Regulatory mechanisms and potential therapeutic targets in precancerous lesions of gastric cancer: A comprehensive review.

Precancerous lesions of gastric cancer (PLGC) represent a critical pathological stage in the transformation from normal gastric mucosa to gastric cancer (GC). The global incidence of PLGC has been rising over the past few decades, with a trend towards younger onset ages. Increasing evidence suggests that early prevention and treatment of PLGC can effectively reverse the malignant development of gastric mucosal epithelial cells. However, there is currently a lack of effective therapeutic drugs and methods. Recent years have witnessed substantial advancements in PLGC research, with the elucidation of novel regulatory mechanisms offering promising avenues for clinical intervention and drug development. This review aims to delineate potential targets for early prevention and diagnosis of GC while exploring innovative approaches to PLGC management. This article focuses on elucidating the regulatory mechanisms of the inflammatory microenvironment, bile acids (BA), glycolysis, autophagy, apoptosis, ferroptosis, and cellular senescence. We pay particular attention to potential therapeutic targets for PLGC, with the goal of providing insights and theoretical basis for clinical research on PLGC.

Application of Subpatellar Venous Catheter Thrombolysis in Early Acute Lower Extremity Deep Vein Thrombosis.

Objective: To compare the effectiveness and safety of intravenous thrombolysis via the subpatellar vein versus the conventional popliteal vein approach in patients with early acute deep venous thrombosis (DVT) of the lower extremities. Methods: This study included 160 early-stage acute lower extremity DVT patients at our hospital from January 2020 to October 2023, randomly assigned to two groups using sealed envelopes. The control group underwent catheter-directed thrombolysis via the popliteal vein, while the study group received thrombolysis via the subpatellar vein. Surgical parameters, limb circumferences, blood parameters, vein patency, and adverse reactions were evaluated. Results: The study group had longer surgery and X-ray times, as well as a lower urokinase dose compared to the control group (P < .05), with no significant difference in thrombolysis time (P > .05). Thigh and calf circumferences and edema rates didn't significantly change before and after thrombolysis in both groups (P > .05). Hematological parameters, including PT, INR, APTT, FIB, TT, and D-D levels, remained similar between the two groups before and after thrombolysis (P > .05). However, after thrombolysis, both groups showed increased PT, INR, APTT, and TT levels and decreased FIB and D-D levels compared to before thrombolysis (P < .05). Porter scores showed no significant differences between the two groups before thrombolysis (P > .05), but after thrombolysis, both groups had reduced Porter scores, with the study group showing a more pronounced decrease (P < .05). Additionally, the study group had a higher vein patency rate and GCQ score than the control group (P < .05). Adverse reactions occurred at a similar rate in both groups (P > .05). Conclusion: Subpatellar vein catheter-directed thrombolysis offers a safe and more effective alternative to traditional popliteal vein approaches for early acute DVT of the lower extremities, improving outcomes such as vein patency and reducing the need for urokinase.

Pararorine A, isoindolinone alkaloid from the endophytic fungus Paramyrothecium roridum and its anti-tumor activity.

Pararorine A, a new isoindolinone alkaloid was isolated from Paramyrothecium roridum, an endophytic fungus from the medicinal plant Gynochthodes officinalis (F.C. How) Razafim. & B. Bremer. The structure of this compound was elucidated by extensive spectroscopic (UV, IR, MS, and NMR) analyses. In addition, the antitumor activity of pararorine A was evaluated against SF-268, MCF-7, HepG2, and A549 tumor cell lines. The results revealed that pararorine A exhibited potent antitumor activities with the IC50 values ranging from 1.69 to 8.95 µM. Moreover, the tumor cell inhibitory activity of pararorine A was evidenced by promoting cytochrome C release and cell cycle arrest as well as the induction of apoptosis by the up-regulation of the protein expressions of JNK and Bax through PARP-cleavage and caspase 3-cleavage.

Irpexols A-C, xanthone derivatives from the endophyte fungus Irpex laceratus A878.

Three new xanthone derivatives irpexols A-C (1-3) and five known xanthones including three dimeric ones were successfully isolated from Irpex laceratus A878, an endophytic fungus of the family Irpicaceae from the medicinal plant Pogostemon cablin (Blanco) Bentham (Lamiaceae). The structures of these compounds were elucidated by extensive spectroscopic analyses including ultraviolet-visible spectroscopy (UV), infrared spectroscopy (IR), mass spectrometry (MS), and nuclear magnetic resonance (NMR). All of the three new compounds (1-3) share a de-aromatic and highly­oxygenated xanthone skeleton. In addition, the cytotoxic activity of compounds 1-8 were evaluated against SF-268, MCF-7, HepG2, and A549 tumor cell lines. The results revealed that compound 6 showed moderate cytotoxic activity with the IC50 values ranging from 24.83 to 45.46 µM, while the IC50 values of the positive control adriamycin was ranging from 1.11 to 1.44 µM.

Expanding the Chemical Diversity of Grisechelins via Heterologous Expression.

Thiazole scaffold-based small molecules exhibit a range of biological activities and play important roles in drug discovery. Based on bioinformatics analysis, a putative biosynthetic gene cluster (BGC) for thiazole-containing compounds was identified from Streptomyces sp. SCSIO 40020. Heterologous expression of this BGC led to the production of eight new thiazole-containing compounds, grisechelins E, F, and I-N (1, 2, 5-10), and two quinoline derivatives, grisechelins G and H (3 and 4). The structures of 1-10, including their absolute configurations, were elucidated by HRESIMS, NMR spectroscopic data, ECD calculations, and single-crystal X-ray diffraction analysis. Grisechelin F (2) is a unique derivative, distinguished by the presence of a salicylic acid moiety. The biosynthetic pathway for 2 was proposed based on bioinformatics analysis and in vivo gene knockout experiments. Grisechelin E (1) displayed moderate antimycobacterial activity against Mycobacterium tuberculosis H37Ra (MIC of 8 µg mL-1).

A new phenylspirodrimane derivative from the deep-sea-derived fungus Stachybotrys chartarum FS705.

A new phenylspirodrimane derivative named stachybotrysin A (1), together with four known analogues (2-5) were isolated and purified from the solid culture of the deep-sea-derived Stachybotrys chartarum FS705. Their structures were determined by comprehensive spectroscopic analysis and the absolute configuration was evaluated by theoretical ECD calculations. Compounds 1-5 were evaluated for their cytotoxic, antibacterial and α-glucosidase inhibitory activities. The results showed that compound 2 displayed mild cytotoxicity with IC50 values in the range of 8.88 ∼ 22.73 µM against four human tumour cell lines, SF-268, MCF-7, HepG-2, and A549. Compound 1 showed strong α-glucosidase inhibitory activity with an IC50 value of 20.68 µM. Compounds 4 and 5 exhibited weak antibacterial activity against Bacillus subtilis.

A new secondary metabolite from the marine-derived fungus Phomopsis lithocarpus FS508.

Based on the One Strain-Many Compounds (OSMAC) strategy, the secondary metabolites of Phomopsis lithocarpus FS508 were investigated. As a result, a new secondary metabolite, 4-methoxy-3-[4-(acetyloxy)-3-methyl-2-butenyl]benzoic acid (1) as well as eleven known compounds were isolated from the fermentation product of the strain FS508. Their structures were determined by NMR, IR, UV, and MS spectroscopic data analyses. All the isolated compounds were evaluated for cytotoxic and anti-inflammatory activities. Among them, compounds 3 and 9 displayed potent cytotoxicity against HepG-2 cell line, and compounds 2, 3 and 12 showed significant anti-inflammatory activities.

Cytotoxic pyrone derivatives from the deep-sea-derived fungus Cladosporium halotolerans FS702.

Two new compounds (R)-6-((8S)-hydroxypropyl)-2-methyl-5,6-dihydro-4H-pyran-4-one (1) and (R)-6-((8R)-hydroxypropyl)-2-methyl-5,6-dihydro-4H-pyran-4-one (2), together with four known compounds were isolated from the marine-derived fungus Cladosporium halotolerans FS702. The structures of these compounds were determined on the basis of extensive spectroscopic analysis including 1D/2D NMR, IR, UV, HRESIMS, ECD calculations as well as the modified Mosher's method. Cytotoxic assay results showed that compound 2 had significant cytotoxic activity against SF-268, MCF-7, HepG-2, and A549 cells lines with IC50 values of 0.16, 0.47, 0.33 and 0.23 µM, respectively.

3-Carboxy-indole derivatives from the deep-sea-derived fungus Phomopsis tersa FS441.

Three new compounds phomtersines A-C (1-3) together with nine known compounds were isolated from the marine-derived fungus Phomopsis tersa FS441. Their structures were sufficiently established by spectroscopic methods, including extensive 1D and 2D NMR techniques and modified Snatzke's method. Moreover, compounds 1-12 were evaluated for cytotoxic and anti-inflammatory activities. As a result, phomtersine B (2) and the known compound 10 showed moderate cytotoxic activity against the four tested cell lines with IC50 values ranging from 20.21 to 36.53 µM, and phomtersine A (1) exhibited moderate inhibitory activity against LPS-induced NO production.

Cytospotones A-D, four new polyketones from the endophytic fungus Cytospora sp. A879.

Three new α-pyrone derivatives cytospotones A-C (1-3) and a new cyclohexenone derivative cytospotone D (4) together with four known α-pyrones were isolated from the endophytic fungus Cytospora sp. A879 of Pogostemon cablin (Blanco) Benth. The structures of 1-4 were elucidated primarily by spectroscopic methods (1D, 2D NMR and HRESIMS), ECD spectra analyses, and ECD calculations. Furthermore, the four new compounds (1-4) were evaluated for their anti-inflammatory and α-glucosidase inhibitory activities. The results showed that compound 1 had moderate inhibitory effect on LPS-induced NO production in RAW 264.7 macrophages.

Anti-Inflammatory Phomalones from the Deep-Sea-Derived Fungus Trichobotrys effuse FS522.

Four new phomalones A-D (1-4), together with five known analogues (5-9) were isolated from the deep-sea-derived fungus Trichobotrys effuse FS522. Their structures of the new compounds established by analysis of their NMR and HR-ESI-MS spectroscopic data, and the absolute configurations of 2 was determined by electronic circular dichroism (ECD) calculations. compounds 4, 6 and 8 substantially inhibited the production of nitric oxide (NO) with IC50 values of 4.64, 13.90, and 34.07 µM.

Potential Anti-Candida albicans Mechanism of Trichoderma Acid from Trichoderma spirale.

Candida albicans is the main causal pathogen of fungal infections in human beings. Although diverse anti-C. albicans drugs have been explored, the drug resistance and side effects of these drugs are intensifying. Thus, it is urgent to explore new anti-C. albicans compounds from natural products. In this study, we identified trichoderma acid (TA), a compound from Trichoderma spirale with a strong inhibitory effect on C. albicans. Transcriptomic and iTRAQ-based proteomic analyses of TA-treated C. albicans in combination with scanning electronic microscopy and reactive oxygen species (ROS) detection were performed to investigate the potential targets of TA. The most significant differentially expressed genes and proteins after TA treatment were verified through Western blot analysis. Our results revealed that mitochondrial membrane potential, endoplasmic reticulum, ribosomes in the mitochondria, and cell walls were disrupted in TA-treated C. albicans, leading to the accumulation of ROS. The impaired enzymatic activities of superoxide dismutase further contributed to the increase in ROS concentration. The high concentration of ROS led to DNA damage and cell skeleton destruction. The expression levels of Rho-related GTP-binding protein RhoE (RND3), asparagine synthetase (ASNS), glutathione S-transferase, and heat shock protein 70 were significantly up-regulated in response to apoptosis and toxin stimulation. These findings suggest that RND3, ASNS, and supereoxide dismutase 5 are the potential targets of TA, as further demonstrated through Western blot analysis. The combination of transcriptomic, proteomic, and cellular analyses would provide clues for the anti-C. albicans mechanism of TA and the defensive response mechanism of C. albicans. TA is thus recognized as a promising new anti-C. albicans leading compound that alleviates the hazard of C. albicans infection in human beings.

Saikosaponin A and Its Epimers Alleviate LPS-Induced Acute Lung Injury in Mice.

The purpose of this work was to illustrate the effect of processing with vinegar on saikosaponins of Bupleurum chinense DC. (BC) and the protective effects of saikosaponin A (SSA), saikosaponin b1 (SSb1), saikosaponin b2 (SSb2), and saikosaponin D (SSD) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice. We comprehensively evaluated the anti-inflammatory effects and potential mechanisms of SSA, SSb1, SSb2, and SSD through an LPS-induced ALI model using intratracheal injection. The results showed that SSA, SSb1, SSb2, and SSD significantly decreased pulmonary edema; reduced the levels of IL-6, TNF-α, and IL-1ß in serum and lung tissues; alleviated pulmonary pathological damage; and decreased the levels of the IL-6, TNF-α, and IL-1ß genes and the expression of NF-κB/TLR4-related proteins. Interestingly, they were similar in structure, but SSb2 had a better anti-inflammatory effect at the same dose, according to a principal component analysis. These findings indicated that it may not have been comprehensive to only use SSA and SSD as indicators to evaluate the quality of BC, especially as the contents of SSb1 and SSb2 in vinegar-processed BC were significantly increased.

Polyketones from the endophytic fungus Cytospora rhizophorae.

Cytosporaphenones D (1) and E (2), two new polyketones, and one new natural product 1,7-dihydroxy-6-methyl-8-formylxanthone (3), along with four known compounds, were isolated from Cytospora rhizophorae, an endophytic fungus from Morinda officinalis. Their structures were elucidated by extensive spectroscopic analyses and X-ray diffraction technique.

Alkyl aromatic derivatives from the endophytic fungus Cytospora rhizophorae.

Two new alkylresorcinols named herein 5'-methoxy-integracins A-B (1-2), two new monomeric alkyl aromatic derivatives 3-(7-hydroxyheptyl)-5-methoxyphenol (5) and 7-(3,5-dihydroxyphenyl) heptyl acetate (6), along with four known compounds including integracins A-B (3-4), 2,4-dihydroxy-6-(8-hydroxyoctyl) benzene (7), and cytosporone B (8) were isolated from the endophytic fungus Cytospora rhizophorae A761. The structures of the four new compounds were elucidated by NMR, HRESIMS data, and electronic circular dichroism (ECD) calculations, whereas the compounds 1 and 2 were disclosed as a class of the natural rare-occurring dimeric alkylresorcinol derivatives. Moreover, the bioassays of the new compounds clarified that compound 1 was a potent inhibitor for the α-glucosidase, and compound 2 showed relatively good activity against the tumor cell lines. It is worth mentioning that the known compound integracin B (4) was first reported to display significant antibacterial activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 6.25 µg ml-1.

Cytospones E-J from the endophytic fungus Cytospora rhizophorae.

Cytospones E-J (1-6), six unreported α-pyrone derivatives, together with six known ones (7-12) were isolated from the solid culture of the endophytic fungus Cytospora rhizophorae A761, an endophytic fungus from Gynochthodes officinalis. The structures of the unreported compounds were unambiguously elucidated through spectroscopic analyses (1D, 2D NMR and HRESIMS), and their absolute configurations were assigned by single-crystal X-ray diffraction (Cu Kα) analyses. Furthermore, cytospones E-J were evaluated for anti-inflammatory and α-glucosidase inhibitory activities.

Cyophiobiolins A-D, ophiobolin sestertepenoids from Cytospora rhizophorae.

Cyophiobiolins A-D, four unreported ophiobolin-type sesterterpenoids, were isolated from Cytospora rhizophorae A761, an endophytic fungus from Gynochthodes officinalis. The structures of these undescribed compounds were fully characterized on the basis of extensively spectroscopic data (1D, 2D NMR and HRESIMS) and single-crystal X-ray diffraction analyses. Moreover, cyophiobiolins A-D were evaluated for in vitro cytotoxic, anti-inflammatory, and antibacterial activities. Cyophiobiolins A-B showed inhibitory potency against lipopolysaccharide (LPS)-induced oxide production with IC50 values of 66.3 µM and 53.3 µM, respectively.

Two New Phenylhydrazone Derivatives from the Pearl River Estuary Sediment-Derived Streptomyces sp. SCSIO 40020.

Two new phenylhydrazone derivatives and one new alkaloid, penzonemycins A-B (1-2) and demethylmycemycin A (3), together with three known compounds including an alkaloid (4) and two sesquiterpenoids (5-6), were isolated from the Streptomyces sp. SCSIO 40020 obtained from the Pearl River Estuary sediment. Their structures and absolute configurations were assigned by 1D/2D NMR, mass spectroscopy and X-ray crystallography. Compound 1 was evaluated in four human cancer cell lines by the SRB method and displayed weak cytotoxicity in three cancer cell lines, with IC50 values that ranged from 30.44 to 61.92 µM, which were comparable to those of the positive control cisplatin. Bioinformatic analysis of the putative biosynthetic gene cluster indicated a Japp-Klingemann coupling reaction involved in the hydrazone formation of 1 and 2.

Neocucurbols A-H, Phomactin Diterpene Derivatives from the Marine-Derived Fungus Neocucurbitaria unguis-hominis FS685.

Neocucurbols A-D (1-4) are diterpene derivatives that possess a complex 6/6/5/5/6 polycyclic ring system with a characteristic tetrahedrofuran bridge ring skeleton. Neocucurbols E-H (5-8) are diterpenes that feature a 6/8/6 tricyclic ring system. Their structures were unambiguously determined by detailed spectroscopic analyses, X-ray diffractions studies, and ECD calculations. All compounds (1-8) were evaluated for in vitro antimicrobial and cytotoxic activities.