CDHu40: a novel marker gene set of neuroendocrine prostate cancer (NEPC).

Prostate cancer (PCa) is the most prevalent cancer affecting American men. Castration-resistant prostate cancer (CRPC) can emerge during hormone therapy for PCa, manifesting with elevated serum prostate-specific antigen (PSA) levels, continued disease progression, and/or metastasis to the new sites, resulting in a poor prognosis. A subset of CRPC patients shows a neuroendocrine (NE) phenotype, signifying reduced or no reliance on androgen receptor (AR) signaling and a particularly unfavorable prognosis. In this study, we incorporated computational approaches based on both gene expression profiles and protein-protein interaction (PPI) networks. We identified 500 potential marker genes, which are significantly enriched in cell cycle and neuronal processes. The top 40 candidates, collectively named as CDHu40, demonstrated superior performance in distinguishing NE prostate cancer (NEPC) and non-NEPC samples based on gene expression profiles compared to other published marker sets. Notably, some novel marker genes in CDHu40, absent in the other marker sets, have been reported to be associated with NEPC in the literature, such as DDC, FOLH1, BEX1, MAST1, and CACNA1A. Importantly, elevated CDHu40 scores derived from our predictive model showed a robust correlation with unfavorable survival outcomes in patients, indicating the potential of the CDHu40 score as a promising indicator for predicting the survival prognosis of those patients with the NE phenotype. Motif enrichment analysis on the top candidates suggests that REST and E2F6 may serve as key regulators in the NEPC progression. Significance: our study integrates gene expression variances in multiple NEPC studies and protein-protein interaction network to pinpoint a specific set of NEPC maker genes namely CDHu40. These genes and scores based on their gene expression levels effectively distinguish NEPC samples and underscore the clinical prognostic significance and potential mechanism.

Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1.

Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPß pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.

Effect of herbal medicine compound promotes beta cell function among type 2 diabetes (T2D) adults: A randomized controlled clinical trial.

Background: Herbal medicine as complementary ways are needed for patients who refuse to take medicine for life. Early intervention and lifestyle could delay the time of taking drugs. Objective: To assess the efficacy of XiaokeGranules vs Sitagliptin in patients who diagnosed T2D. Methods: This is a randomized, double-blind trial. T2D patients were randomly assigned in a 1:1 ratio to Xiaoke Granules and Sitagliptin(50 mg), an anti-diabetic medicine group, for 12 weeks. Before randomization, the consenting participants were subjected to 2 weeks of screening, followed by twelve weeks of intervention. The primary outcome was change from baseline in glycosylated haemoglobin (HbA1C) and homeostasis model assessment-estimated insulin resistance (HOMA-IR) calculation at 12 week. Results: We recruited 103 patients, 84 patients participated in the clinical trial and finally 79 patients finished., the least square mean change in HbA1c and HOMA-IR from baseline was similar in both groups, in which HbA1c (6.93 ± 0.76, P = 0.007) and 2hPG (10.87 ± 2.20, P = 0.016) for the Control group, and HbA1c (6.76 ± 0.67, P < 0.001) and 2hPG (10.52 ± 2.46, P = 0.019). Conclusions: This study revealed that the herbal medicine Xiaoke Granules provides effective glycaemic control with similar safety and immunogenicity profile to Sitagliptin among T2D patients treated for 12 weeks. This study strongly suggests further studies and utilization of Xiaoke Granules usage for controlling hyperglycemia among T2D patients. Trial registration: ClinicalTrials: ChiCTR1900026782.

Discovery of a selective and covalent small-molecule inhibitor of BFL-1 protein that induces robust apoptosis in cancer cells.

Induction of apoptosis by the FDA-approved drug Venetoclax in cancer cells mainly derives from blocking the interactions between BCL-2 and BH3-only proteins. Anti-apoptotic BFL-1, a homolog of BCL-2, also competitively binds to the BH3-only proteins and is responsible for Venetoclax-induced drug resistance. Compared to BCL-2, small-molecule inhibitors of BFL-1 are relatively underexplored. In order to tackle this issue, in-house compound library was screened and a hit compound was identified and optimized to obtain 12 (ZH97) functioning as a covalent and selective inhibitor of BFL-1. 12 modifies BFL-1 at the C55 residue, blocks BFL-1/BID interaction in vitro, promotes cellular cytochrome c release from mitochondria, and induced apoptosis in BFL-1 overexpressing cancer cells. Mechanistic studies show that 12 inhibited BFL-1/PUMA interaction in cell lysate and is effective in cancer cells that harboring high expression level of BFL-1. In summary, blockade of BFL-1/BH3-only proteins interactions with a covalent small-molecule inhibitor induced apoptosis and elicited antitumor activity. Thus, our study demonstrates an appealing strategy for selective modulation of cellular BFL-1 for cancer therapy.

Analysis of Prescription Medication Rules of Traditional Chinese Medicine for Diabetes Treatment Based on Data Mining.

In this study, we have used TCM medical record management platform and SAS statistical software to analyze the cases of a professor in the treatment of type 2 diabetes, in order to explore the medication rules for the treatment of type 2 diabetes, so as to enrich and optimize the diagnosis and treatment plan for type 2 diabetes based on the experience of famous doctors. Chinese medicine treatment provides more diagnosis and treatment ideas. We have collected the professor's treatment of type 2 diabetes, screened out 100 patients, from a total of 285 prescriptions, and entered them into the TCM medical record management platform. We used the TCM medical record management platform and SAS statistical software to analyze his professor's experience in the treatment of type 2 diabetes. The medication analysis is as follows: (1) frequency of medication: 285 cases that met the inclusion criteria used a total of 187 traditional Chinese medicines. Among them, Salvia miltiorrhiza was used most frequently; (2) drug frequency analysis: 285 cases met the inclusion criteria, and the four Qi were mainly cold and warm medicines. The five flavors are mainly sweet, bitter, and pungent drugs. The main meridians are the liver, spleen, and kidney; (3) drug efficacy and classification analysis: 285 cases met the inclusion criteria, and 285 cases met the inclusion criteria and the Chinese medicines involved are the most common medicines used for tonic, heat clearing, blood circulation, and stasis; (4) clustering of medications: 35 Chinese medicines with medication frequency ≥20% are divided into 11 categories. (5) Using the improved Apriori algorithm, the minimum confidence level is selected to be 0.5, data mining is conducted on all type 2 diabetes cases, and a total of 21 recipes are dug out involving 10 Chinese medicines. In this study, with the aid of the TCM medical record management platform and SAS statistical software, cluster analysis, improved Apriori algorithm, and other data mining methods were used to systematically and objectively analyze the professor's treatment of type 2 diabetes cases. The results have clinical significance and can be used for traditional Chinese medicine treatment of type 2 diabetes, which provides an objective basis and provides a certain reference for the current inheritance of traditional Chinese medical experience and summary research.

Norditerpenoid alkaloids from Aconitum and Delphinium: structural relevance in medicine, toxicology, and metabolism.

Covering: 77 A.D. up to 2020Norditerpenoid alkaloids (NDA), typically N-ethylpiperidine containing C19 or C18 natural product diterpenes, are hexacycles with several contiguous often oxygenated stereocentres. As a function of their structural complexity, they display important pharmacological activities. The processed plants are used as important folk drugs and four NDAs have now been clinically approved. Many metabolism studies on Aconitum alkaloids have been reported as the understanding of their biotransformation in living systems and in cell-free systems is important for the development of these alkaloids as drugs. This Highlight sets out the missing links in NDA biosynthesis, their biological applications, SAR, toxicity, metabolism, and analytical studies.

The 1H NMR Spectroscopic Effect of Steric Compression Is Found in [3.3.1]Oxa- and Azabicycles and Their Analogues.

The through-space 1H NMR effect of steric compression by the lone-pair electrons of O- and N-atoms is shown in synthetic [3.3.1]oxa- and azabicycles. The electrons of the compressed proton bond are pushed away by the repulsive force generated by the lone-pair electrons of the heteroatom. There is a corresponding significant increase in the chemical shift of the compressed proton. The intensity of this deshielding effect is related to the proximity and overlap of the lone-pair or compressing atom. The steric compression decreases when the lone-pair electrons of the heteroatom and the compressed proton are not directly overlapped, for example, in [4.3.1]- and [3.2.1]azabicycles. Steric compression is also caused by a proton, deuterium, or an ethyl group close in space to the compressed proton. The protonated [3.3.1]azabicycle adopts a true-boat/true-chair conformation in its crystal lattice, but in solution the conformation is true-chair/true-chair.

Impacts of Steric Compression, Protonation, and Intramolecular Hydrogen Bonding on the 15N NMR Spectroscopy of Norditerpenoid Alkaloids and Their Piperidine-Ring Analogues.

1H-15N HMBC spectra of norditerpenoid alkaloids and their synthetic azabicyclic analogues were obtained to investigate the impacts of the through-space effect of steric compression, protonation, and formation of intramolecular hydrogen bonding on the 15N NMR spectroscopy of these natural products and their piperidine-containing analogues. A rare 15N NMR effect of steric compression is demonstrated in half-cage A/E-rings of norditerpenoid alkaloid free bases and their synthetic azabicyclic analogues, in which the distribution of the lone pair of electrons of the tertiary amine N-atom is sterically restricted by bridged cycloalkanes, e.g., cyclopentane, cyclohexane, and cycloheptane rings. This results in significant changes in the 15N chemical shift, typically by at least ∼10 ppm. The lone pair of electrons of the N-atom in the piperidine ring are sterically compressed whether the bridged cyclohexane ring adopts a chair or boat conformation. The 15N chemical shifts of 1α-OMe norditerpenoid alkaloid free bases significantly increase (ΔδN ≥ 15.6 ppm) on alkaloid protonation and thence the formation of an intramolecular hydrogen bond between N +-H and 1α-OMe. The intramolecular hydrogen bonds between the N-atom and 1α-OH of 1α-OH norditerpenoid alkaloid free bases, karacoline, condelphine, and neoline stabilize their A-rings, adopting an unusual twisted-boat conformation, and they also significantly increase δN of the tertiary amine N-atom.

The 1α-hydroxy-A-rings of norditerpenoid alkaloids are twisted-boat conformers.

The skeletal conformations of naturally occurring norditerpenoid alkaloids fix their substituent functional groups in space, thereby directing their bioactivities. Solution conformations of the A-rings of 4 selected norditerpenoid alkaloid free bases: mesaconitine, karacoline (karakoline), condelphine, and neoline (bullatine B), were analysed by NMR spectroscopy and single-crystal X-ray crystallography. They adopt twisted-chair, twisted-boat, twisted-boat, twisted-boat conformations, respectively. That the A-ring is stabilised in a boat conformer by an intramolecular H-bond from 1α-OH to the N-ethyl tertiary amine is also confirmed in the condelphine single crystal data. The conformations are a result of through-space repulsion between 12-He' and atoms attached to C1 (in the equatorial positions). This causes the A-rings with 1α-OR always to be twisted whether in a chair or a boat conformation. The impact of these studies is in providing a detailed understanding of the shape of the A-ring of these important biologically active natural product alkaloids.

Marine nucleosides: structure, bioactivity, synthesis and biosynthesis.

Nucleosides are glycosylamines that structurally form part of nucleotide molecules, the building block of DNA and RNA. Both nucleosides and nucleotides are vital components of all living cells and involved in several key biological processes. Some of these nucleosides have been obtained from a variety of marine resources. Because of the biological importance of these compounds, this review covers 68 marine originated nucleosides and their synthetic analogs published up to June 2014. The review will focus on the structures, bioactivities, synthesis and biosynthetic processes of these compounds.

An economical and environmentally friendly oxidative biaryl coupling promoted by activated MnO2.

An activated manganese dioxide (MnO2)-BF3·OEt2 oxidation system was developed to efficiently mediate the intramolecular as well as intermolecular biaryl coupling. The oxidative coupling proceeds smoothly at ambient temperature to deliver the corresponding five- to eight-membered tricyclic products in good to excellent yields. The employment of the combination of MnO2 and BF3·OEt2 is attractive on the basis of economical and environmental issues.

[Characteristics of acupuncture in Shanghan Lun (Treatise on Febrile Diseases)].

Through summarization and analysis on etiology, pathology and acupoint selection in chapters about acupuncture in Shanghan Lun (Treatise on Febrile Diseases), written by ZHANG Zhong-jing, famous physician of the Eastern Han Dynasty, five features of acupuncture in the book are concluded: to cut off the pathway of pathogenic factors to prevent progress of diseases; to adopt both acupuncture and herbal medicine to give full play to their respective advantages in treatment; to distinguish pathogenesis carefully and select the proper acupoints; to observe the progressing tendency of diseases to give treatment accordingly; and to understand that yang channels are appropriate for acupuncture, while yin channels can also be selected in treatment. In this way, the law of acupuncture of ZHANG Zhong-jing is expected to be better understood.