Antioxidant aromatic compounds from Amomum villosum and target prediction of active ingredients.

The dried fruit of Amomum villosum is an important spice and medicinal plant that has received great attention in recent years due to its high content of bioactive components and its potential for food additives and drug development. However, the stems and leaves of A. villosum are usually disposed of as waste. Based on the study of the fruits of A. villosum, we also systematically studied its stems and leaves. Fourteen aromatic compounds (1-14) were isolated and identified from A. villosum, including five new compounds (1-5) and nine known compounds (6-14). Among them, compounds 2-5, 8-10, 12-13 were obtained from the fruits of A. villosum, and compounds 1, 6-7,11, 14 were isolated from the stems and leaves of A. villosum. Based on chemical evidence and spectral data analysis (UV, ECD, Optical rotation data, 1D and 2D-NMR, and HR-ESI-MS), the structures of new compounds were elucidated. Furthermore, all compounds were tested for their effects on the survival rate of BV-2 cells in the presence of hydrogen peroxide. Among them, compound 5 showed antioxidant effects. Through network pharmacology screening and the cell thermal shift assay (CETSA), the Phosphoglycerate Mutase 5 (PGAM5) protein was identified as the antioxidant target of compound 5. Molecular docking results showed that compound 5 maintains binding to PGAM5 by forming hydrogen bond interactions with Lys93 and Agr214. In summary, A. villosum had potential medicinal and food values due to the diverse bioactive components.

The mechanism of UNC-51-like kinase 1 and the applications of small molecule modulators in cancer treatment.

Autophagy is a process of self-renewal in cells, which not only provides the necessary nutrients for cells, but also clears necrotic organelles. Autophagy disorders are closely related to diseases such as cancer. UNC-51-like kinase 1 (ULK1) is a serine/threonine protein kinase that plays a crucial role in receiving input from energy and nutrient sensors, activating autophagy to maintain cellular homeostasis under stressful conditions. In recent years, targeting ULK1 has become a highly promising strategy for cancer treatment. This review introduces the regulatory mechanism of ULK1 in autophagy through the AMPK/mTOR/ULK1 pathway and reviews the research progress of ULK1 activators and inhibitors and their applications in cancer treatment. In addition, we analyze the binding modes between ULK1 and modulators through virtual molecular docking, which will provide a reliable basis and theoretical guidance for the design and development of new therapeutic drugs targeting ULK1.

Coumarins and flavones with anti-inflammatory activity isolated from the branches and leaves of Daphne retusa.

In this study, two new (1, 13) and fourteen known (2-12, 14-16) compounds were isolated from the branches and leaves of Daphne retusa. On the basis of chemical evidence and spectral data analysis (UV, ECD NMR, and HR-ESI-MS), the structures of new compounds were elucidated. Furthermore, all compounds have been tested for their inhibitory effects on NO production in LPS-induced RAW 264.7 cells, and compound 3 showed obvious inhibitory effect. Through target screening and molecular docking technology, potential binding targets for compound 3 to exert anti-inflammatory effects have been predicted.

Phenolics and terpenoids with good anti-inflammatory activity from the fruits of Amomum villosum and the anti-inflammatory mechanism of active diterpene.

The fruits of Amomum villosum are often considered a medicinal and food homologous material and have been found to have therapeutic effects in chronic enteritis, gastroenteritis, and duodenal ulcer. The aim of this study is to discover the anti-inflammatory active ingredients from dried ripe fruits of A. villosum and to elucidate the molecular mechanisms. We verified that the inhibitory activity of the ethyl acetate extract was superior to Dexamethasone (Dex), so we ultimately chose to study the ethyl acetate extract from the fruits of A. villosum. A total of 33 compounds were isolated from its ethyl acetate extract, including nine known diterpenoids (compounds 1-9), twelve known sesquiterpenoids (compounds 10-21), ten known phenolics (compounds 22, 23, 25-29, 31-33) and two new phenolics (24 and 30). On the basis of chemical evidences and spectral data analysis (UV, ECD, Optical rotation data, 1D and 2D-NMR, HR-ESI-MS, NMR chemical shift calculations), the structures of new compounds were elucidated. Among these compounds, isocoronarin D (5) was found to have good anti-inflammatory activity. Further research has found that isocoronarin D can down-regulate the protein levels of COX2 and NOS2, activate Nrf2/Keap1 and suppress NF-κB signaling pathway in LPS-induced RAW264.7 cells. In addition, isocoronarin D inhibited inflammasome assembly during inflammasome activation by hampering the binding of NLRP3 and ASC. Further evidence revealed that isocoronarin D suppressed the assembly of the NLRP3 inflammasome via blocking the formation of ASC specks. From these results, isocoronarin D may be the important bioactive compound of A. villosum and exhibits anti-inflammatory effects by regulating the NF-κB/Nrf2/NLRP3 axis in macrophages.

Cytotoxic withanolides from the stems and leaves of Physalis ixocarpa.

The stems and leaves of the tomatillo (Physalis ixocarpa or Physalis philadelphica) were considered agricultural waste during the processing of tomatillo fruits. However, their potential value for utilization has not yet been explored. The investigation resulted in the isolation of a total of 29 withanolides, out of which 15 never reported. These newly discovered withanolides were then tested for their cytotoxicity against eight different human tumor cell lines. Compounds 2-3, 6-7, 17, 19, and 25-27 displayed encouraging cytotoxic effects. Given the potent inhibitory activity of physagulin C (25) on the proliferation of HepG2 cells in vitro, further investigation was conducted to determine its molecular mechanism. Physagulin C inhibited epithelial-mesenchymal transition (EMT) process through the down-regulation of the JAK2/STAT3 and PI3K/AKT/mTOR pathways. Withanolides presenting in the stems and leaves of tomatillo make the plant possess potential commercial importance. Therefore, tomatillos could be commercialized worldwide in the food and pharmaceutical industries.

Research progress of hexokinase 2 in inflammatory-related diseases and its inhibitors.

Hexokinase 2 (HK2) is a crucial enzyme involved in glycolysis, which converts glucose into glucose-6-phosphate and plays a significant role in glucose metabolism. HK2 can mediate glycolysis, which is linked to the release of inflammatory factors. The over-expression of HK2 increases the production of pro-inflammatory cytokines, exacerbating the inflammatory reaction. Consequently, HK2 is closely linked to various inflammatory-related diseases affecting multiple systems, including the digestive, nervous, circulatory, respiratory, reproductive systems, as well as rheumatoid arthritis. HK2 is regarded as a novel therapeutic target for inflammatory-related diseases, and this article provides a comprehensive review of its roles in these conditions. Furthermore, the development of potent HK2 inhibitors has garnered significant attention in recent years. Therefore, this review also presents a summary of potential HK2 inhibitors, offering promising prospects for the treatment of inflammatory-related diseases in the future.

Nectin-4 has emerged as a compelling target for breast cancer.

The incidence of breast cancer in women has increased year by year, becoming one of the most common malignant tumors in females worldwide. Most patients can be treated with surgery and endocrine drugs, but there are still some patients who lack effective treatment, such as triple-negative breast cancer (TNBC). Nectin-4, a protein encoded by poliovirus receptor-associated protein 4, is a Ca2+-independent immunoglobulin-like protein. It is mainly involved in the adhesion between cells. In recent years, studies have found that Nectin-4 is overexpressed in breast cancer and several other malignancies. Otherwise, several monoclonal antibodies and inhibitors targeting Nectin-4 have shown prosperous outcomes, so Nectin-4 has great potential to be a therapeutic target for breast cancer. The present review systematically describes the significance of Nectin-4 in each aspect of breast cancer, as well as the molecular mechanisms of these aspects mediated by Nectin-4. We further highlight ongoing or proposed therapeutic strategies for breast cancer specific to Nectin-4.

Arf6 as a therapeutic target: Structure, mechanism, and inhibitors.

ADP-ribosylation factor 6 (Arf6), a small G-protein of the Ras superfamily, plays pivotal roles in multiple cellular events, including exocytosis, endocytosis, actin remodeling, plasma membrane reorganization and vesicular transport. Arf6 regulates the progression of cancer through the activation of cell motility and invasion. Aberrant Arf6 activation is a potential therapeutic target. This review aims to understand the comprehensive function of Arf6 for future cancer therapy. The Arf6 GEFs, protein structure, and roles in cancer have been summarized. Comprehending the mechanism underlying Arf6-mediated cancer cell growth and survival is essential. The structural features of Arf6 and its efforts are discussed and may be contributed to the discovery of future novel protein-protein interaction inhibitors. In addition, Arf6 inhibitors and mechanism of action are listed in the table. This review further emphasizes the crucial roles in drug resistance and attempts to offer an outlook of Arf6 in cancer therapy.

[Nursing cooperation in surgical collection of testis tissues from prepubertal male patients for cryopreservation: A study of 4 cases].

OBJECTIVE: To explore nursing cooperation in surgical collection of the testis tissue from prepubertal male patients for cryopreservation. METHODS: We retrospectively analyzed the methods and effects of perioperative nursing in surgical collection of the testis tissue from 4 prepubertal male patients for cryopreservation in our Center of Reproductive Medicine. Before, during and after operation, we took strict measures in making sterilized ice containers, intraoperative nursing cooperation, protection of the isolated testis tissues and transferring of the samples. RESULTS: Testis tissues were successfully collected from all the 4 prepubertal males, 31, 31, 20 and 34 samples from each case respectively, well protected and subjected to slow cryopreservation after standard processing in the embryo laboratory. CONCLUSION: In surgical collection of the testis tissue for cryopreservation, preparation of sterilized ice containers, intraoperative nursing cooperation and protection and transferring of the samples are essential for standard processing and cryopreservation of the testis tissue in the embryo laboratory.

Three New Labdane-Type Diterpenoids from the Fruits of Amomum villosum and Their Anti-Inflammatory Activities.

Three new labdane-type diterpenoids, calcaratarin E, villosumtriol, and 12-epi-villosumtriol (1-3) were isolated from the fruits of Amomum villosum, along with seven known diterpenoids (4-10). Through comprehensive analysis of chemical evidence and spectral data including UV, 1D and 2D NMR, HR-ESI-MS, IR, and X-ray crystallography, the structures of these novel compounds were successfully determined. Additionally, the inhibitory effects of compounds 2-10 on NO production in lipopolysaccharide (LPS)-induced RAW264.7 cells were evaluated. Notably, compound 6 exhibited the most significant inhibitory effect with an IC50 value of 1.74±0.69 µM.

Research progress of plant-derived natural alkaloids in central nervous system diseases.

Central nervous system (CNS) disease is one of the most important causes of human death. Because of their complex pathogenesis, more and more attention has been paid to them. At present, drug treatment of the CNS is the main means; however, most drugs only relieve symptoms, and some have certain toxicity and side effects. Natural compounds derived from plants can provide safer and more effective alternatives. Alkaloids are common nitrogenous basic organic compounds found in nature, which exist widely in many kinds of plants and have unique application value in modern medicine. For example, Galantamine and Huperzine A from medicinal plants are widely used drugs on the market to treat Alzheimer's disease. Therefore, the main purpose of this review is to provide the available information on natural alkaloids with the activity of treating central nervous system diseases in order to explore the trends and perspectives for the further study of central nervous system drugs. In this paper, 120 alkaloids with the potential effect of treating central nervous system diseases are summarized from the aspects of sources, structure types, mechanism of action and structure-activity relationship.

Long non­coding RNAs as potential therapeutic targets in non­small cell lung cancer (Review).

Non­small cell lung cancer (NSCLC) is one of the most common malignancies with a high morbidity and mortality rate. Long non­coding RNAs (lncRNAs) have been reported to be closely associated with the occurrence and progression of NSCLC. In addition, lncRNAs have been documented to participate in the development of drug resistance and radiation sensitivity in patients with NSCLC. Due to their extensive functional characterization, high tissue specificity and sex specificity, lncRNAs have been proposed to be novel biomarkers and therapeutic targets for NSCLC. Therefore, in the current review, the functional classification of lncRNAs were presented, whilst the potential roles of lncRNAs in NSCLC were also summarized. Various physiological aspects, including proliferation, invasion and drug resistance, were all discussed. It is anticipated that the present review will provide a perspective on lncRNAs as potential diagnostic molecular biomarkers and therapeutic targets for NSCLC.

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer.

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Anomanolide C suppresses tumor progression and metastasis by ubiquitinating GPX4-driven autophagy-dependent ferroptosis in triple negative breast cancer.

Anomanolide C (AC), a natural withanolide isolated from Tubocapsicum anomalum, has been reported to have exhibits remarkable anti-tumour activities in several types of human cancers, particularly triple-negative breast cancer (TNBC). However, its intricate mechanisms still remain need to be clarified. Here, we evaluated whether AC could inhibit cell proliferation and the role of AC in ferroptosis induction and autophagy activation. Subsequently, the anti-migration potential of AC was found via autophagy-dependent ferroptosis. Additionally, we found that AC reduced the expression of GPX4 by ubiquitination and inhibited TNBC proliferation and metastasis in vitro and in vivo. Moreover, we demonstrated that AC induced autophagy-dependent ferroptosis, and led to Fe2+ accumulation via ubiquitinating GPX4. Moreover, AC was shown to induce autophagy-dependent ferroptosis as well as to inhibit TNBC proliferation and migration via GPX4 ubiquitination. Together, these results demonstrated that AC inhibited the progression and metastasis of TNBC by inducing autophagy-dependent ferroptosis via ubiquitinating GPX4, which might shed light on exploiting AC as a new drug candidate for the future TNBC therapy.

Synthesis of Lathyrol PROTACs and Evaluation of Their Anti-Inflammatory Activities.

Lathyrol is a core scaffold structure of many lathyrane diterpenoids with potent anti-inflammatory activity isolated from Euphorbia lathyrism. It was chosen as a framework to design and synthesize a series of proteolysis targeting chimeras. A total of 15 derivatives were obtained. Compound 13 exhibited inhibitory activity on LPS-induced NO production in RAW264.7 cells (IC50 = 5.30 ± 1.23 µM) with low cytotoxicity. Furthermore, compound 13 significantly degraded v-maf musculoaponeurotic fibrosarcoma oncogene homologue F (MAFF) protein, a target of lathyrane diterpenoid, concentration- and time-dependently. The mechanism of action of 13 is related to activating the Keap1/Nrf2 pathway. It also inhibited the expression of NF-κB, blocked the nuclear translocation of NF-κB, and activated autophagy in LPS-induced RAW264.7 cells. Based on the results obtained, compound 13 might be a promising anti-inflammatory agent.

Ent-kauranes and ent-atisanes from Euphorbia wallichii and their anti-inflammatory activity.

Phytochemical investigation on the whole plant of Euphorbia wallichii led to the identification of twelve diterpenoids, including nine undescribed ones, in which wallkauranes A-E (1-5) were classified as ent-kaurane diterpenoids and wallatisanes A-D (6-9) were assigned as ent-atisane diterpenoids. The biological evaluation of these isolates against NO production was conducted in the LPS-induced RAW264.7 macrophage cells model, resulting in the identification of a series of potent NO inhibitors, with the most active wallkaurane A showing an IC50 value of 4.21 µM. The mechanistic study disclosed that wallkaurane A could inhibit pro-inflammatory cytokines generation such as TNF-α, IL-1ß, and IL-6, and decrease the expression of iNOS and COX-2. Wallkaurane A could regulate the NF-κB signaling pathways and the JAK2/STAT3 signaling pathway to suppress the inflammatory reaction in LPS-induced RAW264.7 cells. Meanwhile, wallkaurane A could also inhibit the JAK2/STAT3 signaling pathway, thereby suppressing apoptosis in LPS-induced RAW264.7 cells.

A new phenylpropanoid-substituted epicatechin from the rhizome of Smilax china.

A new phenylpropanoid-substituted epicatechin, (2 R,3S,9R)-methyl {2-(3,4-dihydroxyphenyl)-3,5,8a,4a-tetrahydroxy-3,4-dihydro-2H,12H-pyrano[2,3-α]xanthen-12-yl}acetate (1) was isolated from the rhizome of Smilax china, along with twelve known compounds (2 - 13), which were isolated from the Smilax genus for the first time. On the basis of chemical evidences and spectral data analysis (UV, ECD, 1 D and 2 D-NMR, HR-ESI-MS), the structures of compound 1 was elucidated. Furthermore, all compounds have been tested for their inhibitory effects on NO production in LPS-induced RAW 264.7 cells, and compounds 6, 7, 11 and 13 have obvious inhibitory effect, in which the IC50 value of compound 7 reached 11.63 ± 1.29 µM. Through target screening and molecular docking, we can speculate that compound 7 may exert its anti-inflammatory effect by binding to MAPKAP kinase 2 and Leukocyte Proteases Cathepsin G & Chymase.

Chemical constituents from the stems and leaves of Amomum villosum Lour. and their anti-inflammatory and antioxidant activities.

Amomum villosum Lour. is a medicinal and edible plant, whose medicinal parts are dried and mature fruits, and its stems and leaves are always treated as waste. HPLC-MS/MS analysis showed that the chemical components contained in the stems/leaves of A. villosum and those in fruits are quite different. To discover potential active ingredients from the stems/leaves of A. villosum, phytochemical evaluation of the stems/leaves of A. villosum was conducted to isolate and identify-four undescribed compounds (1, 2a, 2b, and 3) along with 41 known ones (4a, 4b, 5a, 5b, and 6-42). All isolated compounds were assessed for their anti-inflammatory and antioxidant activities. Among them, compounds 5b, 33, 34, and 38 exhibited anti-inflammatory activity, and compounds 1, 4a, 4b, 6, 7, 15, 33, 35, 37, and 41 showed antioxidant effects. Among them, the new compound 1 showed a significant antioxidant effect via activation of NRF2/HO-1 pathways. Therefore, the leaves and stems of A. villosum may be served as a potential medicine or dietary supplement for preventing and treating diseases resulting from inflammation and oxidative stress.

Xanthones and Phenylpropanoids from the Whole Herb of Swertia pseudochinensis and Their Anti-Inflammatory Activity.

An undescribed xanthone dimer, 1,3,5,8-tetrahydroxy-7-(1',5',8'-trihydroxy-3'-methoxy-2'-xanthonyl)xanthone (1) was separated together with eleven known compounds (2-12) from the dried whole herb of Swertia pseudochinensis. It was the first time that the compounds 8-12 were isolated from the Swertia genus. The structure of compound 1 was illuminated based on chemical evidence and spectral data analysis (UV, 1D and 2D-NMR, HR-ESI-MS). Moreover, the inhibitory effects of all compounds on NO production in LPS-induced RAW 264.7 cells were tested, compounds 8, 9, 10, 11 and 12 showing significant inhibition. The IC50 value of compound 12 was 3.05±1.10 µM. Using target screening and molecular docking, we hypothesized that compound 12 may bind neutrophil elastase to exert its anti-inflammatory effects.

Diterpenoids with anti-inflammatory activity from Euphorbia wallichii.

The Euphorbia plants are the focus of natural product drug discovery because of their fascinating structural diversity and broad biological activities. Here we reported the discovery of eight undescribed diterpenoids, including two ent-trachylobanes, five ent-atisanes, and one ent-abietane, together with 15 known ones from the whole plant of Euphorbia wallichii. Their chemical structures were elucidated by detailed spectrometry data analysis and X-ray crystallography. Among them, wallichane G represents a rare ent-atisane type pentacyclic diterpenoid featuring a tetrahydrofuran moiety. Furthermore, bioassays indicated that jolkinolide B exhibited potent inhibitory activities on the production of NO, with an IC50 value of 3.84 ± 0.25 µM. Meanwhile, the mechanistic study revealed that jolkinolide B could obviously downregulate the expression of iNOS, COX-2, NF-κB, and phosphorylated IκBα in a dose-dependent manner and strongly upregulate the expression of Nrf2 and HO-1 protein, thereby suppressing the inflammatory process in macrophage cells induced by LPS.