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Background: Diabetes mellitus (DM) is a long-term metabolic disease accompanied by difficulties in wound healing placing a severe financial and physical burden on patients. As one of the important signal transduction molecules, both endogenous and exogenous hydrogen sulfide (H2S) was found to promote diabetic wound healing in recent studies. H2S at physiological concentrations can not only promote cell migration and adhesion functions, but also resist inflammation, oxidative stress and inappropriate remodeling of the extracellular matrix. Aim of Review: The purpose of this review is to summarize current research on the function of H2S in diabetic wound healing at all stages, and propose future directions. Key Scientific Concepts of Review: In this review, first, the various factors affecting wound healing under diabetic pathological conditions and the in vivo H2S generation pathway are briefly introduced. Second, how H2S may improve diabetic wound healing is categorized and described. Finally, we discuss the relevant H2S donors and new dosage forms, analyze and reveal the characteristics of many typical H2S donors, which may provide new ideas for the development of H2S-released agents to improve diabetic wound healing.

Chromone has emerged as one of the most important synthetic scaffolds for antitumor activity, which promotes the development of candidate drugs with better activity. In this study, a series of nitrogen mustard derivatives of chromone were designed and synthesised, in order to discover promising anti-breast tumour candidates. Almost all target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cell lines. In particular, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed the most potent antiproliferative activity with IC50 values of 1.83 and 1.90 μM, respectively, and it also exhibited certain selectivity between tumour cells and normal cells. Further mechanism exploration against MDA-MB-231 cells showed that it possibly induced G2/M phase arrest and apoptosis by generating intracellular ROS and activating DNA damage. In addition, it also inhibited MDA-MB-231 cells metastasis, invasion and adhesion. Overall, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed potent antitumor activities and relatively low side effects, and deserved further investigation.

Sinomenine, a morphinane-type isoquinoline-derived alkaloid, was first isolated from stems and roots of Sinomenium diversifolius (Miq.) in 1920. Later discovery by researchers confirmed various essential biological efficacy sinomenine exerted in vitro and in vivo. In this study, a series of 15 sinomenine/furoxan hybrid compounds were designed and synthesised in search of a TNBC drug candidate. Some of the target compounds exhibited strong antiproliferative activities against cancer cell lines, especially for TNBC cells, compared to positive controls. Among them, hybrid 7Cc exerted superior cytotoxic effects on cancer cell lines with exceptionally low IC50 (0.82 μM) against MDA-MB-231 cells with the highest safety index score. Further studies in mechanism displayed that 7Cc could induce an S phase cell cycle arrest, stimulate apoptosis in MDA-MB-231 cells, disrupt mitochondrial membrane potential and exert a genotoxic effect on DNA in cancer cells. In addition, 7Cc also notably inhibited MDA-MB-231 cells in both migration, invasion and adhesion.

Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions. In recent years, molecular glues have been widely used as protein degraders. In addition, however, molecular glues play a variety of vital roles, such as complex stabilization, interactome modulation and transporter inhibition, enabling challenging therapeutic targets to be druggable and offering an exciting novel approach for drug discovery. Since most molecular glues are identified serendipitously, exploration of their systematic discovery and rational design are important. In this review, representative examples of molecular glues with various physiological functions are divided into those mediating homo-dimerization, homo-polymerization and hetero-dimerization according to their aggregation modes, and we attempt to elucidate their mechanisms of action. In particular, we aim to highlight some biochemical techniques typically exploited within these representative studies and classify them in terms of three stages of molecular glue development: starting point, optimization and identification.

The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).

As one of the most lethal diseases, pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities. Furthermore, pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found. Although combinations of new drugs, multimodal therapies, and adjuvants prolong survival, most patients still relapse after surgery and eventually die. Consequently, the search for more effective treatments for pancreatic cancer is highly relevant and justified. As a newly re-discovered mediator of gasotransmission, hydrogen sulfide (H2S) undertakes essential functions, encompassing various signaling complexes that occupy key processes in human biology. Accumulating evidence indicates that H2S exhibits bimodal modulation of cancer development. Thus, endogenous or low levels of exogenous H2S are thought to promote cancer, whereas high doses of exogenous H2S suppress tumor proliferation. Similarly, inhibition of endogenous H2S production also suppresses tumor proliferation. Accordingly, H2S biosynthesis inhibitors and H2S supplementation (H2S donors) are two distinct strategies for the treatment of cancer. Unfortunately, modulation of endogenous H2S on pancreatic cancer has not been studied so far. However, H2S donors and their derivatives have been extensively studied as potential therapeutic agents for pancreatic cancer therapy by inhibiting cell proliferation, inducing apoptosis, arresting cell cycle, and suppressing invasion and migration through exploiting multiple signaling pathways. As far as we know, there is no review of the effects of H2S donors on pancreatic cancer. Based on these concerns, the therapeutic effects of some H2S donors and NO–H2S dual donors on pancreatic cancer were summarized in this paper. Exogenous H2S donors may be promising compounds for pancreatic cancer treatment.

Brefeldin A has a wide range of anticancer activity against a variety of tumor cells. Its poor pharmacokinetic properties and significant toxicity seriously hinder its further development. In this manuscript, 25 brefeldin A-isothiocyanate derivatives were designed and synthesized. Most derivatives showed good selectivity between HeLa cells and L-02 cells. In particular, 6 exhibited potent antiproliferative activity against HeLa cells (IC50 = 1.84 μM) with no obvious cytotoxic activity to L-02 (IC50 > 80 μM). Further cellular mechanism tests indicated that 6 induced HeLa cell cycle arrest at G1 phase. Cell nucleus fragmentation and decreased mitochondrial membrane potential suggested 6 could induce apoptosis in HeLa cells through the mitochondrial-dependent pathway.

A series of furoxan derivatives of chromone were prepared. The antiproliferative activities were tested against five cancer cell lines HepG2, MCF-7, HCT-116, B16, and K562, and two normal human cell lines L-02 and PBMCs. Among them, compound 15a exhibited the most potent antiproliferative activity. It was also found 15a produced more than 8 µM of NO at the peak time of 45 min by Griess assay. Generally, antiproliferative activity is positively related to NO release to some extent. Further in-depth studies on apoptosis-related mechanisms showed that 15a caused S-phase cell cycle arrest in a concentration-dependent manner and induced apoptosis significantly through mitochondria-related pathways. Human apoptosis protein array assay also demonstrated 15a increased the expression levels of pro-apoptotic Bax, Bad, HtrA2 and Trail R2/DR5. The expression of catalase and cell cycle blocker claspin were similarly up-regulated. In balance, 15a induced K562 cells death through both endogenous and exogenous pathways.

Fascaplysin is a planar structure pentacyclic alkaloid isolated from sponges, which can effectively induce the apoptosis of cancer cells. In addition, fascaplysin has diverse biological activities, such as antibacterial, anti-tumor, anti-plasmodium, etc. Unfortunately, the planar structure of fascaplysin can be inserted into DNA and such interaction also limits the further application of fascaplysin, necessitating its structural modification. In this review, the biological activity, total synthesis and structural modification of fascaplysin will be summarized, which will provide useful information for pharmaceutical researchers interested in the exploration of marine alkaloids and for the betterment of fascaplysin in particular.

Furin is a potential target protein associated with numerous diseases; especially closely related to tumors and multiple viral infections including SARS-CoV-2. Most of the existing efficient furin inhibitors adopt a substrate analogous structure, and other types of small molecule inhibitors need to be discovered urgently. In this study, a high-throughput screening combining virtual and physical screening of natural product libraries was performed, coupled with experimental validation and preliminary mechanistic assays at the molecular level, cellular level, and molecular simulation. A novel furin inhibitor, permethrin, which is a derivative from pyrethrin I generated by Pyrethrum cinerariifolium Trev. was identified, and this study confirmed that it binds to a novel allosteric pocket of furin through non-competitive inhibition. It exhibits a very favorable protease-selective inhibition and good cellular activity and specificity. In summary, permethrin shows a new parent nucleus with a new mode of inhibition. It could be used as a highly promising lead compound against furin for targeting related tumors and various resistant viral infections, including SARS-CoV-2.

Phytochemical investigations of leaves and twigs from Garcinia oligantha Merr. resulted in the isolation of five undescribed triterpene derivatives (1–5) and six known analogs (6–11). Their structures were determined based on extensive spectroscopic data and high-resolution mass spectra analyses. Compounds 1–11 were tested for their in vitro cytotoxicity against three human cancer cell lines (HeLa, HepG-2, and MCF-7). Compounds 1, 2, 8, and 11 exhibited broad and significant cytotoxicity against the tested cell lines with IC50 values ranging from 5.04 to 21.55 μM. Compounds 5 and 9 showed cytotoxicity against HeLa and MCF-7 with IC50 values ranging from 13.22 to 19.62 μM. The preliminary structure–activity relationship for the 11 isolated compounds is also discussed.

Abstract Background The simple and caged xanthones from Clusiaceae showed significant antineoplastic activity. This study aims to identify structural diverse xanthones and search for novel antitumor natural products from this family plants. Methods The structures of new compounds 1a and 1b were elucidated mainly through comprehensive NMR and MS spectroscopic data, and their absolute configurations were determined by the comparison of the experimental and calculated electronic circular dichroism. Results A pair of new xanthone enantiomers, (+)- and (−)-cracochinxanthone A (1a and 1b), along with thirty known analogues (2–31), were isolated from extracts of the stems and leaves of C. cochinchinense. Preliminary biological assay of some isolates against HL-60, PC-3, and MDA-MB-231 cancer cell lines. Conclusion Some isolated xanthones exhibited high sensitivity against three human malignant cell lines and the structure–activity relationship study showed that the prenyl and geranyl units may play an important role in antitumor activity.

Hydrogen sulfide (H2S) is considered as a novel second-messenger molecule associated with the modulation of various physiological and pathological processes. In the field of antitumor research, endogenous H2S induces angiogenesis, accelerates the cell cycle and inhibits apoptosis, which results in promoting oncogenesis eventually. Interestingly, high concentrations of exogenous H2S liberated from donors suppress the growth of various tumors via inducing cellular acidification and modulating several signaling pathways involved in cell cycle regulation, proliferation, apoptosis and metastasis. The selective release of certain concentrations of H2S from H2S donors in the target has been considered as an alternative tumor therapy strategy. Triple-negative breast cancer (TNBC), an aggressive subtype with less than one year median survival time, is known to account for approximately 15–20% of all breast cancers. Due to the lack of approved targeted therapy, the clinical treatment of TNBC is still hindered by metastasis as well as recurrence. Significant efforts have been spent on developing novel treatments of TNBC, and remarkable progress in the control of TNBC by H2S donors and their derivatives have been made in recent years. This review summarizes various pathways involved in antitumor and anti-metastasis effects of H2S donors and their derivatives on TNBC, which provides novel insights for TNBC treatment.

Abstract The receptor for activated C kinase 1 (RACK1) is a WD40 type protein that is involved in multiple signaling pathways and is conserved from prokaryotes to eukaryotes. Here we report that rice RACK1A (OsRACK1A) is regulated by circadian clocks and plays an important role in the salt stress response. OsRACK1A was found to follow a rhythmic expression profile under circadian conditions at both the transcription and the translation levels, although the expression was arrhythmic under salt stress. Analysis of plant survival rates, fresh weight, proline content, malondialdehyde, and chlorophyll showed that suppression of OsRACK1A enhanced tolerance to salt stress. The ion concentration in both roots and leaves revealed that OsRACK1A-suppressed transgenic rice could maintain low Na+ and high K+ concentrations. Furthermore, OsRACK1A-suppressed transgenic rice accumulated significantly more abscisic acid (ABA) and more transcripts of ABA- and stress-inducible genes compared with the wild-type plants. Real-time quantitative polymerase chain reaction analysis revealed that many stress-related genes, including APETALA 2/Ethylene Responsive Factor (AP2/ERF) transcription factors, were upregulated in the OsRACK1A-suppressed transgenic rice line. We identified putative interactors of OsRACK1A, and found that OsRACK1A interacted with many salt stress-responsive proteins directly. These results suggest that OsRACK1A is regulated by circadian rhythm, and involved in the regulation of salt stress responses.

Protein tyrosine phosphatase 1B (PTP1B) is an attractive molecular target for anti-diabetes, anti-obesity, and anti-cancer drug development. From the seeds of Silybum marianum, nine flavonolignans, namely, silybins A, B (1, 2), isosilybins A, B (3, 4), silychristins A, B (5, 6), isosilychristin A (7), dehydrosilychristin A (8), and silydianin (11) were identified as a novel class of natural PTP1B inhibitors (IC50 1.3 7–23.87 µM). Analysis of structure–activity relationship suggested that the absolute configurations at C-7" and C-8" greatly affected the PTP1B inhibitory activity. Compounds 1–5 were demonstrated to be non-competitive inhibitors of PTP1B based on kinetic analyses. Molecular docking simulations resulted that 1–5 docked into the allosteric site, including α3, α6, and α7 helix of PTP1B. At a concentration inhibiting PTP1B completely, compounds 1–5 moderately inhibited VHR and SHP-2, and weakly inhibited TCPTP and SHP-1. These results suggested the potentiality of these PTP1B inhibitors as lead compounds for further drug developments.

Phenazines are a large group of nitrogen-containing heterocycles, providing diverse chemical structures and various biological activities. Natural phenazines are mainly isolated from marine and terrestrial microorganisms. So far, more than 100 different natural compounds and over 6000 synthetic derivatives have been found and investigated. Many phenazines show great pharmacological activity in various fields, such as antimicrobial, antiparasitic, neuroprotective, insecticidal, anti-inflammatory and anticancer activity. Researchers continued to investigate these compounds and hope to develop them as medicines. Cimmino et al. published a significant review about anticancer activity of phenazines, containing articles from 2000 to 2011. Here, we mainly summarize articles from 2012 to 2021. According to sources of compounds, phenazines were categorized into natural phenazines and synthetic phenazine derivatives in this review. Their pharmacological activities, mechanisms of action, biosynthetic pathways and synthetic strategies were summarized. These may provide guidance for the investigation on phenazines in the future.

In the present study, the hypoglycemic effect of silychristin A on streptozotocin (STZ)-induced type 1 diabetes in rats was evaluated and the underlying pharmacological mechanism was further elucidated in vitro. Silychristin A significantly lowered the glucose level, increased insulin secretion, and improved the structure of β cells in STZ-induced rats. Accordantly, reactive oxygen species (ROS) production induced by STZ or high concentration of glucose (HG) was effectively suppressed by silychristin A in pancreatic INS-1 β cells evaluated by flow cytometry. Western blot analysis demonstrated that silychristin A markedly suppressed STZ or HG induced cell apoptosis. In addition, in vitro inhibitory effect of silychristin A on α-glucosidase and molecular docking analysis revealed that silychristin A could reduce the digestion rate of carbohydrates. These findings indicate that silychristin A may be useful as a potential functional food ingredient against oxidative stress-mediated destruction of pancreatic islet β cells and inhibition of α-glucosidase activity.

Dolastatin 10 (Dol-10), a leading marine pentapeptide isolated from the Indian Ocean mollusk Dolabella auricularia, contains three unique amino acid residues. Dol-10 can effectively induce apoptosis of lung cancer cells and other tumor cells at nanomolar concentration, and it has been developed into commercial drugs for treating some specific lymphomas, so it has received wide attention in recent years. In vitro experiments showed that Dol-10 and its derivatives were highly lethal to common tumor cells, such as L1210 leukemia cells (IC50 = 0.03 nM), small cell lung cancer NCI-H69 cells (IC50 = 0.059 nM), and human prostate cancer DU-145 cells (IC50 = 0.5 nM), etc. With the rise of antibody-drug conjugates (ADCs), milestone progress was made in clinical research based on Dol-10. A variety of ADCs constructed by combining MMAE or MMAF (Dol-10 derivatives) with a specific antibody not only ensured the antitumor activity of the drugs themself but also improved their tumor targeting and reduced the systemic toxicity. They are currently undergoing clinical trials or have been approved for marketing, such as Adcetris®, which had been approved for the treatment of anaplastic large T-cell systemic malignant lymphoma and Hodgkin lymphoma. Dol-10, as one of the most medically valuable natural compounds discovered up to now, has brought unprecedented hope for tumor treatment. It is particularly noteworthy that, by modifying the chemical structure of Dol-10 and combining with the application of ADCs technology, Dol-10 as a new drug candidate still has great potential for development. In this review, the biological activity and chemical work of Dol-10 in the advance of antitumor drugs in the last 35 years will be summarized, which will provide the support for pharmaceutical researchers interested in leading exploration of antitumor marine peptides.

Angelica dahurica has been frequently used as a food additive and a folk medicinal herb in Asian countries. The aim of this study was to isolate key active compounds from A. dahurica with antioxidant and anticancer activities. Three new furocoumarin dimers and twenty known coumarins were obtained from A. dahurica. Their structures were identified by extensive 1D and 2D NMR, CD, and HR-ESIMS spectroscopic analyses and screened by UPLC-MS/MS. Imperatorin oxypeucedanin hydrate, xanthotoxol, bergaptol, and 5-methoxy-8-hydroxypsoralen exhibited moderate DPPH• scavenging activity and strong ABTS•+ scavenging activity. Isoimperatorin, phelloptorin, and pabularinone showed significant inhibition on HepG2 cells with IC50 values of 8.19, 7.49, and 7.46 µM, respectively. Furthermore, pabularinone also showed moderate inhibition on HeLa cells with an IC50 value of 13.48 µM. These results suggested that A. dahurica could be explored as new and potential natural antioxidants and cancer prevention agents for use in functional foods.

Four new phenolic compounds, vitexnegheteroins A–D (1–4), were isolated from the seeds of Vitex negundo var. heterophylla, together with eight known compounds. Their structures were established on the basis of extensive 1D and 2D NMR experiments, as well as their mass spectroscopic data. The absolute configuration of compound 4 was determined by comparing its experimental CD spectrum with that calculated by the time-dependent density functional theory (TDDFT) method. The antioxidant and anti-inflammatory activities of these phenolics were also evaluated. Most of the compounds showed strong ABTS radical scavenging activities and all the tested isolates exhibited inhibitory effects on lipopolysaccharide-induced NO production in murine microglial BV-2 cells. The bioactive studies supported the traditional use of this edible aromatic plant and disclosed the potency of it to be developed as new antioxidant and anti-inflammatory functional food.

Marine natural products are considered to be valuable resources that are furnished with diverse chemical structures and various bioactivities. To date, there are seven compounds derived from marine natural products which have been approved as therapeutic drugs by the U.S. Food and Drug Administration. Numerous bromotyrosine derivatives have been isolated as a type of marine natural products. Among them, psammaplin A, including the oxime groups and carbon−sulfur bonds, was the first identified symmetrical bromotyrosine-derived disulfide dimer. It has been found to have a broad bioactive spectrum, especially in terms of antimicrobial and antiproliferative activities. The highest potential indole-derived psammaplin A derivative, UVI5008, is used as an epigenetic modulator with multiple enzyme inhibitory activities. Inspired by these reasons, psammaplin A has gradually become a research focus for pharmacologists and chemists. To the best of our knowledge, there is no systematic review about the biological activity and structural modification of psammaplin A. In this review, the pharmacological effects, total synthesis, and synthesized derivatives of psammaplin A are summarized.

To search for novel nitric oxide (NO) releasing anti-tumor agents, a series of novel furoxan/oridonin hybrids were designed and synthesized. Firstly, the nitrate/nitrite levels in the cell lysates were tested by a Griess assay and the results showed that these furoxan-based NO-releasing derivatives could produce high levels of NO in vitro. Then the anti-proliferative activity of these hybrids against four human cancer cell lines was also determined, among which, 9h exhibited the most potential anti-tumor activity with IC50 values of 1.82 µM against K562, 1.81 µM against MGC-803 and 0.86 µM against Bel-7402, respectively. Preliminary structure-activity relationship was concluded based on the experimental data obtained. These results suggested that NO-donor/natural product hybrids may provide a promising approach for the discovery of novel anti-tumor agents.

Diterpenoids are widely distributed natural products and have caused considerable interest because of their unique skeletons and antibacterial and antitumor activities and so on. In light of recent discoveries, ent-kaurane diterpenoids, which exhibit a wide variety of biological activities, such as anticancer and anti-inflammatory activities, pose enormous potential to serve as a promising candidate for drug development. Among them, spirolactone-type 6,7-seco-ent-kaurane diterpenoids, with interesting molecular skeleton, complex oxidation patterns, and bond formation, exhibit attractive activities. Furthermore, spirolactone-type diterpenoids have many modifiable sites, which allows for linking to various substituents, suitable for further medicinal study. Hence, some structurally modified derivatives with improved cytotoxicity activities are also achieved. In this review, natural bioactive spirolactone-type diterpenoids and their synthetic derivatives were summarized.

The receptor for activated C kinase 1 (RACK1) is one member of the most important WD repeat-containing family of proteins found in all eukaryotes and is involved in multiple signaling pathways. However, compared with the progress in the area of mammalian RACK1, our understanding of the functions and molecular mechanisms of RACK1 in the regulation of plant growth and development is still in its infancy. In the present study, we investigated the roles of rice RACK1A gene (OsRACK1A) in controlling seed germination and its molecular mechanisms by generating a series of transgenic rice lines, of which OsRACK1A was either over-expressed or under-expressed. Our results showed that OsRACK1A positively regulated seed germination and negatively regulated the responses of seed germination to both exogenous ABA and H2O2. Inhibition of ABA biosynthesis had no enhancing effect on germination, whereas inhibition of ABA catabolism significantly suppressed germination. ABA inhibition on seed germination was almost fully recovered by exogenous H2O2 treatment. Quantitative analyses showed that endogenous ABA levels were significantly higher and H2O2 levels significantly lower in OsRACK1A-down regulated transgenic lines as compared with those in wildtype or OsRACK1A-up regulated lines. Quantitative real-time PCR analyses showed that the transcript levels of OsRbohs and amylase genes, RAmy1A and RAmy3D, were significantly lower in OsRACK1A-down regulated transgenic lines. It is concluded that OsRACK1A positively regulates seed germination by controlling endogenous levels of ABA and H2O2 and their interaction.

A series of nine enmein-type ent-kaurane diterpenoid and furoxan-based nitric oxide (NO) donor hybrids (10a–i) were designed and synthesized from commercially available oridonin (1). These hybrids were evaluated for their antiproliferative activity against Bel-7402, K562, MGC-803, and CaEs-17 human cancer cell lines and L-02 normal liver cells. The antiproliferative activity against tumor cells was stronger than the lead compound 1 and parent molecule 9 in most cases. Especially, compound 10f showed the strongest activity against human hepatocarcinoma Bel-7402 cell line with an IC50 of 0.81 μM and could also release 33.7 μmol/L NO at the time point of 60 min. Compounds 10a–i also showed cytotoxic selectivity between tumor and normal liver cells with IC50 ranging from 22.1 to 33.9 μM. Furthermore, the apoptotic properties on Bel-7402 cells revealed that 10f could induce S phase cell cycle arrest and apoptosis at low micromolar concentrations. The effects of 10f on apoptosis-related proteins were also investigated. The potent antiproliferative activities and mechanistic studies warrant further preclinical investigations.

Isodon rubescens has been used as a traditional green tea for more than 1000 years and many medicinal functions of I. rubescens are also very useful, such as its well-known antitumor and antibacterial activities. Oridonin, a bioactive ent-kaurane diterpenoid, is the major ingredient of this medicinal tea. Herein, 22 novel oridonin derivatives were designed and synthesized. The antibacterial activity was evaluated for the first time. Compound 12 was the most promising one with MIC of 2.0 μg/mL against B. subtilis, which was nearly 3-fold stronger than positive control chloromycetin. The antiproliferative property was also assayed and compound 19 showed stronger activity than taxol. The apoptosis-inducing ability, cell cycle arrest effect at S phase and influence of mitochondrial membrane potential by 19 in CaEs-17 cancer cells were first disclosed. Based on the above results, the cell apoptosis induced by compound 19 in CaEs-17 cells was most probably involved in the intrinsic apoptotic pathway.

Oxidative stress is one of the main causes of testicular spermatogenesis disorders. Resveratrol (RES) can inhibit oxidative stress levels, reduce germ cell damage, and promote spermatogenesis. To investigate the molecular mechanism by which RES promotes spermatogenesis, the effects of hydrogen peroxide (H2O2) on the pathological damage of mouse testis tissue were assessed. The expression of key genes associated with pyroptosis, apoptosis, and autophagy, and the effects of RES on this process were determined. Experimental mice were divided into three groups with intraperitoneally injection of H2O2 (3 mmol/kg/d), RES (100 mg/kg/d) + H2O2 (3 mmol/kg/d), and normal saline, respectively. The testicular tissues were collected, and the pathological changes were observed by hematoxylin and eosin staining. The ultrastructure was observed using transmission electron microscopy (TEM). The transcriptional levels of pyroptosis, apoptosis, and autophagy-related genes were measured and analyzed by fluorescence quantitative polymerase chain reaction. The results showed that, in the H2O2 group, the basal membrane of spermatogenic tubules was damaged, atrophic, and thin. Interstitial cells were fragmented, and the gap of spermatogenic tubules increased. Compared with the H2O2 group, the pathological damage of testicular tissue structure in the H2O2 + RES group was significantly ameliorated. TEM results showed no evident damage to the cell structure in the control group, while apoptosis, autophagy, and pyroptosis were observed in the testicular tissue of H2O2 and H2O2 + RES groups, where cell damage was less, but apoptotic bodies, autophagosomes, and pyroptosomes were observed. The transcription levels of key pyroptosis genes increased in the H2O2 group but decreased significantly after RES treatment. The results indicated that H2O2 could induce pyroptosis, while RES inhibited pyroptosis and led to the release of inflammatory factors by regulating the expression of genes in signaling pathways. After H2O2 injection, the transcript levels of key apoptosis genes in testicular tissue were lower than those in the control group, while RES promoted the occurrence of H2O2-induced apoptosis, to achieve the purpose of protecting itself from oxidative damage. H2O2 could promote autophagy in mouse testicular tissue. RES enhanced the level of H2O2-induced autophagy, removed the damaged cells in the testicular tissue, and protected the development of the body. This study provided the experimental basis for the study of RES in oxidative damage, pyroptosis, apoptosis, and autophagy, and theoretical guidance and new ideas for drug development and treatment of male reproductive diseases in clinical practice. [ABSTRACT FROM AUTHOR]

Tobacco smoke is the leading risk factor for lung cancer, accounting for over 80% of lung cancer deaths. Reducing the damage of cigarette smoke to the lungs through dietary therapy is currently a research hotspot. It has been reported that cigarette smoke extract induced inflammation and contributed to pyroptosis through the ROS/NLRP3/caspase-1 pathway in human bronchial epithelial cells. To investigate the effect of ginger and snow pear beverage on smoke-induced pyroptosis, ginger, snow pear, loquat, honey, and skimmed milk powder were used to prepare a lung moistening drink with excellent palatability. Male rats were divided into the drink group and control group and exposed to cigarette smoke for 60 days. Blood biochemical indices and organ coefficients were measured, and lung and small intestine tissues were excised for HE staining. The mRNA expression of pyroptosis in the lung tissue was evaluated by fluorescence quantitative polymerase chain reaction (qPCR). The results showed that globulin and urea nitrogen levels were significantly higher in control (C) group than that in beverage (B) group, while the opposite effect was observed for the albumin/globulin ratio and cholesterol level. The changes in the weight of the lung tissue were obvious and significantly higher in group B than that in group C. The histological structure of the lung tissue in group C was abnormal with evidence of significant pathological changes in the alveolar wall and capillary bronchial tube wall along with a few inflammatory cells. The pathological changes in group B showed significantly improved. The small intestinal villus length, intestinal crypt depth, goblet cell number, and V/C value were significantly higher in group B. In addition, the drink significantly reduced the mRNA expression of NLRP3, caspase1, GSDMD, IL-18, and IL-1β genes in the lung tissue. The results indicated that the tested drink exerted protective effects on the lungs and small intestine, which inhibited the release of inflammatory factors from the cellular pyroptosis signaling pathway, alleviated the occurrence of pyroptosis, protected the lung tissue, and reduced the cigarette smoke-induced damage and lesions. [ABSTRACT FROM AUTHOR]