drug-like' molecular features than their monomers. Identification of DSLs is important to uncover potential lead compounds for the development of new anti-inflammatory and anticancer drugs. METHODS: High-performance liquid chromatography coupled with electrospray mass spectrometry (HPLC/ESI-MS(n) ) in positive-ion mode was developed to analyze structurally related groups of DSLs in the species of Inula japonica Thunb. The aerial part of I. japonica was also analyzed by using HPLC-diode-array detection (DAD)/ESI-MS(n) for the purpose of method validation. RESULTS: In positive-ion mode, a wealth of precursor molecular ions and product ions was detected for 24 DSL standards by MS(n) analysis under collision-induced dissociation. Retro-Diels-Alder (RDA) cleavage of the guaiane-type SL, neutral losses of acetoxy group, CO2 and water during the MS(n) process yielded characteristic product ions. The chemical constituents of the crude extract of I. japonica have also been analyzed by the developed method. CONCLUSIONS: The results indicated that the developed analytical method could be employed as a rapid, effective technique for structural characterizations of DSL-type constituents in I. japonica. This study may also arouse interest for further structural analysis of other DSL-containing type herbal medicines.

Cytotoxic pentacyclic triterpenoids from Prinsepia utilis.

Phytochemical investigation of the aerial parts of Prinsepia utilis Royle resulted in the isolation and identification of ten pentacyclic triterpenoids, including two new triterpenoids, 2α-O-trans-p-coumaroyl-3ß,19α-dihydroxy-urs-12-en-28-oic acid (1) and 2α-O-cis-p-coumaroyl-3ß,19α-dihydroxy-urs-12-en-28-oic acid (2), along with eight known pentacyclic triterpenoids (3-10). The structures were elucidated by extensive spectroscopic methods and by comparison to previously reported spectroscopic data. Most of these compounds showed significant cytotoxic activities against four human cancer cell lines (A549, HCT116, MDA-MB-231, and CCRF-CEM), and the structure-activity relationships are also discussed.

The inhibitory effect of 20(S)-protopanaxatriol (ppt) towards UGT1A1 and UGT2B7.

Ginseng, a commonly used natural product, has been frequently reported to induce herb-drug interaction with many clinical drugs. The intestinal bacterial metabolites of ginsenosides have been widely regarded as the substance basis for ginseng-drug interactions. To date, little is known about the inhibitory effect of intestinal bacterial metabolites of ginsenosides towards UDP-glucuronosyltransferases (UGTs). In vitro investigation of the inhibition of 20(S)-protopanaxatriol (ppt) towards UGT1A1 and UGT2B7 was carried out. The results showed that ppt exhibited strong noncompetitive inhibition towards UGT1A1 and competitive inhibition towards UGT2B7. The inhibition kinetic parameters (Ki ) were calculated to be 8.8 and 2.2 µM for UGT1A1 and UGT2B7, respectively. Using the maximum plasma concentration of ppt, the alteration of area under the concentration-time curve was calculated to be 20% and 70% respectively for UGT1A1-mediated and UGT2B7-mediated metabolism. However, given that the varied contribution of these two UGT isoforms towards drug metabolism and the influence of herb complexity and individual difference, the explanation of these results should be paid more caution.

Cut-off point of mature oocyte for routine clinical application of rescue IVM: a retrospective cohort study.

BACKGROUND: The rescue in vitro mature(Rescue IVM) technique allows the use of immature oocytes collected in conventional COH to obtain more mature oocytes for fertilization through in vitro maturation. Some studies have shown that Rescue IVM could improve clinical outcomes in patients undergoing IVF/ICSI, but the effectiveness and the indications for the clinical application of this technique remain controversial. It remains to be studied whether Rescue IVM should be universally applied in all conventional IVF/ICSI cycles. METHOD: This is a large retrospective cohort study that included a total of 22,135 female patients undergoing their first IVF treatment cycles. The effect of the number of mature oocytes(metaphaseII[MII]) on the cumulative live birth rate was investigated in a population with routine IVF/ICSI first. The receiver operating characteristic curve(ROC) analysis was used to explore the cut-off point of the number of MII affecting CLBR. Secondly, Patients undergoing ICSI with Rescue IVM were included in the analysis with those who underwent ICSI only during the same period, grouped according to the MII cut-off values. Multi-factor binary logistic regression and inverse probability weighting (IPW) were used to investigate whether Rescue IVM influenced the final cumulative live birth rate(CLBR). RESULTS: The CLBR increased with the number of MIIoocytes (P < 0.001). The ROC analysis showed the cut-off point for the number of MIIoocytes to have a significant effect on CLBR was 9 (sensitivity 0.715, specificity 0.656). Furthermore, 912 patients who underwent ICSI with Rescue IVM were included and compared to those who underwent ICSI only during the same period, and found Rescue IVM significantly increased the number of available MIIoocytes. For patients with MII numbers < 9, Rescue IVM significantly improves their clinical pregnancy rate(55.6% vs. 46.7%, P = 0.001) and CLBR(65.4% vs. 48.1%, P < 0.001), but not for those patients with MII numbers ≥ 9. CONCLUSION: This study further clarifies the candidates for the application of Rescue IVM technique: patients with an MII oocytes < 9 in a conventional IVF/ICSI cycle. In contrast, it is not necessary for patients who already have sufficient mature oocytes(≥ 9), to avoid over-medication.

Diminished ovarian reserve may not be associated with a poorer fresh cycle outcome in women < 38 years.

BACKGROUND: Previous studies have discussed the pregnancy outcomes of diminished ovarian reserve (DOR) patients. However, data on embryonic development potential, neonatal outcomes, and maternal complications of DOR patients still remained unknown. This is the first study to investigate the risk of DOR on pregnancy and perinatal outcomes among women < 38 years. METHODS: Retrospective cohort study was conducted. Patients (< 38 years of age) undergoing their first oocyte retrieval cycle were included. Patients were divided into DOR group and non-DOR group. Pregnancy outcomes of fresh cycle and cumulative live birth rate and perinatal outcomes after one oocyte retrieved cycle were compared between DOR and non-DOR group. RESULT(S): From January 2016 to September 2020, there were 8,179 patients involved: 443 patients in the DOR group and 7,736 patients in the non-DOR group. The incidences of live birth and clinical pregnancy did not differ significantly between patients with or without DOR after fresh cycle transfer, but the cumulative live birth rate was significantly lower in DOR group. Among women who had singleton live births, after binary logistic regression, the rates of maternal complications and neonatal outcomes were comparable in the two groups. CONCLUSION(S): DOR patients (< 38 years of age) showed similar pregnancy outcomes in the first fresh embryo transfer cycle but a lower chance of live birth after a whole oocyte retrieval cycle to non-DOR patients and DOR is not associated with adverse perinatal outcomes.