Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities.

The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.

Phytochemical and pharmacological properties of the genus Tamarix: a comprehensive review.

The genus Tamarix in the Tamaricaceae family consists of more than 100 species of halophyte plants worldwide that are mainly used to improve saline-alkali land and for coastal windbreaks, sand fixation, and afforestation in arid areas. A considerable number of species in this genus are also used as traditional medicines to treat various human diseases, especially in Asian and African countries. This review presents a comprehensive summary of 655 naturally occurring compounds derived from the genus Tamarix, categorized into flavonoids (18.0%), phenols (13.9%), tannins (9.3%), terpenoids (10.5%), essential oils (31.0%), and others (17.3%). The investigation revealed that the crude extracts and phytochemicals of this genus exhibited significant therapeutic potential, including anti-inflammatory, anti-Alzheimer, anticancer, antidiabetic, antibacterial, and antifungal activities. Six species of Tamarix have anticancer effects by causing cancer cell death, inducing autophagy, and stopping cell division. Seven species from the same genus have the potential for treating diabetes by inhibiting α-glycosidase activity, suppressing human islet amyloid polypeptide, regulating blood glucose levels, and modulating autophagy or inflammation. The focus on antibacterial and antidiabetic effects is due to the presence of volatile oil and flavonoid components. Extensive research has been conducted on the biological activity of 30 constituents, including 15 flavonoids, 5 phenols, 3 terpenoids, 1 tannin, and 6 others. Therefore, future research should thoroughly study the mechanisms of action of these and similar compounds. This is the most comprehensive review of the phytochemistry and pharmacological properties of Tamarix species, with a critical assessment of the current state of knowledge.

Narcissin induces developmental toxicity and cardiotoxicity in zebrafish embryos via Nrf2/HO-1 and calcium signaling pathways.

Narcissin is a natural flavonoid from some edible and traditional medicinal plants. It has been proven to have multiple biological functions and exhibits potential therapeutic effects on hypertension, cancer, and Alzheimer's disease. However, the toxicity of narcissin is largely unknown. Here, we revealed that narcissin treatment led to reduced hatchability, increased malformation rate, shorter body length, and slowed blood flow in zebrafish. Furthermore, bradycardia, pericardial edema, increased SV-BA distance, diminished stroke volume, ejection fraction, and ventricular short-axis shortening rate were also found. A large accumulation of ROS, increased apoptotic cells, and histopathological changes were detected in the heart region. Moreover, the gene expression profiles and molecular docking analysis indicated that Nrf2/HO-1 and calcium signaling pathways were involved in narcissin-induced toxicity. In conclusion, here we provide the first evidence that demonstrates narcissin-induced developmental toxicity and cardiotoxicity in zebrafish via Nrf2/HO-1 and calcium signaling pathways for the first time.

Apocynum venetum leaf extract alleviated doxorubicin-induced cardiotoxicity by regulating organic acid metabolism in gut microbiota.

Apocynum venetum leaf is commonly utilized for its beneficial effects in reducing blood pressure, inducing sedation, promoting diuresis, anti-aging, and cardioprotection, which also exhibit positive effects on the gut microbiota. The gut microbiota plays a role as an endocrine organ by producing bioactive metabolites that can directly or indirectly impact host physiology, specifically cardiovascular diseases. In this study, main chemical components of A. venetum leaf extract (AVLE) were identified by LC-MS, and an orally administered AVLE was employed to treat mice with doxorubicin (Dox)-induced cardiotoxicity. The results showed that AVLE contained hyperoside and oganic acids. The pharmacological findings revealed that AVLE regulated the gut microbiota, resulting in a significant increase in the levels of two organic acids, indole-3-propionic acid (IPA) and acetic acid (AA). Both IPA and AA exhibited the ability to reduce BNP, CK, and LDH levels in mice with Dox-induced cardiotoxicity. Moreover, IPA demonstrated an improvement in Dox-induced cardiac injury by inhibiting apoptosis, while AA promoted increased secretion of ghrelin through the parasympathetic nervous system, subsequently reducing cardiac fibrosis by decreasing collagen I, collagen III, and activin A. Hence, our study demonstrates that AVLE exerts a beneficial cardioprotective effect by modulating the gut microbiota, providing a potential novel target for the treatment and prevention of Dox-induced cardiotoxicity.

Traditional Chinese Medicine for Breast Cancer: A Review.

A total of 18% of global breast cancer (BC) deaths are attributed to BC in China, making it one of the five most common cancers there. There has been a steady rise in BC morbidity and mortality in women in the last few years and it is now a leading cancer among Chinese women. Conventional treatments for BC are currently effective but have several limitations and disadvantages, and Traditional Chinese medicine (TCM) plays a vital role in the overall process of cancer prevention and therapy. It is known that TCM can treat a variety of conditions at a variety of sites and targets. In recent years, increasingly, research has been conducted on TCM's ability to treat BC. TCM has shown positive results in the treatment of breast cancer and the adverse effects of radiotherapy and chemotherapy. This review describes the progress of clinical observation and mechanism research of TCM in the treatment of breast cancer in recent years. It provides some ideas and theoretical basis for the treatment of BC with TCM.

Clinical development and informatics analysis of natural and semi-synthetic flavonoid drugs: A critical review.

BACKGROUND: Flavonoids are one of the most important metabolites with vast structural diversity and a plethora of potential pharmacological applications, which have drawn considerable attention in the laboratory. Nevertheless, it remains uncertain how many candidates were progressed to clinical application. AIM OF REVIEW: We carried out a critical review of natural and semi-synthetic flavonoid drugs and candidates undergoing different clinical phases worldwide by applying an adequate search method and conducted a brief cheminformatic and bioinformatic analysis. It was expected that the obtained results might narrow the screening scope and reduce the cost of drug research and development. KEY SCIENTIFIC CONCEPTS OF REVIEW: To our knowledge, this is the most systematic summarization of flavonoid-based drugs and clinical candidates to date. It was found that a total of 19 flavonoid-based drugs have been approved for the market, and of these, natural flavonoids accounted for 52.6%. Besides, a total of 36 flavonoid-based clinical candidates are undergoing or suspended in different phases, and of these, natural flavonoids account for 44.4%. Thus, natural flavonoids remain the best option for finding novel agents/active templates, and when investigated in conjunction with synthetic chemicals and biologicals, they offer the potential to discover novel structures that can lead to effective agents against a variety of human diseases. Additionally, flavonoid-based marketed drugs have been successful in cardiovascular treatment, and the related drugs account for more than 30% of marketed drugs. However, the use of flavonoids as antineoplastic and immunomodulating agents is not likely for approximately 50% of the candidates suspended in the clinical stage. Interestingly, the marketed drugs covered a broader range of chemical spaces based on size, polarity, and three-dimensional structure compared to the clinical candidates. In addition, flavonoid glycosides with poor oral bioavailability account for 36.8% of the marketed drugs, and thus, they could be thoroughly investigated.

Comprehensive survey of target prediction web servers for Traditional Chinese Medicine.

Traditional Chinese medicine (TCM) is characterized by multi-components, multiple targets, and complex mechanisms of action and therefore has significant advantages in treating diseases. However, the clinical application of TCM prescriptions is limited due to the difficulty in elucidating the effective substances and the lack of current scientific evidence on the mechanisms of action. In recent years, the development of network pharmacology based on drug systems research has provided a new approach for understanding the complex systems represented by TCM. The determination of drug targets is the core of TCM network pharmacology research. Over the past years, many web tools for drug targets with various features have been developed to facilitate target prediction, significantly promoting drug discovery. Therefore, this review introduces the widely used web tools for compound-target interaction prediction databases and web resources in TCM pharmacology research, and it compares and analyzes each web tool based on their basic properties, including the underlying theory, algorithms, datasets, and search results. Finally, we present the remaining challenges for the promising future of compound-target interaction prediction in TCM pharmacology research. This work may guide researchers in choosing web tools for target prediction and may also help develop more TCM tools based on these existing resources.

PPARG: A Promising Therapeutic Target in Breast Cancer and Regulation by Natural Drugs.

Breast cancer (BC) is the most common type of cancer among females. Peroxisome proliferator-activated receptor gamma (PPARG) can regulate the production of adipocyte-related genes and has anti-inflammatory and anti-tumor effects. Our aim was to investigate PPARG expression, its possible prognostic value, and its effect on immune cell infiltration in BC, and explore the regulatory effects of natural drugs on PPARG to find new ways to treat BC. Using different bioinformatics tools, we extracted and comprehensively analyzed the data from the Cancer Genome Atlas, Genotype-Tissue Expression, and BenCaoZuJian databases to study the potential anti-BC mechanism of PPARG and potential natural drugs targeting it. First, we found that PPARG was downregulated in BC and its expression level correlates with pathological tumor stage (pT-stage) and pathological tumor-node-metastasis stage (pTNM-stage) in BC. PPARG expression was higher in estrogen receptor-positive (ER+) BC than in estrogen receptor-negative (ER-) BC, which tends to indicate a better prognosis. Meanwhile, PPARG exhibited a significant positive correlation with the infiltration of immune cells and correlated with better cumulative survival in BC patients. In addition, PPARG levels were shown to be positively associated with the expression of immune-related genes and immune checkpoints, and ER+ patients had better responses to immune checkpoint blocking. Correlation pathway research revealed that PPARG is strongly associated with pathways, such as angiogenesis, apoptosis, fatty acid biosynthesis, and degradation in ER+ BC. We also found that quercetin is the most promising natural anti-BC drug among natural medicines that upregulate PPARG. Our research showed that PPARG may reduce BC development by regulating the immune microenvironment. Quercetin as PPARG ligands/agonists is a potential natural drug for BC treatment.

Vitex rotundifolia L. f. and Vitex trifolia L.: A review on their traditional medicine, phytochemistry, pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Vitex rotundifolia L. f. and Vitex trifolia L. belong to the genus Vitex, and Vitex rotundifolia L. f. evolved from Vitex trifolia L. Both are essential ethnic medicinal plants with a long history, commonly used to treat headaches, fever, diarrhea, hair loss, wound recovery, and other diseases. AIM OF THE REVIEW: The research status of Vitex trifolia L. and its relative species Vitex rotundifolia L. f. were reviewed from the aspects of traditional medicinal use, phytochemistry, and pharmacological activities, to provide a reference for the further development and utilization of Vitex rotundifolia L. f. and Vitex trifolia L. MATERIALS AND METHODS: In this paper, a comprehensive search of published literature was conducted through various books and online databases to obtain relevant information on Vitex rotundifolia L. f. and Vitex trifolia L. The search terms "(Vitex rotundifolia) OR (Vitex trifolia) OR (Fructus viticis)" were entered in PubMed, Web of Science, China national knowledge infrastructure (CNKI), Wanfang Data, Baidu Scholar, respectively. In addition to setting the year threshold of "2018-2022" on Baidu Scholar, other databases searched all fields and found 889, 283, 1263, 1023, and 147 articles, respectively. Among them, review, repetition, overlapping data, and other reasons were excluded, and finally, a total of 164 articles were included in the review study. RESULTS: A total of 369 compounds have been identified, including 159 terpenoids, 51 flavonoids, 83 phenylpropanoids, and 76 other compounds. Pharmacological studies have shown that Vitex rotundifolia L. f. and Vitex trifolia L. have a variety of pharmacological activities, such as anti-tumor, analgesic, antipyretic, anti-inflammatory, antioxidant, antibacterial, and estrogen-like activity. Modern clinical use for treating cold headaches, diarrhea dysentery, irregular menstruation, and other diseases. CONCLUSIONS: As traditional medicinal plants, Vitex rotundifolia L. f. and Vitex trifolia L. have wealthy chemical constituents and extensive pharmacological activities and are widely used in clinical practice from traditional to modern times. However, the research on the pharmacological activities of Vitex rotundifolia L. f. and Vitex trifolia L. is not in-depth, and the potential active components still need to be explored.

Discovery of natural polyphenols from the wild vegetable Suaeda salsa L. with potential cardioprotective functions.

Suaeda salsa L. (Chenopodiaceae) is a wild vegetable distributed along the northern coast of China. Searching for potential agents with health benefits from S. salsa L. led to the identification of 14 flavonoids (1-14), eight phenolic acids (15-22), one coumarin (23), one benzoquinone (24), two sesquiterpenes (25, 26), and three lignins (27-29) from an aqueous ethanol (EtOH) extract of the above-ground whole plant using various column chromatographic methods. High-resolution electrospray ionization mass spectrometry (HRESIMS) analyses and nuclear magnetic resonance (1H and 13C NMR) spectroscopy were adopted to examine the structural properties of the compounds. To date, our study is the first to identify 20 compounds from this genus. Some compounds exhibited significant health benefits in zebrafish models. Compounds 2, 4, 23, and 28 significantly improved oxidative damage, while compounds 1-5, 7, 11, 13, 18, 19, and 23 significantly improved zebrafish lateral line neuromast inflammation. Additionally, compounds 1, 4, 8, 13, and 16 significantly promoted zebrafish angiogenesis, while compounds 3-5 and 18 significantly improved zebrafish arrhythmia. Furthermore, a flavonoid-targeted metabolomics study revealed that flavanone was the precursor of all of the flavonoids and had its highest accumulation in August, while the others showed their highest accumulation in September. Thus, the best time to harvest most of the bioactive polyphenols is during September. The present study revealed that the wild vegetable S. salsa L. might be developed as a potential cardioprotective functional food.

Ultrasonic-assisted stewing enhances the aroma intensity of chicken broth: A perspective of the aroma-binding behavior of fat.

This experiment investigated the underlying mechanism of ultrasonic-assisted stewing to enhance the aroma intensity of chicken broth by measuring fat content, oil droplet sizes, zeta potential, viscosity, surface protein loading, lipid oxidation, and aroma compound concentrations. As the thermo-ultrasound time increased, the fat content increased from 0.3 % to 1.2 %, resulting in a milky white appearance. After 1 h of thermo-ultrasound, the broth had the smallest particle size and the highest surface protein load, viscosity, and emulsion stability, as well as the highest total amount of aroma-active compounds of 314.70 ng/mg. With the further extension of thermo-ultrasound time, lipid oxidation increased, but the stability of chicken broth decreased, lowering the content of aroma-active compounds. These outcomes suggested that thermo-ultrasound could enhance the aroma intensity of chicken broth by increasing the fat content and the emulsion stability of the broth.

A bibliometric and visualization-based analysis of temozolomide research hotspots and frontier evolution.

The literature related to TMZ research in the Web of Science (WOS) database was analyzed using bibliometrics and visualization by Citespace and VOSviewer.The publication status (number of publications, institutions, and frequency of citations), collaborations, and research focus was analyzed to clarify the current situation of TMZ research. And the recent research on TMZ provides a detailed summary. Based on objective data analysis, this study provides a complete analysis portraying the progression of historical milestones in TMZ development and future research directions from various TMZ research domains.

MIS-TLIF or CLIF for single segmental lumbar degenerative disease.

We aimed to compare the effect of minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and Crenel lateral interbody fusion (CLIF) on single segmental lumbar degenerative disease. Patients with single segmental lumbar degenerative disease undergoing MIS-TLIF (n = 28) and CLIF (n = 28) were enrolled from April to October 2017. Preoperative medical history, anthropometric data, and clinical data were recorded. Visual analogue scores and Oswestry disability index (ODI) were assessed. Radiography was performed before and after surgery. X-ray films were evaluated according to the Bridwell method, visual analogue scores and ODI scores were evaluated. There were no significant differences in the gender, age, clinical diagnosis, involved segment or preoperative ODI score between 2 groups (P > .05). During 12-month follow-up, MIS-TLIF group had less intraoperative blood loss, drainage, postoperative bedridden time, and hospital stay (P < .05), but more operation time and radiation exposure time compared with CLIF group (P < .05). CLIF group reported less pain than MIS-TLIF group (P > .05). Both groups had similar lumbar fusion rate (P > .05). Overall, CLIF has less complications, less trauma and faster recovery for the treatment of single segmental lumbar degenerate disease when compared with MIS-TLIF. Evaluation of more patients and long-term follow-up are still needed to further validate our findings.

Structural Modifications and Biological Activities of Natural α- and ß-Cembrenediol: A Comprehensive Review.

As one of the most characteristic ingredients of glandular trichome secretions from Nicotiana tabacum L. (tobacco), natural cembrenediols, namely, (1S,2E,4S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (α-cembrenediol/α-CBD) and its C-4 epimer (ß-cembrenediol/ß-CBD), have attracted considerable attention for their potent antitumor, neuroprotective, antimicrobial, and other activities. Many researchers are committed to exploring the possibility of utilizing these two cembrenediols and their derivatives both in human medicine and in agricultural fungicides. To the best of our knowledge, this review is the first to provide a comprehensive summary of the chemical modifications and bioactivities of α- and ß-CBD from their discovery to the present day; the review highlights their potential medicinal value for humans. The extensive references from 1962 to 2022 provided herein were systematically gathered from the SciFinder, Web of Science, and Google Scholar databases. We expect this review to assist in providing practical ideas for future drug development based on α- and ß-CBD and in further facilitating the utilization of the tobacco cembrenediols.

The complete mitochondrial genome of Anas zonorhyncha (Swinhoe, 1866) (Anatidae: Anas).

The complete mitochondrial genome of Anas zonorhyncha was first reported. The length of the entire mitochondrial genome was 16,605 base pairs, including 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and a D-loop region. A phylogenetic tree of A. zonorhyncha was constructed with a group of related species in the family of Anatidae, indicating a close genetic relationship between A. zonorhyncha and A. poecilorhyncha.

Antifungal Secondary Metabolites Produced by the Fungal Endophytes: Chemical Diversity and Potential Use in the Development of Biopesticides.

Plant diseases caused by phytopathogenic fungi can lead to huge losses in the agricultural fields and therefore remain a continuous threat to the global food security. Chemical-based fungicides contributed significantly in securing crop production. However, indiscriminate application of fungicides has led to increased chemical resistance and potential risks to human health and environment. Thus, there is an urgent need for searching for new bioactive natural products and developing them into new biopesticides. Fungal endophytes, microorganisms that reside in the fresh tissues of living plants, are regarded as untapped sources of novel natural products for exploitation in agriculture and/or medicine. Chemical examination of endophytic fungi has yielded enormous antifungal natural products with potential use in the development of biopesticides. This review summarizes a total of 132 antifungal metabolites isolated from fungal endophytes in the past two decades. The emphasis is on the unique chemical diversity of these metabolic products, together with their relevant antifungal properties. Moreover, some "star molecules," such as griseofulvin and trichothecene, as well as their synthetic derivatives that possess high potential as candidates of new natural fungicides, are also presented herein.

Cytotoxic xanthones from the plant endophytic fungus Paecilamyces sp. TE-540.

One new xanthone, chryxanthone C (1), together with four known analogues (2-5), were isolated from the cultures of Paecilamyces sp. TE-540, an endophytic fungus obtained from the leaves of Nicotiana tabacum L. The structure of 1 was elucidated by comprehensive spectral analysis including HRESIMS and 1D/2D NMR, which were confirmed by Cu Kα X-ray crystallography. Compound 1 featured an unusual dihydropyran ring fused to an aromatic ring, rather than the commonly occurring prenyl moiety. The cytotoxicity of compounds 1-5 were evaluated against five human tumour cell lines and 4 exhibited moderate to strong cytotoxicities with IC50 values ranging from 5.6 to 14.2 µM.

Expression changes of IL-17 in zoledronic acid combined with PVP technology in the treatment of postmenopausal osteoporotic vertebral compression fracture and its predictive value of relapse.

OBJECTIVE: To investigate the expression of interleukin-17 (IL-17) in zoledronic acid combined with PVP technology for patients with postmenopausal osteoporotic vertebral compression fracture (OVCF) and its predictive value for relapse. METHODS: 101 OVCF patients treated in our hospital from April 2013 to January 2015 were collected as a research group and treated by zoledronic acid combined with PVP technology. 80 healthy people with physical examination were assigned to the control group. ELISA was used to detect the expression of IL-17 in serum of the two groups. Patients were followed up for 2 years. The expression of IL-17 before treatment was compared between patients with relapse and patients without relapse. The predictive value of IL-17 in relapse was drawn according to ROC curve. RESULTS: Before treatment, the expression of IL-17 in the research group increased significantly (p<0.05). After treatment, the expression of IL-17 in the research group decreased significantly (p<0.05). The level of IL-17 in patients with relapse was significantly higher than that in patients without relapse (p<0.05). CONCLUSIONS: IL-17 is highly expressed in postmenopausal patients with osteoporotic vertebral compression fracture and is expected to be a potential predictor of relapse in postmenopausal patients with OVCF.

Transcriptome Profiling and Cytological Assessments for Identifying Regulatory Pathways Associated With Diorcinol N-Induced Autophagy in A3 Cells.

Fungal secondary metabolites serve as a rich resource for exploring lead compounds with medicinal importance. Diorcinol N (DN), a fungal secondary metabolite isolated from an endophytic fungus, Arthrinium arundinis, exhibits robust anticancer activity. However, the anticancer mechanism of DN remains unclear. In this study, we examined the growth-inhibitory effect of DN on different human cancer cell lines. We found that DN decreased the viability of A3 T-cell leukemia cells in a time- and concentration-dependent manner. Transcriptome analysis indicated that DN modulated the transcriptome of A3 cells. In total, 9,340 differentially expressed genes were found, among which 4,378 downregulated genes and 4,962 upregulated genes were mainly involved in autophagy, cell cycle, and DNA replication. Furthermore, we demonstrated that DN induced autophagy, cell cycle arrest in the G1/S phase, and downregulated the expression of autophagy- and cell cycle-related genes in A3 cells. By labeling A3 cells with acridine orange/ethidium bromide, Hoechst 33,258, and monodansylcadaverine and via transmission electron microscopy, we found that DN increased plasma membrane permeability, structural disorganization, vacuolation, and autophagosome formation. Our study provides evidence for the mechanism of anticancer activity of DN in T-cell leukemia (A3) cells and demonstrates the promise of DN as a lead or even candidate molecule for the treatment of acute lymphoblastic leukemia.

Antimicrobial Meroterpenoids and Erythritol Derivatives Isolated from the Marine-Algal-Derived Endophytic Fungus Penicillium chrysogenum XNM-12.

One new meroterpenoid-type alkaloid, oxalicine C (1), and two new erythritol derivatives, penicierythritols A (6) and B (7), together with four known meroterpenoids (2-5), were isolated from the marine algal-derived endophytic fungus Penicillium chrysogenum XNM-12. Their planar structures were determined by means of spectroscopic analyses, including UV, 1D and 2D NMR, and HRESIMS spectra. Their stereochemical configurations were established by comparing the experimental and calculated electronic circular dichroism (ECD) spectra for compound 1, as well as by comparison of the optical rotations with literature data for compounds 6 and 7. Notably, oxalicine C (1) represents the first example of an oxalicine alkaloid with a cleaved α-pyrone ring, whereas penicierythritols A (6) and B (7) are the first reported from the Penicillium species. The antimicrobial activities of compounds 1-7 were evaluated. Compounds 1 and 6 exhibited moderate antibacterial effects against the plant pathogen Ralstonia solanacearum with minimum inhibitory concentration (MIC) values of 8 and 4 µg/mL, respectively. Compound 6 also possesses moderate antifungal properties against the plant pathogen Alternaria alternata with a MIC value of 8 µg/mL.