Deoxyshikonin: a promising lead drug grass against drug resistance or sensitivity to Helicobacter pylori in an acidic environment.

Helicobacter pylori (H. pylori) is closely associated with the diseases such as gastric sinusitis, peptic ulcers, and gastric adenocarcinoma. Its drug resistance is very severe, and new antibiotics are urgently needed. Nine comfrey compounds were screened by antimicrobial susceptibility testing, among which deoxyshikonin had the best inhibitory effect, with a minimum inhibitory concentration (MIC) of 0.5-1 µg/mL. In addition, deoxyshikonin also has a good antibacterial effect in an acidic environment, it is highly safe, and H. pylori does not readily develop drug resistance. Through in vivo experiments, it was proven that deoxyshikonin (7 mg/kg) had a beneficial therapeutic effect on acute gastritis in mice infected with the multidrug-resistant H. pylori BS001 strain. After treatment with desoxyshikonin, colonization of H. pylori in the gastric mucosa of mice was significantly reduced, gastric mucosal damage was repaired, inflammatory factors were reduced, and the treatment effect was better than that of standard triple therapy. Therefore, deoxyshikonin is a promising lead drug to solve the difficulty of drug resistance in H. pylori, and its antibacterial mechanism may be to destroy the biofilm and cause an oxidation reaction.

Relationship between Helicobacter pylori infection and digestive tract diseases and analysis of risk factors: a cross-sectional study based on 3867 Chinese patients.

Helicobacter pylori (H. pylori) infect nearly half of the global population, contributing to upper digestive tract diseases. This 2019 cross-sectional study included 3,867 patients undergoing esophagogastroduodenoscopy (EGD) and 2,875 undergoing both colonoscopy and EGD. Subjects were categorized into H. pylori positive and negative groups by rapid urease test (RUT). In addition to exploring the relationship between H. pylori infection and upper gastrointestinal diseases, this study further revealed that H. pylori infection was closely related to lower digestive tract diseases, including colorectal polyp (63.28%) and colorectal cancer (75.76%), as well as upper and lower gastrointestinal comorbidities, including chronic atrophic gastritis with colorectal polyp (79.85%), peptic ulcer with colorectal polyp (79.72%), gastric polyp with colorectal polyp (66.24%), and chronic atrophic gastritis with colorectal cancer (92.86%). Besides, a univariate logistic regression analysis was conducted to compare the differences between the two groups (including gender, nationality, marital status, smoking history, drinking history, living area, age, BMI, glycosylated hemoglobin, fasting blood glucose, total cholesterol, and triglyceride levels), the results identified marital status and age as independent risk factors for H. pylori infection (OR, 1.435; 95% CI, 1.042 to 1.977; OR, 1.007; 95% CI, 1.001 to 1.013). Further clarification of the correlation between the prevalence of gastrointestinal diseases and H. pylori infection will be important for H. pylori infection management strategies and the treatment and prevention of gastrointestinal diseases.

Microbial gatekeepers: unraveling the role of the gut microbiota enzyme DPP4 in diabetes management.

Wang et al. identified dipeptidyl peptidase 4 (DPP4) as a gut microbe-derived enzyme that impacts on host glucose metabolism. They further introduced a novel therapeutic, daurisoline-d4 (Dau-d4), a selective microbial DPP4 (mDPP4) inhibitor that shows promise in improving glucose tolerance, highlighting the potential of therapies that target both host enzymes and gut microbial enzymes.

FBXL19 promotes malignant behaviours by activating MAPK signalling and negatively correlates with prognosis in hepatocellular carcinoma.

FBXL19 is a member of the Skp1-Cullin-F-box family of E3 ubiquitin ligases and is linked to a variety of vital biological processes, such as cell proliferation, migration, and differentiation. Previous studies have identified it as an oncogene in breast cancer and glioma. However, its role in hepatocellular carcinoma (HCC) remains unclear. To comprehensively elucidate its role in tumour biology and its underlying mechanisms, a variety of sophisticated methods, including bioinformatics analysis, RNA-sequencing technique, and in vitro cell biology experiments, were used. Here, we found that FBXL19 was upregulated in patients with HCC and correlated with poor prognosis. In in vitro experiments, the specific targeting of short hairpin RNAs via lentiviruses successfully induced the knockdown of FBXL19, resulting in notable inhibition of the proliferation, migration, and invasion of HCC cells. Furthermore, FBXL19 downregulation resulted in significant induction of G0/G1 phase cell cycle arrest. Importantly, FBXL19 knockdown inhibited tumour malignant behaviour primarily by inactivating extracellular signal-regulated protein kinase 1/2 and p38 mitogen-activated protein kinases. In conclusion, this study revealed that FBXL19 was upregulated in patients with HCC, and that its expression was negatively correlated with prognosis. Thus, FBXL19 displays oncogenic properties in HCC by activating mitogen-activated protein kinase signalling.

Transcriptome sequencing and metabolome analysis reveal the metabolic reprogramming of partial hepatectomy and extended hepatectomy.

Surgical resection remains a critical treatment option for many patients with primary and secondary hepatic neoplasms. Extended hepatectomy (eHx) may be required for some patients with large tumors, which may cause liver failure and death. Partial hepatectomy (pHx) and eHx mouse models were constructed, liver tissues were sampled at 18, 36, and 72 h posthepatectomy. Transcriptome and metabolome analyses were employed to explore the different potential mechanisms in regeneration and injury between pHx and eHx. The results showed that eHx was associated with more severe liver injury and lower survival rates than pHx. Transcriptomics data showed there were 1842, 2129, and 1277 differentially expressed genes (DEGs) in eHx and 962, 1305, and 732 DEGs in pHx at 18, 36, and 72 h posthepatectomy, respectively, compared with the those in the sham groups. Compared with pHx, the number of DEGs in the eHx group reached a maximum of 230 at 18 h after surgery and decreased sequentially to 87 and 43 at 36 and 72 h. Metabolomics analysis identified a total of 1399 metabolites, and 48 significant differentially produced metabolites (DPMs) were screened between eHx and pHx. Combined analysis of DEGs and DPMs indicated that cholesterol metabolism and insulin resistance may be two important pathways for liver regeneration and mouse survival postextended hepatectomy. Our results showed the global influence of pHx and eHx on the transcriptome and metabolome in mouse liver, and revealed cholesterol metabolism and insulin resistance pathways might be involved in regeneration post-pHx and -eHx.

Linolenic acid-metronidazole inhibits the growth of Helicobacter pylori through oxidation.

BACKGROUND: Resistance to antibiotics is one the main factors constraining the treatment and control of Helicobacter pylori (H. pylori) infections. Therefore, there is an urgent need to develop new antimicrobial agents to replace antibiotics. Our previous study found that linolenic acid-metronidazole (Lla-Met) has a good antibacterial effect against H. pylori, both antibiotic-resistant and sensitive H. pylori. Also, H. pylori does not develop resistance to Lla-Met. Therefore, it could be used for preparing broad-spectrum antibacterial agents. However, since the antibacterial mechanism of Lla-Met is not well understood, we explored this phenomenon in the present study. AIM: To understand the antimicrobial effect of Lla-Met and how this could be applied in treating corresponding infections. METHODS: H. pylori cells were treated with the Lla-Met compound, and the effect of the compound on the cell morphology, cell membrane permeability, and oxidation of the bacteria cell was assessed. Meanwhile, the differently expressed genes in H. pylori in response to Lla-Met treatment were identified. RESULTS: Lla-Met treatment induced several changes in H. pylori cells, including roughening and swelling. In vivo experiments revealed that Lla-Met induced oxidation, DNA fragmentation, and phosphatidylserine ectropionation in H. pylori cells. Inhibiting Lla-Met with L-cysteine abrogated the above phenomena. Transcriptome analysis revealed that Lla-Met treatment up-regulated the expression of superoxide dismutase SodB and MdaB genes, both anti-oxidation-related genes. CONCLUSION: Lla-Met kills H. pylori mainly by inducing oxidative stress, DNA damage, phosphatidylserine ectropionation, and changes on cell morphology.

Corylin inhibits the progression of Non-small cell lung cancer cells by regulating NF-κB signaling pathway via targeting p65.

BACKGROUND: Lung cancer is characterized by high-risk and high mortality, among which non-small cell lung cancer (NSCLC) conquers a dominant position. Previous studies have reported that corylin has anti-inflammatory, anti-oxidant, and anti-tumor effects; however, its role in NSCLC cells remains unclear. HYPOTHESIS: Corylin inhibits the progression of NSCLC cells. METHODS: A lentivector NF-κB luciferase reporter was constructed by molecular cloning. Corylin was screened and identified as an NF-κB pathway inhibitor by luciferase reporter assay. Corylin inhibited the expression of NF-κB downstream genes, which was detected by qRT-PCR. The effect of corylin on NSCLC cells was detected by colony formation assay, cell apoptosis, cell proliferation, in vitro invasion, and cell scratch assay. Corylin inhibited p65 nuclear translocation and was detected by molecular docking, immunofluorescence assay, and Western blot analysis. RESULTS: We constructed a lentiviral expression vector, containing an NF-κB luciferase reporter and established a stable A549 cell line for its expression. Using this cell line, corylin was screened and identified as an NF-κB pathway inhibitor. It was found that corylin inhibited the expression of NF-κB downstream genes and inhibited the proliferation and migration of NSCLC cells. Meanwhile, it was also found that corylin significantly reversed the increased proliferation of NSCLC cell lines induced by p65 overexpression. Molecular docking analysis showed that corylin could bind to p65 by hydrogen bonding. Further study showed that corylin inhibited the NF-κB signaling pathway by blocking p65 nuclear translocation. CONCLUSIONS: Our study screened and identified corylin as an NF-κB inhibitor and elucidated the molecular mechanism by which corylin inhibits the growth of NSCLC cells. The present study provides a novel strategy for improving the prognosis and treatment of NSCLC patients.

Single-Cell Transcriptomics Reveals Killing Mechanisms of Antitumor Cytotoxic CD4+ TCR-T Cells.

T cell receptor-engineered T cells (TCR-Ts) have emerged as potent cancer immunotherapies. While most research focused on classical cytotoxic CD8+ T cells, the application of CD4+ T cells in adoptive T cell therapy has gained much interest recently. However, the cytotoxic mechanisms of CD4+ TCR-Ts have not been fully revealed. In this study, we obtained an MHC class I-restricted MART-127-35-specific TCR sequence based on the single-cell V(D)J sequencing technology, and constructed MART-127-35-specific CD4+ TCR-Ts and CD8+ TCR-Ts. The antitumor effects of CD4+ TCR-Ts were comparable to those of CD8+ TCR-Ts in vitro and in vivo. To delineate the killing mechanisms of cytotoxic CD4+ TCR-Ts, we performed single-cell RNA sequencing and found that classical granule-dependent and independent cytolytic pathways were commonly used in CD4+ and CD8+ TCR-Ts, while high expression of LTA and various costimulatory receptors were unique features for cytotoxic CD4+ TCR-Ts. Further signaling pathway analysis revealed that transcription factors Runx3 and Blimp1/Tbx21 were crucial for the development and killing function of cytotoxic CD4+ T cells. Taken together, we report the antitumor effects and multifaceted killing mechanisms of CD4+ TCR-Ts, and also indicate that MHC class I-restricted CD4+ TCR-Ts could serve as potential adoptive T cell therapies.

Ochraceopetalin, a Mixed-Biogenetic Salt of Polyketide and Amino Acid Origins from a Marine-Derived Aspergillus ochraceopetaliformis Fungus.

Ochraceopetalin (1), a mixed-biogenetic salt compound and its component 2 were isolated from the culture broths of a marine-derived fungus, Aspergillus ochraceopetaliformis. Based on combined spectroscopic and chemical analyses, the structure of 1 was determined to be a sulfonated diphenylether-aminol-amino acid ester guanidinium salt of an unprecedented structural class, while 2 was determined to be the corresponding sulfonated diphenylether. Ochraceopetaguanidine (3), the other guanidine-bearing aminol amino acid ester component, was also prepared and structurally elucidated. Compound 1 exhibited significant cytotoxicity against K562 and A549 cells.

Hydrogen abstraction/addition reactions in soot surface growth.

The hydrogen abstraction (HB) and addition reactions (HD) by H radicals are examined on a series of polycyclic aromatic hydrocarbon (PAH) monomers and models of quasi-surfaces using quasi-classical trajectory (QCT) method. QCT results reproduce the rate constants of HB reactions on PAH monomers from density functional theory (DFT) in the range of 1500-2700 K. The PAH size has a minor impact on the rates of HB reactions, especially at temperatures beyond 2100 K. In contrast, HD reactions have a clear size dependence, and a larger PAH yields a higher rate. It was also found that the preferred reaction pathway changes from HB to HD reactions at ∼1900 K. The rates of surface HB and HD reactions exceed those in the gas phase by nearly one factor of magnitude. Further analysis of the detailed trajectory of the QCT method reveals that about 50% of surface reactions can be attributed to the events of surface diffusion, which depends on the local energy transfer in gas-surface interactions. However, this phenomenon is not preferred in PAH monomers, as expected. Our finding here questions the treatment of the surface reactions of soot as the product of the first collision between the gaseous species and particle surface. The surface diffusion-induced reactions should be accounted for in the rates of the surface HB and HD reactions. The rate constants of HB and HD reactions on each reactive site (surface zig-zag, surface free-edge and pocket free-edge sites) were calculated by QCT method, and are recommended for the further development of surface chemistry models in soot formation.

LHPP inhibits hepatocellular carcinoma cell growth and metastasis.

Hepatocellular carcinoma (HCC) has a poor prognosis, owing to its high potential for growth and metastasis. In this study, we aimed to investigate the roles of Phospholysine Phosphohistidine Inorganic Pyrophosphate Phosphatase (LHPP)in human HCCcell growth and metastasis. We analyzed the LHPP expression level in human HCC tissues paired normal tissues in the Oncomine database, and assessed the relationship between the LHPP expression levels with HCC patient's overall survival and the prognostic value of LHPP in human HCC by Kaplan-Meier survival analysis. Real-time PCR and Western Blot were used to examine the expression levels of LHPP in normal liver cell line (LO2) and human HCC cell lines (SMCC-7721, HepG2, Huh7, MHCC-97 H, and LM3). Through lentivirus infection, we established human HCC stable cell lines (Huh7 and LM3) overexpressing LHPP. Then, we detected these cell viability, colony , and invasion. Subsequently, we performed the gene set enrichment analysis (GSEA) for the RNA-seq data of HCC patients from TCGA. Finally, we examined the expression level of several oncogenes, including CCNB1, PKM2, MMP7, and MMP9, in these cells via real-time PCR assay. Here, we found thatLHPPis significantly downregulated in the human HCC tissues paired normal tissues. Furthermore, the high expression level of LHPP is associated with better clinical outcomes in human HCC. Overexpression of LHPPinhibitscell growth and metastasis in human HCC cells, and LHPP expression levels negatively correlate with cell cycle and metastasis in HCC tissues. Moreover, the level of LHPP is negatively correlated with CCNB1, PKM2, MMP7, and MMP9 in human HCC cells and HCC tissues. These findings highlight a novel tumor suppressor in human HCC growth and metastasis, and provide a promising diagnostic and prognostic factor for humanHCC.

Antitumor Activity of Asperphenin A, a Lipopeptidyl Benzophenone from Marine-Derived Aspergillus sp. Fungus, by Inhibiting Tubulin Polymerization in Colon Cancer Cells.

Marine-derived microorganisms are a valuable source of novel bioactive natural products. Asperphenin A is a lipopeptidyl benzophenone metabolite isolated from large-scale cultivation of marine-derived Aspergillus sp. fungus. The compound has shown potent antiproliferative activity against various cancer cells. However, the underlying mechanism of action remained to be elucidated. In this study, we demonstrated the antitumor activity and molecular mechanism of asperphenin A in human colon cancer cells for the first time. Asperphenin A inhibited the growth of colon cancer cells through G2/M cell cycle arrest followed by apoptosis. We further discovered that asperphenin A can trigger microtubule disassembly. In addition to its effect on cell cycle, asperphenin A-induced reactive oxygen species. The compound suppressed the growth of tumors in a colon cancer xenograft model without any overt toxicity and exhibited a combination effect with irinotecan, a topoisomerase I inhibitor. Moreover, we identified the aryl ketone as a key component in the molecular structure responsible for the biological activity of asperphenin A using its synthetic derivatives. Collectively, this study has revealed the antiproliferative and antitumor mechanism of asperphenin A and suggested its possibility as a chemotherapeutic agent and lead compound with a novel structure.

TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway.

Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy.

The epigallocatechin gallate derivative Y6 reverses drug resistance mediated by the ABCB1 transporter both in vitro and in vivo.

Previously, we reported that Y6, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin (DOX)--mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y6 in reversing drug resistance both in vitro and in vivo by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter (ABCB1 or P-glycoprotein, P-gp). Our results showed that Y6 significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y6 significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y6 exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mouse tumor xenograft model, Y6 (110 mg/kg, intragastric administration), in combination with doxorubicin (2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y6 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.

Asperphenins A and B, Lipopeptidyl Benzophenones from a Marine-Derived Aspergillus sp. Fungus.

Asperphenins A (1) and B (2), novel diastereomeric lipopeptidyl benzophenone metabolites, were isolated from a marine-derived Aspergillus sp. fungus. On the basis of the results of combined spectroscopic analyses, the structures of these compounds were determined to be linear assemblies of three motifs: a hydroxy fatty acid, a tripeptide, and a trihydroxybenzophenone. The absolute configurations were assigned using chemical modifications and electronic circular dichroism (ECD) calculations. The novel compounds exhibited significant cytotoxicity on diverse cancer cells.

Lumazine peptides from the marine-derived fungus Aspergillus terreus.

Terrelumamides A (1) and B (2), two new lumazine-containing peptides, were isolated from the culture broth of the marine-derived fungus Aspergillus terreus. From the results of combined spectroscopic and chemical analyses, the structures of these compounds were determined to be linear assemblies of 1-methyllumazine-6-carboxylic acid, an amino acid residue and anthranilic acid methyl ester connected by peptide bonds. These new compounds exhibited pharmacological activity by improving insulin sensitivity, which was evaluated in an adipogenesis model using human bone marrow mesenchymal stem cells. In addition, the compounds exhibited fluorescence changes upon binding to DNA, demonstrating their potential applications to DNA sequence recognition.

Alkaloidal metabolites from a marine-derived Aspergillus sp. fungus.

Fumiquinazoline S (1), a new quinazoline-containing alkaloid, and the known fumiquinazolines F (6) and L (7) of the same structural class were isolated from the solid-substrate culture of an Aspergillus sp. fungus collected from marine-submerged wood. In addition, isochaetominines A-C (2-4) and 14-epi-isochaetominine C (5), new alkaloids possessing an unusual amino acid-based tetracyclic core framework related to the fumiquinazolines, were isolated from the same fungal strain. The structures of these compounds were determined by combined spectroscopic methods, and the absolute configurations were assigned by NOESY, ROESY, and advanced Marfey's analyses along with biogenetic considerations. The new compounds exhibited weak inhibition against Na(+)/K(+)-ATPase.

Cytotoxic diterpenoid pseudodimers from the Korean sponge Phorbas gukhulensis.

Four new cytotoxic diterpenoid pseudodimers (2-5), along with a previously reported one, gukulenin A (1), were isolated from the marine sponge Phorbas gukhulensis collected off the coast of Gagu-do, Korea. These novel compounds, designated gukulenins C-F (2-5), were determined by extensive spectroscopic analyses to be pseudodimers of the gagunins, like gukulenin A. The termini of the tropolone-containing side chains in gukulenins C-E (2-4) were found to have diverse modifications involving acetamides or taurine, whereas gukulenin F (5) was formed from 1 by the ring-opening of a cyclic hemiketal. The relative and absolute configurations were assigned by Murata's and modified Snatzke's methods using a HETLOC experiment and a CD measurement of a dimolybdenum complex, respectively. All of these compounds exhibited significant cytotoxicity against the K562 and A549 cell lines.