Four lathyrane diterpenoids from the seeds of Euphorbia lathyris.

Four new diterpenoids, including three secolathyrane diterpenoids (1-3) and one lathyrane diterpenoid (4), together with seven known diterpenoids, were obtained in the shelled seeds of Euphorbia lathyris. In particular, 1-3 possess a rare split ring structure, and currently only one compound with the same skeleton has been identified in E. lathyris. Compound 4 furnishes an unprecedented oxygen bridge structure. The structures were identified using various spectral techniques, including NMR, HR-ESI-MS, single-crystal X-ray diffraction and calculated electronic circular dichroism (ECD). The biosynthetic pathway of 1-4 was inferred. Furthermore, the cytotoxic activities of all compounds (1-11) were measured on three human tumor cells. New compounds 2 and 3 showed moderate cytotoxic activities against U937 cells with IC50 values of 22.18 and 25.41 µM, respectively.

Auranofin inhibits the occurrence of colorectal cancer by promoting mTOR-dependent autophagy and inhibiting epithelial-mesenchymal transformation.

Colorectal cancer (CRC) is one of the world's most common and deadly cancers. According to GLOBOCAN2020's global incidence rate and mortality estimates, CRC is the third main cause of cancer and the second leading cause of cancer-related deaths worldwide. The US Food and Drug Administration has approved auranofin for the treatment of rheumatoid arthritis. It is a gold-containing chemical that inhibits thioredoxin reductase. Auranofin has a number of biological activities, including anticancer activity, although it has not been researched extensively in CRC, and the mechanism of action on CRC cells is still unknown. The goal of this research was to see how Auranofin affected CRC cells in vivo and in vitro . The two chemical libraries were tested for drugs that make CRC cells more responsive. The CCK-8 technique was used to determine the cell survival rate. The invasion, migration, and proliferation of cells were assessed using a transwell test and a colony cloning experiment. An electron microscope was used to observe autophagosome formation. Western blotting was also used to determine the degree of expression of related proteins in cells. Auranofin's tumor-suppressing properties were further tested in a xenograft tumor model of human SW620 CRC cells. Auranofin dramatically reduced the occurrence of CRC by decreasing the proliferation, migration, and invasion of CRC cells, according to our findings. Through a mTOR-dependent mechanism, auranofin inhibits the epithelial-mesenchymal transition (EMT) and induces autophagy in CRC cells. Finally, in-vivo tests revealed that auranofin suppressed tumor growth in xenograft mice while causing no harm. In summary, auranofin suppresses CRC cell growth, invasion, and migration. Auranofin inhibits the occurrence and progression of CRC by decreasing EMT and inducing autophagy in CRC cells via a mTOR-dependent mechanism. These findings suggest that auranofin could be a potential chemotherapeutic medication for the treatment of human CRC.

Establishment and validation of a clinical diagnostic model for gastric low-grade intraepithelial neoplasia.

OBJECTIVE: A clinical diagnostic model of gastric low-grade intraepithelial neoplasia (LGIN) was developed and validated to improve the identification of precancerous lesions in gastric cancer. METHODS: A retrospective analysis of 1211 patients with chronic atrophic gastritis (CAG) and 1089 patients with LGIN admitted to the Endoscopy Center of the First Affiliated Hospital of Bengbu Medical College from January 2016 to December 2021 was performed to record basic clinical and pathological information.A total of 1756 patients were included after screening and were divided unequally and randomly into 2 groups, one for establishing an LGIN predictive nomogram (70% of patients) and the other for external validation of the model (30% of patients). R software was used for statistical analysis. RESULTS: The nomogram was built with 10 predictors: age, sex, lesion location, intestinal metaplasia, multiple location, lesion size, erosion, edema, surface white fur, and form. The calibration curves showed good agreement between the predicted and actual diagnoses. The C-indexes were 0.841 (95% CI: 0.820-0.863) in the training dataset, 0.833 in the internal validation dataset, and 0.842 in the external validation dataset (Hosmer-Lemeshow test, P = .612), showing satisfactory stableness. CONCLUSIONS: This study provides a visual mathematical model that can be used to diagnose high-risk LGIN, improve follow-up or endoscopic treatment and the detection rate of precancerous gastric cancer lesions, reduce the incidence of gastric cancer, and provide a reliable basis for the treatment of LGIN.

Colloidal bismuth pectin-containing quadruple therapy as the first-line treatment of Helicobacter pylori infection: A multicenter, randomized, double-blind, non-inferiority clinical trial.

BACKGROUND: Bismuth-containing quadruple therapy is an effective regimen for Helicobacter pylori (H. pylori) treatment. No head-to-head comparison trials have been conducted to evaluate the efficacy of colloidal bismuth pectin (CBP) in quadruple therapy for eradicating H. pylori. We aimed to compare the efficacy and safety of CBP quadruple therapy and bismuth potassium citrate (BPC) quadruple therapy for 14 days in the first-line treatment of H. pylori. METHODS: In this multicenter, randomized, double-blind, non-inferiority clinical trial, H. pylori-infected subjects without eradication history were randomized to receive amoxicillin 1 g twice daily, tetracycline 500 mg three time daily, esomeprazole 20 mg twice daily in combination with CBP 200 mg three time daily or BPC 240 mg twice daily for 14 days. 13 C-urea breath tests were used to access the eradication rate at least 4 weeks after treatment. RESULTS: Between April 2021 and July 2022, 406 patients were assessed for eligibility and 339 subjects were randomized. The cure rates (primary outcome) of CBP and BPC quadruple therapy were 90.5% and 92.3% (p = 0.56) by intention-to-treat analysis, respectively, and 96.1% and 96.2% (p = 1.00) by per-protocol analysis, respectively. CBP quadruple therapy was non-inferior to BPC quadruple therapy in the intention-to-treat and per-protocol analysis (p < 0.025). The frequency of adverse events and compliance were not different among the two groups (p > 0.05). CONCLUSIONS: Both CBP and BPC quadruple therapy for 14 days provide high efficacy, good compliance, and safety in the first-line treatment of H. pylori in China.

Efficacy of keverprazan for duodenal ulcer: A phase II randomized, double-blind, parallel-controlled trial.

BACKGROUND AND AIM: Considering the limitation of varying acid suppression of proton pump inhibitors, this study was aimed to assess the efficacy, safety, and dose-effect relationship of keverprazan, a novel potassium-competitive acid blocker, in the treatment of duodenal ulcer (DU) compared with lansoprazole. METHODS: A randomized, double-blind, double-dummy, multicenter, low-dose, high-dose, and positive-drug parallel-controlled study was conducted to verify the non-inferiority of keverprazan (20 or 30 mg) to lansoprazole of 30 mg once daily for 4 to 6 weeks and dose-effect relationship of keverprazan in the treatment of patients with active DU confirmed by endoscopy. RESULTS: Of the 180 subjects randomized, including 55 cases in the keverprazan_20 mg group, 61 cases in the keverprazan_30 mg group, and 64 cases in the lansoprazole_30 mg group, 168 subjects (93.33%) completed the study. The proportions of healed DU subjects in the keverprazan_20 mg, keverprazan_30 mg, and lansoprazole_30 mg groups were respectively 87.27%, 90.16%, and 79.69% at week 4 (P = 0.4595) and were respectively 96.36%, 98.36%, and 92.19% at week 6 (P = 0.2577). The incidence of adverse events in the keverprazan_20 mg group was lower than that in the lansoprazole_30 mg (P = 0.0285) and keverprazan_30 mg groups (P = 0.0398). CONCLUSIONS: Keverprazan was effective and non-inferior to lansoprazole in healing DU. Based on the comparable efficacy and safety data, keverprazan of 20 mg once daily is recommended for the follow-up study of acid-related disorders. (Trial registration number: ChiCTR2100043455.).

Association between lactate-to-albumin ratio and 28-days all-cause mortality in patients with acute pancreatitis: A retrospective analysis of the MIMIC-IV database.

Objective: The Lactate-to-Albumin Ratio (LAR) has been applied as a new predictor in sepsis, heart failure, and acute respiratory failure. However, the role of LAR in predicting all-cause mortality in patients with acute pancreatitis has not been evaluated. Therefore, this study aimed to elucidate the correlation between LAR and 28-d all-cause mortality in patients with Acute Pancreatitis (AP). Methods: This study is a retrospective cohort study with the data from the MIMIC-IV (v1.0) database. We included adult patients with acute pancreatitis who were admitted to the intensive care unit in the study. The primary outcome was to evaluate the ability of LAR to predict death at 28-d of hospital admission in patients with AP. Results: A total of 539 patients with acute pancreatitis were included in this study. They were divided into a survival group (486 patients) and a death group (53 patients) according to whether they survived within 28-d of admission, and the mortality rate of patients within 28-d of admission was 9.8%. LAR was shown to be an independent predictor of all-cause mortality within 28-d of admission in patients with AP by multivariate COX regression analysis (HR, 1.59; 95% CI, 1.23 - 2.05; P < 0.001). the Area Under the Curve (AUC) value for LAR was 74.26% (95% CI: 67.02% - 81.50%), which was higher than that for arterial blood lactate (AUC = 71.25%) and serum albumin (AUC = 65.92%) alone. It was not inferior even when compared to SOFA (AUC = 75.15%). The optimal cutoff value for separating the survival and death groups according to Receiver Operating Characteristic (ROC) was found to be 1.1124. plotting Kaplan-Meier analysis with this cutoff value showed that patients with LAR ≥ 1.1124 had significantly higher all-cause mortality within 28-d of admission than those with LAR < 1.1124 (P < 0.001). The final subgroup analysis showed no significant interaction of LAR with each subgroup (P for interaction: 0.06 - 0.974). Conclusion: LAR can be used as an independent predictor of all-cause mortality in AP patients within 28-d of admission, with superior prognostic performance than arterial blood lactate or serum albumin alone.

A new quinolone alkaloid from the fruits of Tetradium ruticarpum.

A rare new quinolone alkaloid containing three degrees of unsaturation in the side chain, named as 1-methyl-2-[(6Z,9Z,12Z)-6,9,12-pentadecatriene]-4(1H)-quinolone (1), together with three known quinolone alkaloids 1-methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]-4(1H)-quinolone (2), 1-methyl-2-[(4Z,7Z)-4,7-tridecadienyl]-4(1H)-quinolone (3), 1-methyl-2-[(Z)-8-tridecenyl]-4(1H)-quinolone (4), were isolated from the fruits of Tetradium ruticarpum (A.Juss.) T.G.Hartley. Their structures were elucidated by physicochemical properties and spectroscopic data. All compounds were evaluated for their cytotoxic activities against three human tumor cell lines, including Lovo, MDA-MB-231, HeLa cells, by MTT method in 96-well microplates, and compounds 1 exhibited potent activity against MDA-MB-231 cells with IC50 values of 7.95 µM.

Mechanisms and pharmacokinetic/pharmacodynamic profiles underlying the low nephrotoxicity and ototoxicity of etimicin.

Etimicin (ETM), a fourth-generation aminoglycosides (AGs), is now widely clinically used in China due to its high efficacy and low toxicity. However, the mechanisms underlying its low nephrotoxicity and ototoxicity remain unclear. In the present study we compared the antibacterial and toxicity profiles of etimicin, gentamicin (GM, a second-generation AG), and amikacin (AMK, a third-generation AG), and investigated their pharmacokinetic properties in the toxicity target organs (kidney and inner ear) and subcellular compartments. We first demonstrated that ETM exhibited superior antibacterial activities against clinical isolates to GM and AMK, and it exerted minimal nephrotoxicity and ototoxicity in rats following multi-dose administration. Then, we conducted pharmacokinetic studies in rats, showed that the three AGs accumulated in the kidney and inner ear with ETM being distributed to a lesser degree in the two toxicity target organs as compared with GM and AMK high-dose groups. Furthermore, we conducted in vitro experiments in NRK-52E rat renal tubular epithelial cells and HEI-OC1 cochlear hair cells, and revealed that all the three AGs were distributed predominantly in the mitochondria with ETM showing minimal accumulation; they not only directly inhibited the activity of mitochondrial complexes IV and V but also inhibited mitochondrial function and its related PGC-1α-NRF1-TFAM pathway; ETM caused minimal damage to the mitochondrial complex and mitochondrial biogenesis. Our results demonstrate that the minimal otonephrotoxicity of ETM results from its lesser accumulation in mitochondria of target cells and subsequently lesser inhibition of mitochondrial function. These results provide a new strategy for discovering novel AGs with high efficacy and low toxicity.

Two new quinolone alkaloids from the nearly ripe fruits of Tetradium ruticarpum.

Tetradium ruticarpum (Juss.) Benth. belong to the family of Rutaceae. The complete and nearly ripe fruits of T. ruticarpum is used as traditional Chinese medicine and phytochemical investigations have been conducted on extracts of the seeds of T. ruticarpum to provide scientific validation of its properties. In this study, we successfully isolated two new quinolone alkaloids (1-2) from the MeOH extractive of nearly ripe fruits of T. ruticarpum. The structure elucidation of these compounds was determined by one- and two-dimensional nuclear magnetic resonance, ultraviolet and electrospray ionisation time-of-flight mass spectrometry. This finding expands the understanding of the natural constituents of the Rutaceae, in particular, the Tetradium genera.

Wuchuyuamide V, a new amide alkaloid from the fruits of Tetradium trichotomum.

Tetradium trichotomum Lour., is a plant species endemic to tropical South East Asia with particular medicinal importance. However, very little analysis in this plant has been studied up to now from a phytochemical viewpoint. One new amide alkaloid (wuchuyuamide V, 1), as well as two known amide alkaloids-wuchuyuamide III (2), and wuchuyuamide I (3) were obtained from the fruits of T. trichotomum for the first time. The structures of wuchuyuamide V (1) and wuchuyuamide III (2) were unambiguously elucidated by 1D and 2D-NMR spectra, mass spectrometry, and single-crystal X-ray diffraction.

The complete chloroplast genome of Torilis scabra (Apiaceae).

Torilis scabra (Thunb.) DC. is widely distributed in China and Japan and has been introduced to North America. In this study, the complete chloroplast genome sequence of the T. scabra was obtained by de novo assembly using the NGS data. The chloroplast genome of T. scabra was 157,855 bp in length and divided into four distinct regions, such as large single-copy region (85,362 bp), small single-copy region (17,993 bp), and a pair of inverted repeat regions (27,250 bp). The genome annotation predicted a total of 127 genes, including 82 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. Phylogenetic analysis with reported chloroplast genomes showed that T. scabra has a close genetic relationship with Anthriscus cerefolium.

The complete chloroplast genome of Ageratum conyzoides (Asteraceae).

Ageratum conyzoides L. is an important Chinese medicinal plant. In this study, we reported the complete chloroplast genome of A. conyzoides. The chloroplast genome sequence is 151,309 bp in length and consisted of a large single copy (LSC) region (83,884 bp), a small single copy (SSC) region (17,771 bp), and two inverted repeats (IRs) (24,827 bp). It was composed of 126 genes and they were 81 protein-coding genes, 30 tRNA genes, 8 rRNA genes, and 7 pseudogene. Phylogenetic analysis with reported chloroplast genomes can not only show that A. conyzoides has a close genetic relationship with Centaurea diffusa and Carthamus tinctorius, but also provide new evidence for the identification of Praxelis clematidea and A. conyzoides.

Apatinib, a selective VEGFR2 inhibitor, improves the delivery of chemotherapeutic agents to tumors by normalizing tumor vessels in LoVo colon cancer xenograft mice.

Tumor vascular normalization has been proposed as a therapeutic strategy for malignant neoplasms, which can also interpret the synergistic effect of anti-angiogenesis agents combined with chemotherapy. Apatinib (Apa), a highly selective VEGFR2 inhibitor, attracts much attentions due to its encouraging anticancer activity, especially in the clinical trials of combined treatment. In this study, we investigated whether Apa could promote vascular normalization in tumor in a certain time window. Mice bearing LoVo colon cancer xenograft were orally administrated Apa (150 mg kg-1 per day) for 5, 7, 10, or 12 days. Apa significantly inhibited tumor growth and decreased the microvessel density. Using multi-photon microscopy and electron microscopy, we found that Apa improved tumor vessel morphology by pruning distorted vessel branches and decreased the gap between endothelial cells after a 7-day treatment. Furthermore, Apa decreased vessel leakage and increased pericyte coverage on vascular endothelial cells, suggesting that tumor vessels were more mature and integrated. The intratumoral distribution of adriamycin (ADR) in Apa group was improved from day 7 to 10 without change in plasma drug concentration. Tumor blood perfusion was also increased in this window, and the expression of hypoxia induced factor 1α was downregulated, suggesting the effect of Apa on alleviating tumor hypoxic micro-environment. In conclusion, Apa may improve the effective perfusion of tumor vessels and increase the intratumoral distribution of ADR in a certain time window via normalizing tumor vessels. This normalization window (7 to 10 days of treatment) may contribute to develop a regimen of combined medication in clinic use of Apa.

Three new quinazolines from Evodia rutaecarpa and their biological activity.

In this research, we investigated the profile and bioactivities of quinazoline alkaloids, a class of natural products boasting multiple bioactivities, from the unripe fruit of Evodia rutaecarpa (Juss.) Benth. Three new quinazoline alkaloids, evodiamide A (1), evodiamide B (2), and evodiamide C (3), as well as eight known quinazolines, were isolated from the MeOH extract of E. rutaecarpa. The new compounds are rare quinazolinedione derivatives with linked heterocyclic nuclei. Among these quinazolines, rhetsinine (8) showed potential as a pesticide and exhibited excellent inhibition against Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicola, and Xanthomonas campestris pv. campestris, with respective EC50 values of 3.13, 14.32, and 32.72 nmol.

Suaeglaucin A, a new coumaronochromone from Suaeda glauca.

A new isoflavane, suaeglaucin A (1), which was isolated from the herb of Suaeda glauca (Bunge) Bunge, was elucidated as 5,6,8-trimethoxy-7- hydroxycoumaronochromone based on its MS and 1D and 2D NMR spectroscopic data. The structure of compound 1 was confirmed by X-ray crystallographic analysis. Five known compounds (2-6) were also isolated. All compounds were isolated for the first time from Chenopodiaceae. We found that compounds 2 and 4 possessed moderate antioxidant activity.

Genome-wide searches and molecular analyses highlight the unique evolutionary path of flavone synthase I (FNSI) in Apiaceae.

Flavone synthase is a key enzyme for flavone biosynthesis and is encoded by two gene families: flavone synthase I (FNSI) and flavone synthase II (FNSII). FNSII is widely distributed in plants, while FNSI has been reported in rice (Oryza sativa) and seven species of Apiaceae. FNSI has likely evolved from the duplication of flavanone 3ß-hydroxylase (F3H). In this study, we used multiple bioinformatics tools to identify putative FNSI and F3H genes from 42 publicly available genome and transcriptome datasets. Results showed that rice FNSI does not share a common ancestral sequence with other known FNSI genes and that FNSI is absent from species outside of Apiaceae. Positive selection site identification analysis revealed that four sites within the FNSI tree branches of Apiaceae evolved under significant positive selection. The putative F3H genes identified in this study provide a valuable resource for further function analysis of flavone synthase.

Hesperetin alleviates renal interstitial fibrosis by inhibiting tubular epithelial-mesenchymal transition in vivo and in vitro.

Hesperetin (HES) is a flavonoid that has been reported to exert protective effects against cardiac remodeling, lung fibrosis and hepatic fibrosis. However, reports on the effects and potential mechanisms of HES in renal fibrosis are limited. In the present study, a unilateral ureteric obstruction (UUO) mouse model and a transforming growth factor (TGF)-ß1-activated normal rat kidney (NRK)-52E cell model were established. HES was subsequently administered to these models to evaluate its anti-fibrotic effects and potential underlying mechanisms of action. The results demonstrated that HES reduced obstruction-induced renal injury and deposition of the extracellular matrix components collagen-I and fibronectin in UUO mouse kidneys (P<0.05). Furthermore, HES treatment significantly suppressed EMT, as evidenced by decreased expression of α-smooth muscle actin and E-cadherin, (P<0.05). Additionally, HES inhibited the hedgehog signaling pathway in UUO mice and TGF-ß1-treated NRK-52E cells. The present findings indicate that HES treatment may inhibit EMT and renal fibrosis in vivo and in vitro by antagonizing the hedgehog signaling pathway.

Oxymatrine inhibits renal fibrosis of obstructive nephropathy by downregulating the TGF-ß1-Smad3 pathway.

This study investigated whether oxymatrine (OMT) treatment can ameliorate renal interstitial fibrosis in unilateral ureteral obstruction (UUO) mice model. Moreover, the potential mechanisms of such treatment were analyzed. Twenty-four C57/BL6 mice were randomly divided into three groups, namely sham group, vehicle plus unilateral ureteral obstruction (UUO)-treated group, and 100 mg/kg/d OMT plus UUO-treated group. All mice were euthanized seven days after surgery, and their kidneys were harvested. Renal injury, fibrosis, expression of proinflammatory cytokines, and the transforming growth factor-ß1/Smads (TGF-ß/Smads) and nuclear factor-kappa B (NF-κB)-signaling pathways were assessed. The results showed OMT significantly prevented kidney injury and fibrosis, as evidenced by decreased expression of collagen-1 and fibronectin. Furthermore, OMT administration inhibited the release of inflammatory factors including tumor necrosis factor-α, (TNF-α) interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), as well as phosphorylated NF-κB p65. In addition, OMT blocked the activation of myofibroblasts by inhibiting the TGF-ß/Smad3-signaling pathway. The findings indicate that OMT-attenuated renal fibrosis and inflammation, and this renoprotective effect may be ascribed to the inactivation of the TGF-ß/Smad3 and NF-κB p65 pathways.

[Chemical Constituents of Ethyl Acetate Fraction of Suaeda glauca].

OBJECTIVE: To study the chemical constituents of Suaeda glauca. METHODS: The chemical constituents were isolated and purified with several separation and purification techniques. Their structures were identified by physicochemical properties and various spectroscopic methods. RESULTS: Ten compounds were isolated from the ethyl acetate fraction as lignoceric acid (1), ß-amyrin-n-nonyl ether(2), ß-sitosterol(3), ß-daucosterol(4), quercetin(5), luteolin(6), luteolin-7-O-ß-D-glucoside(7), isorhamnetin(8), scopoletin (9) and stigmasterol(10). CONCLUSION: Compounds 1, 2, 6, 7, 8, 9 and 10 are isolated from Suaeda genus for the first time and compounds 3 - 5 are isolated from this plant for the first time.

[Investigation on human Cryptosporidium infection in local area of Anhui Province].

OBJECTIVE: To investigate the status of Cryptosporidium infection in the population in the local area of Anhui Province, and discuss the risk factors of the infection, so as to provide the evidence for the prevention and treatment of cryptosporidiosis. METHODS: Qianshan County and Lingbi County of Anhui Province were selected as investigation spots, and the oocysts of Cryptosporidium in the feces of the investigation objects and the specific IgG antibody against Cryptosporidium in the serum were checked by using the pathogenic modified acid fast staining method and ELISA, respectively, so as to determine the status of Cryptosporidium infection in these investigation objects. At the same time, the questionnaire surveys were conducted in the investigation objects so as to know about the risk factors of Cryptosporidium infection. RESULTS: A total of 668 people were investigated in the two counties, 635 people received etiological examinations, and 15 people were positive with the positive rate of 2.36%; 642 people received serological examinations, and 140 people were positive with the positive rate of 21.81%; 628 people received pathogenic and serological examinations at the same time, and the examination results of the both methods showed that 12 people were positive (there were 4 people in Qianshan County and 8 people in Lingbi County) , and the positive rate was 1.94%. The rates of Cryptosporidium infection in the population of Qianshan County and Lingbi County were 1.24% (4/322) and 2.71% (8/295) respectively, and the difference had no statistical significance (P > 0.05). The single factor analysis found that the rate of Cryptosporidium infection was higher in the children and diarrhea patients; the multivariate logistics regression analysis indicated that the rate of Cryptosporidium infection was higher in the people who bred poultry and the diarrhea patients. CONCLUSIONS: The positive rate of serum antibody of Cryptosporidium in the population of the local area of Anhui Province is higher, which indicates that the previous infection is serious, and the rate of Cryptosporidium infection in human is relative to the age, diarrhea and whether there are poultries to be bred in the family, which is worthy of attention in the future prevention and treatment.