Abdominal aortic aneurysm (AAA) is a deadly condition of the aorta, carrying a significant risk of death upon rupture. Currently, there is a dearth of efficacious pharmaceutical interventions to impede the advancement of AAA and avert it from rupturing. Here, we investigated dihydromyricetin (DHM), one of the predominant bioactive flavonoids in Ampelopsis grossedentata (A. grossedentata), as a potential agent for inhibiting AAA. DHM effectively blocked the formation of AAA in angiotensin II-infused apolipoprotein E-deficient (ApoE^-/-) mice. A combination of network pharmacology and whole transcriptome sequencing analysis revealed that DHM's anti-AAA action is linked to heme oxygenase (HO)-1 (Hmox-1 for the rodent gene) and hypoxia-inducible factor (HIF)-1α in vascular smooth muscle cells (VSMCs). Remarkably, DHM caused a robust rise (∼10-fold) of HO-1 protein expression in VSMCs, thereby suppressing VSMC inflammation and oxidative stress and preserving the VSMC contractile phenotype. Intriguingly, the therapeutic effect of DHM on AAA was largely abrogated by VSMC-specific Hmox1 knockdown in mice. Mechanistically, on one hand, DHM increased the transcription of Hmox-1 by triggering the nuclear translocation and activation of HIF-1α, but not nuclear factor erythroid 2-related factor 2 (NRF2). On the other hand, molecular docking, combined with cellular thermal shift assay (CETSA), isothermal titration calorimetry (ITC), drug affinity responsive target stability (DARTS), co-immunoprecipitation (Co-IP), and site mutant experiments revealed that DHM bonded to HO-1 at Lys243 and prevented its degradation, thereby resulting in considerable HO-1 buildup. In summary, our findings suggest that naturally derived DHM has the capacity to markedly enhance HO-1 expression in VSMCs, which may hold promise as a therapeutic strategy for AAA.

Gelsemium elegans (G. elegans) is an extremely poisonous plant that is widely distributed in southern China and southeastern Asia. G. elegans poisoning events occur frequently in southern China, and are therefore an urgent public health problem requiring multidisciplinary action. However, the toxic components and toxicological mechanisms remain unclear. Here, we describe a systematic investigation on the toxic components of G. elegans, resulting in the isolation and identification of 120 alkaloids. Based on acute toxicity screening, the structure-toxicity relationship of Gelsemium alkaloids was proposed for the first time. Moreover, gelsedine- and humantenine-type alkaloids were detected in the clinical blood sample, and were confirmed to be causative in the poisoning. The most toxic compound, gelsenicine (1), had selective inhibitory effects toward ventral respiratory group (VRG) neurons in the medulla, which is the main brain region controlling respiration in the central nervous system. Gelsenicine (1) strongly inhibited the firing of action potentials in VRG neurons through its ability to stimulate GABA_A receptors, the main receptors involved in inhibitory neurotransmission. Application of GABA_A receptor antagonists successively reversed action potential firing in gelsenicine (1)-treated VRG neurons. Importantly, the GABA_A receptor antagonists securinine and flumazenil significantly increased the survival of poisoned animals. Our findings provide insight into the components and mechanisms of G. elegans toxicity, and should assist the development of effective emergency treatments for G. elegans poisoning.

Purpose To investigate the clinicopathological and molecular genetic characteristics of Warthin-like mucoepidermoid carcinoma(WLMEC).Methods Eight cases of WLMEC were collected.HE staining,immunohisto-chemistry,and fluorescence in situ hybridization were performed to observe their histological morphology,immunophe-notype,and molecular genetic characteristics.Clinical information was analyzed,and follow-up was conducted.Re-sults Among the eight cases of WLMEC,three were male and five were female,aged from 28 to 65 years(median age:47 years),all occurring in the parotid gland.All eight cases had clear boundaries and appeared as polycystic structures.Besides the homogeneously eosinophilic material,blue-stained mucoid material was visible in the cyst cavi-ty.The epithelium was arranged in various ways,including single-layer,double-layer,or multi-layer.The cells had a bland-looking morphology with round or oval nuclei.Compared to Warthin tumor,the cytoplasm was significantly less eosinophilic and flatter.Mitotic figures were rare.A prominent lymphoid stroma with abundant plasma cell infiltration was observed,especially in areas adjacent to the epithelium.The tumor cells expressed CK(AE1/AE3),CK5/6,p63,and CK7.The epithelial arrangement was disordered,unlike the typical double-layered structure seen in Warthin tumor.The Ki67 index ranged from 1％to 5％.MAML2 gene rearrangement was detected in all eight cases.No recur-rence was observed during the follow-up period of 1 to 54 months after surgical resection.Conclusion WLMEC is a rare low-grade malignant tumor originating from salivary glands.Compared with Warthin tumor,patients with WLMEC are younger and more commonly female.The presence of epithelial cells that are not typically arranged in a regular double layer with strong eosinophilia,as well as the abundance of plasma cells beneath the epithelium,serve as impor-tant diagnostic clues.Performing MAML2 gene testing on suspicious cases can aid in the accurate diagnosis of this dis-ease.

Purpose To investigate the clinicopathological and molecular genetic characteristics of Warthin-like mucoepidermoid carcinoma(WLMEC).Methods Eight cases of WLMEC were collected.HE staining,immunohisto-chemistry,and fluorescence in situ hybridization were performed to observe their histological morphology,immunophe-notype,and molecular genetic characteristics.Clinical information was analyzed,and follow-up was conducted.Re-sults Among the eight cases of WLMEC,three were male and five were female,aged from 28 to 65 years(median age:47 years),all occurring in the parotid gland.All eight cases had clear boundaries and appeared as polycystic structures.Besides the homogeneously eosinophilic material,blue-stained mucoid material was visible in the cyst cavi-ty.The epithelium was arranged in various ways,including single-layer,double-layer,or multi-layer.The cells had a bland-looking morphology with round or oval nuclei.Compared to Warthin tumor,the cytoplasm was significantly less eosinophilic and flatter.Mitotic figures were rare.A prominent lymphoid stroma with abundant plasma cell infiltration was observed,especially in areas adjacent to the epithelium.The tumor cells expressed CK(AE1/AE3),CK5/6,p63,and CK7.The epithelial arrangement was disordered,unlike the typical double-layered structure seen in Warthin tumor.The Ki67 index ranged from 1％to 5％.MAML2 gene rearrangement was detected in all eight cases.No recur-rence was observed during the follow-up period of 1 to 54 months after surgical resection.Conclusion WLMEC is a rare low-grade malignant tumor originating from salivary glands.Compared with Warthin tumor,patients with WLMEC are younger and more commonly female.The presence of epithelial cells that are not typically arranged in a regular double layer with strong eosinophilia,as well as the abundance of plasma cells beneath the epithelium,serve as impor-tant diagnostic clues.Performing MAML2 gene testing on suspicious cases can aid in the accurate diagnosis of this dis-ease.

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba, a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba, can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

[This corrects the article DOI: 10.1016/j.apsb.2021.08.015.].

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.

To study the chemical constituents of petroleum ether extract from the stems and leaves of Humulus scandens (family of Moraceae), fifteen compounds were isolated from the stems and leaves of H.scandens by silica gel, Sephadex LH-20, ODS, and preparative HPLC chromatography.The structures were identified by physicochemical data and spectroscopic method as tectochrysin (1), chrysin (2), 5-hydroxy-3, 4'', 6, 7-tetramethoxyflavone (3), (2S)-5-hydroxy-7, 8-dimethoxyflavanone (4), imperatorin (5), phellopterin (6), ethyl 4-hydroxy-3-(3''-methyl-2''-butenyl)benzoate (7), p-hydroxy-phenylpropionic acid (8), ethyl p-hydroxycinnamate (9), p-hydroxybenzaldehyde (10), anofinic acid (11), 5,6-dehydrokavain (12), physcion (13), olean-12-ene-3,?11-dione (14) and ergosta-4, 6, 8 (14), 22-tetraen-3-one (15), respectively.All compounds were isolated from this plant for the first time.

Eleven alkaloids were isolated from the twigs and leaves of Ervatamia pandacaqui using chromatographic methods of silica gel, Sephadex LH-20, ODS, and HPLC.Their structures were elucidated by physical,chemical and spectroscopic methods and determined as voacristine 7-hydroxyindolenine (1),iboxygaine (2), 19S-hydroxyibogamine (3), 3-oxotabersonine (4), perivine (5), pericyclivine (6), rhazinalinol (7), geissoschizol (8), 3, 14-dihydroolivacine (9), vallesamine (10), and conolobine A (11), respectively.All compounds were isolated from this plant for the first time.