Structure Identification of Ganoderma lucidum Spore Polysaccharides and Their Antitumor Activity In Vivo.

Ganoderma lucidum spore powder, valued for its nutritional and medicinal properties, contains polysaccharides crucial for its efficacy. However, the complex structural nature of these polysaccharides necessitates further investigation to fully realize their potential. This study aimed to investigate the effects of acid heat treatment on Ganoderma lucidum spore polysaccharides (GLSPs) to enhance their properties and application in antitumor activity. The GLSP was obtained via acid heat treatment, concentration, and centrifugal separation. This process led to a notable reduction in polysaccharide molecular weight, increasing water solubility and bioavailability. Analytical techniques including NMR spectroscopy and methylation analysis revealed a polysaccharide composition comprising four distinct monosaccharides, with molecular weights of 3291 Da (Mw) and 3216 Da (Mn). Six different linkage modes were identified, with a molar ratio of 1:5:2:3:4:3. In vivo experiments demonstrated the GLSP's significant inhibitory effect on the growth of four tumor models (sarcoma S180, Lewis lung cancer, liver cancer H22, and colon cancer C26) in mice, with no observed toxicity. These findings suggest the GLSP's potential as an antitumor therapeutic agent for clinical use.

CD155 as an emerging target in tumor immunotherapy.

CD155 is an immunoglobulin-like protein overexpressed in almost all the tumor cells, which not only promotes proliferation, adhesion, invasion, and migration of tumor cells, but also regulates immune responses by interacting with TIGIT, CD226 or CD96 receptors expressed on several immune cells, thereby modulating the functionality of these cellular subsets. As a novel immune checkpoint, the inhibition of CD155/TIGIT, either as a standalone treatment or in conjunction with other immune checkpoint inhibitors, has demonstrated efficacy in managing advanced solid malignancies. In this review, we summarize the intricate relationship between on tumor surface CD155 and its receptors, with further discussion on how they regulate the occurrence of tumor immune escape. In addition, novel therapeutic strategies and clinical trials targeting CD155 and its receptors are summarized, providing a strong rationale and way forward for the development of next-generation immunotherapies.

Degraders in epigenetic therapy: PROTACs and beyond.

Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently gaining prominence as a pivotal objective in the treatment of cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from the Food and Drug Administration (FDA) for the therapeutic intervention of diverse diseases; many have drawbacks, such as limited applicability, toxicity, and resistance. Since the discovery of the first proteolysis-targeting chimeras (PROTACs) in 2001, studies on targeted protein degradation (TPD)-encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), degradation TAG (dTAG), Trim-Away, a specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), and other lysosome-based strategies-have achieved remarkable progress. In this review, we comprehensively highlight the small-molecule degraders beyond PROTACs that could achieve the degradation of epigenetic proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related targets, histone methylation/demethylation related targets, and other epigenetic targets) via proteasomal or lysosomal pathways. The present difficulties and forthcoming prospects in this domain are also deliberated upon, which may be valuable for medicinal chemists when developing more potent, selective, and drug-like epigenetic drugs for clinical applications.

LSD1 in drug discovery: From biological function to clinical application.

Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono-, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1-targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.

Dapagliflozin Suppresses Isoprenaline-Induced Cardiac Hypertrophy Through Inhibition of Mitochondrial Fission.

ABSTRACT: Dapagliflozin (DAPA) is a novel oral hypoglycemic agent, and there is increasing evidence that DAPA has a protective effect against cardiovascular disease. The study aimed to investigate how DAPA inhibits cardiac hypertrophy and explore its potential mechanisms. By continuously infusing isoprenaline (ISO) for 2 weeks using a subcutaneous osmotic pump, a cardiac hypertrophic model was established in male C57BL/6 mice. On day 14 after surgery, echocardiography showed that left ventricle mass (LV mass), interventricular septum, left ventricle posterior wall diastole, and left ventricular posterior wall systole were significantly increased, and ejection fraction was decreased compared with control mice. Masson and Wheat Germ Agglutinin staining indicated enhanced myocardial fibrosis and cell morphology compared with control mice. Importantly, these effects were inhibited by DAPA treatment in ISO-induced mice. In H9c2 cells and neonatal rat cardiomyocytes, we found that mitochondrial fragmentation and mitochondrial oxidative stress were significantly augmented in the ISO-induced group. However, DAPA rescued the cardiac hypertrophy in ISO-induced H9c2 cells and neonatal rat cardiomyocytes. Mechanistically, we found that DAPA restored the PIM1 activity in ISO-induced H9c2 cells and subsequent increase in dynamin-associated protein 1 (Drp1) phosphorylation at S616 and decrease in Drp1 phosphorylation at S637 in ISO-induced cells. We found that DAPA mitigated ISO-induced cardiac hypertrophy by suppressing Drp1-mediated mitochondrial fission in a PIM1-dependent fashion.

Experimental and theoretical studies on inhibition against tyrosinase activity and melanin biosynthesis by antioxidant ergothioneine.

Ergothioneine, a natural derivative of histidine with a thiol/thine tautomeric structure, exhibits exceptional antioxidant properties and inhibition activities on tyrosinase. In this study, enzyme kinetics experiments and chromatographic spectral analysis revealed that ergothioneine inhibited tyrosinase in a reversible and non-competitive manner, with an inhibition constant of 0.554 mg/mL (2.41 mM). As the concentration of ergothioneine increased, the extremely flexible loop structure of tyrosinase extended from 40.1 % to 41.0 %, effectively covering the active center or binding site. Theoretical molecular docking simulation results show that ergothioneine forms complexes with tyrosinase through hydrogen bonding and salt bridges in the active center of Cu ions. Additionally, it was observed that ergothioneine's antioxidant had a stronger reducing impact on dopaquinone, an intermediate in melanin production, than the effect of ascorbic acid at an equivalent concentration (0.5 mg/mL). Ergothioneine reduced the intracellular reactive oxygen species to lower levels than the control group without UVA radiation and regulated the proliferation and differentiation in B16-F10 melanocytes. Clinical trials have shown that a 0.1 % concentration of ergothioneine can effectively suppress melanin production in irradiated skin. The significant reduction in melanin index and an increase in the individual type angle (ITA°) degree were measured after 4 weeks. These results collectively suggest that ergothioneine may be a promising inhibitor of natural antioxidant tyrosinase. Furthermore, due to its safety and efficacy, ergothioneine could be considered one of the bioactive substances for further study on diseases related to melanin production and tyrosinase activity which is of great significance for the cosmetics, medicine and food industries.

Novel acridine-based LSD1 inhibitors enhance immune response in gastric cancer.

Recently, histone lysine specific demethylase 1 (LSD1) has become an emerging and promising target for cancer immunotherapy. Herein, based on our previously reported LSD1 inhibitor DXJ-1 (also called 6x), a series of novel acridine-based LSD1 inhibitors were identified via structure optimizations. Among them, compound 5ac demonstrated significantly enhanced inhibitory activity against LSD1 with an IC50 value of 13 nM, about 4.6-fold more potent than DXJ-1 (IC50 = 73 nM). Molecular docking studies revealed that compound 5ac could dock well into the active site of LSD1. Further mechanism studies showed that compound 5ac inhibited the stemness and migration of gastric cancer cells, and reduced the expression of PD-L1 in BGC-823 and MFC cells. More importantly, BGC-823 cells were more sensitive to T cell killing when treated with compound 5ac. Besides, the tumor growth was also suppressed by compound 5ac in mice. Together, 5ac could serve as a promising candidate to enhance immune response in gastric cancer.

Phenothiazine-Based LSD1 Inhibitor Promotes T-Cell Killing Response of Gastric Cancer Cells.

Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for cancer treatment. Although several LSD1 inhibitors have entered clinical trials, the discovery of novel potent LSD1 inhibitors remains a challenge. In this study, the antipsychotic drug chlorpromazine was characterized as an LSD1 inhibitor (IC50 = 5.135 µM), and a series of chlorpromazine derivatives were synthesized. Among them, compound 3s (IC50 = 0.247 µM) was the most potent one. More importantly, compound 3s inhibited LSD1 in the cellular level and downregulated the expression of programmed cell death-ligand 1 (PD-L1) in BGC-823 and MFC cells to enhance T-cell killing response. An in vivo study confirmed that compound 3s can inhibit MFC cell proliferation without significant toxicity in immunocompetent mice. Taken together, our findings indicated that the novel LSD1 inhibitor 3s tethering a phenothiazine scaffold may serve as a lead compound for further development to activate T-cell immunity in gastric cancer.

Discovery of acridine-based LSD1 inhibitors as immune activators targeting LSD1 in gastric cancer.

LSD1 is overexpressed in various cancers and promotes tumor cell proliferation, tumor expansion, and suppresses immune cells infiltration and is closely associated with immune checkpoint inhibitors therapy. Therefore, the inhibition of LSD1 has been recognized as a promising strategy for cancer therapy. In this study, we screened an in-house small-molecule library targeting LSD1, an FDA-approved drug amsacrine for acute leukemia and malignant lymphomas was found to exhibit moderate anti-LSD1 inhibitory activity (IC50 = 0.88 µM). Through further medicinal chemistry efforts, the most active compound 6x increased anti-LSD1 activity significantly (IC50 = 0.073 µM). Further mechanistic studies demonstrated that compound 6x inhibited the stemness and migration of gastric cancer cell, and decreased the expression of PD-L1 (programmed cell death-ligand 1) in BGC-823 and MFC cells. More importantly, BGC-823 cells are more susceptible to T-cell killing when treated with compound 6x. Moreover, tumor growth was also suppressed by compound 6x in mice. Altogether, our findings demonstrated that acridine-based novel LSD1 inhibitor 6x may be a lead compound for the development of activating T cell immune response in gastric cancer cells.

Safe and Effective Antioxidant: The Biological Mechanism and Potential Pathways of Ergothioneine in the Skin.

Ergothioneine, a sulfur-containing micromolecular histidine derivative, has attracted increasing attention from scholars since it was confirmed in the human body. In the human body, ergothioneine is transported and accumulated specifically through OCTN-1, especially in the mitochondria and nucleus, suggesting that it can target damaged cells and tissues as an antioxidant. It shows excellent antioxidant, anti-inflammatory effects, and anti-aging properties, and inhibits melanin production. It is a mega antioxidant that may participate in the antioxidant network system and promote the reducing glutathione regeneration cycle. This review summarizes studies on the antioxidant effects of ergothioneine on various free radicals in vitro to date and systematically introduces its biological activities and potential mechanisms, mostly in dermatology. Additionally, the application of ergothioneine in cosmetics is briefly summarized. Lastly, we propose some problems that require solutions to understand the mechanism of action of ergothioneine. We believe that ergothioneine has good prospects in the food and cosmetics industries, and can thus meet some needs of the health and beauty industry.

Triazole-fused pyrimidines in target-based anticancer drug discovery.

In recent decades, the development of targeted drugs has featured prominently in the treatment of cancer, which is among the major causes of mortality globally. Triazole-fused pyrimidines, a widely-used class of heterocycles in medicinal chemistry, have attracted considerable interest as potential anticancer agents that target various cancer-associated targets in recent years, demonstrating them as valuable templates for discovering novel anticancer candidates. The current review concentrates on the latest advancements of triazole-pyrimidines as target-based anticancer agents, including works published between 2007 and the present (2007-2022). The structure-activity relationships (SARs) and multiple pathways are also reviewed to shed light on the development of more effective and biotargeted anticancer candidates.

Possible Mechanisms of Oxidative Stress-Induced Skin Cellular Senescence, Inflammation, and Cancer and the Therapeutic Potential of Plant Polyphenols.

As the greatest defense organ of the body, the skin is exposed to endogenous and external stressors that produce reactive oxygen species (ROS). When the antioxidant system of the body fails to eliminate ROS, oxidative stress is initiated, which results in skin cellular senescence, inflammation, and cancer. Two main possible mechanisms underlie oxidative stress-induced skin cellular senescence, inflammation, and cancer. One mechanism is that ROS directly degrade biological macromolecules, including proteins, DNA, and lipids, that are essential for cell metabolism, survival, and genetics. Another one is that ROS mediate signaling pathways, such as MAPK, JAK/STAT, PI3K/AKT/mTOR, NF-κB, Nrf2, and SIRT1/FOXO, affecting cytokine release and enzyme expression. As natural antioxidants, plant polyphenols are safe and exhibit a therapeutic potential. We here discuss in detail the therapeutic potential of selected polyphenolic compounds and outline relevant molecular targets. Polyphenols selected here for study according to their structural classification include curcumin, catechins, resveratrol, quercetin, ellagic acid, and procyanidins. Finally, the latest delivery of plant polyphenols to the skin (taking curcumin as an example) and the current status of clinical research are summarized, providing a theoretical foundation for future clinical research and the generation of new pharmaceuticals and cosmetics.

Propensity-score-matched analysis of D2 and D3 right hemicolectomy for colon cancer.

BACKGROUND: Complete mesocolic excision with D3 lymph node dissection in right-sided colon cancer is associated with improved oncological outcomes, but can potentially be associated with higher rates of complications compared to conventional D2 right hemicolectomy. This study aims to evaluate the oncological and perioperative outcomes of patients who underwent D3 right hemicolectomy, comparing to conventional right hemicolectomy. METHODS: From 2015 to 2020, 360 patients underwent right hemicolectomy for colonic malignancies. Data was retrospectively analysed from a prospectively collected database. A propensity-score-matched analysis was performed between the two groups to evaluate their outcomes. RESULTS: About 88(24.4%) patients underwent D3 right hemicolectomy, with the rest undergoing D2 right hemicolectomy. After propensity-matched analysis, D3 right hemicolectomy had a higher lymph node yield (median of 26 versus 23, p = 0.005), lower overall recurrence rate (11.7% versus 25.7%, p = 0.03), and lower overall mortality rate (14.5% versus 30.1%, p = 0.02) There were no significant differences in the complication rates. There were no anastomotic leaks. D3 right hemicolectomy was associated with an improved 3-year disease-free survival (DFS) with a hazard ratio of 0.63 (P = 0.21), and also an improved 3-year overall survival (OS) with a hazard ratio of 0.68 (P = 0.31). CONCLUSION: D3 right hemicolectomy is associated with a higher lymph node yield, without increasing morbidity or mortality. It is also associated with significantly lower recurrence and overall mortality rates in this study. Short term 3-year DFS and OS also trend towards favouring D3 right hemicolectomy. However, this study is limited by the small sample size and retrospective nature.

Generation, secretion and degradation of cancer immunotherapy target PD-L1.

Cancer immunotherapy is a rapidly developing and effective method for the treatment of a variety of malignancies in recent years. As a significant immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) play the most significant role in cancer immune escape and cancer immunotherapy. Though PD-L1 have become an important target for drug development and there have been various approved drugs and clinic trials targeting it, and various clinical response rate and adverse reactions prevent many patients from benefiting from it. In recent years, combination trials have become the main direction of PD-1/PD-L1 antibodies development. Here, we summarized PD-L1 biofunctions and key roles in various cancers along with the development of PD-L1 inhibitors. The regulators that are involved in controlling PD-L1 expression including post-translational modification, mRNA level regulation as well as degradation and exosome secretory pathway of PD-L1 were focused. This systematic summary may provide comprehensive understanding of different regulations on PD-L1 as well as a broad prospect for the search of the important regulator of PD-L1. The regulatory factors of PD-L1 can be potential targets for immunotherapy and increase strategies of immunotherapy in combination.

Multi-Omics Reveal Additive Cytotoxicity Effects of Aflatoxin B1 and Aflatoxin M1 toward Intestinal NCM460 Cells.

Aflatoxin B1 (AFB1) is a common crop contaminant, while aflatoxin M1 (AFM1) is implicated in milk safety. Humans are likely to be simultaneously exposed to AFB1 and AFM1; however, studies on the combined interactive effects of AFB1 and AFM1 are lacking. To fill this knowledge gap, transcriptomic, proteomic, and microRNA (miRNA)-sequencing approaches were used to investigate the toxic mechanisms underpinning combined AFB1 and AFM1 actions in vitro. Exposure to AFB1 (1.25-20 µM) and AFM1 (5-20 µM) for 48 h significantly decreased cell viability in the intestinal cell line, NCM460. Multi-omics analyses demonstrated that additive toxic effects were induced by combined AFB1 (2.5 µM) and AFM1 (2.5 µM) in NCM460 cells and were associated with p53 signaling pathway, a common pathway enriched by differentially expressed mRNAs/proteins/miRNAs. Specifically, based on p53 signaling, cross-omics showed that AFB1 and AFM1 reduced NCM460 cell viability via the hsa-miR-628-3p- and hsa-miR-217-5p-mediated regulation of cell surface death receptor (FAS), and also the hsa-miR-11-y-mediated regulation of cyclin dependent kinase 2 (CDK2). We provide new insights on biomarkers which reflect the cytotoxic effects of combined AFB1 and AFM1 toxicity.

Optimization of Ultrasound-Assisted Cellulase Extraction from Nymphaea hybrid Flower and Biological Activities: Antioxidant Activity, Protective Effect against ROS Oxidative Damage in HaCaT Cells and Inhibition of Melanin Production in B16 Cells.

In this study, ultrasonic-assisted cellulase extraction (UCE) was applied to extract flavonoids and polyphenols from the Nymphaea hybrid flower. The extraction conditions were optimized using the response surface method (RSM) coupled with a Box-Behnken design. The crude extract of Nymphaea hybrid (NHE) was further purified using AB-8 macroporous resins, and the purified extract (NHEP) was characterized by FTIR and HPLC. In vitro activity determination by chemical method showed that NHEP displayed strong free radical scavenging abilities against the DPPH and ABTS radicals, good reduction power, and hyaluronidase inhibition. The cell viability by CCK-8 assays showed that NHEP had no significant cytotoxicity for B16 and HaCaT cells when the concentration was below 100 µg/mL and 120 µg/mL, respectively. NHEP with a concentration of 20-160 µg/mL can more effectively reduce the ROS level in H2O2 damaged HaCaT cells compared with 10 µg/mL of VC. The 40 µg/mL of NHEP had similar activity against intracellular melanin production in the B16 melanoma cells compared with 20 µg/mL Kojic acid. Good activities of antioxidation, whitening and protective effect against H2O2-induced oxidative damage promote the potential for NHEP as a functional raw material in the field of cosmetics and medicine.

Integrated analysis of lncRNA and mRNA expression profiles in the submandibular glands of DIO mice.

OBJECTIVE: Obesity contributes to the dysfunction of salivary gland. To explore the specific underlying mechanism for obesity-induced hyposalivation, a model for high-fat diet-induced obese (DIO) mice were constructed to analyze long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) expression profiles. METHODS: The DIO group and control group were fed a diet containing 60 kcal% fat and a normal chow diet for 16 weeks respectively. Microarray analyses were performed to detect the expression profiles of lncRNA and mRNA in submandibular gland tissues from control group mice and DIO mice. Gene ontology, kyoto encyclopedia of genes and genomes, protein-protein interaction, coding-non-coding gene co-expression, transcription factors and competing endogenous RNA analyses were performed to examine the function of differentially expressed genes. RESULTS: Microarray analyses identified that 624 lncRNAs, along with 297 mRNAs were differentially expressed. Bioinformatic analyses revealed that "complement and coagulation cascades," "glutathione metabolism," "cysteine and methionine metabolism," and "estrogen signaling pathway" were significantly associated with candidate lncRNAs. Transcription factors analysis on candidate lncRNAs revealed several genes such as tribbles pseudokinase 3 may play regulatory roles. CONCLUSIONS: Our results revealed the expression profiles of lncRNAs and mRNAs and provided new insights into the mechanism of obesity-induced hyposalivation using bioinformatic analyses.

Long noncoding RNA SNHG9 facilitates growth of glioma stem-like cells via miR-326/SOX9 axis.

BACKGROUND: Glioma stem-like cells (GSCs) are greatly responsible for the progression of glioma. Long noncoding RNAs (lncRNAs) play an important role in glioma tumor progression. This study aims to explore the role and underlying mechanism of lncRNA SNHG9 in regulating GSC cell growth. METHODS: GSCs were obtained from glioma cells (U87 and U251) and referred to as GSC-87 and GSC-251, respectively. The interactions between miR-326 and SNHG9 or SOX9 were analyzed using luciferase reporter assay. Cell growth of GSCs was evaluated by EdU assay and sphere formation assay. RESULTS: SNHG9 expression was significantly higher in GSC-87 and GSC-251 cells than in U87 and U251 cells. SNHG9 overexpression promoted GSC cell growth, whereas SNHG9 knockdown inhibited GSC cell growth. Mechanistically, SNHG9 acted as a competitive endogenous RNA of miR-326 to elevate the expression of SOX9, a direct target of miR-326. Moreover, transfection with miR-326 inhibitor counteracted SNHG9 knockdown-mediated inhibition of GSC cell growth. CONCLUSIONS: SNHG9 facilitates growth of GSCs via the miR-326/SOX9 axis. This study provides a promising therapeutic target for glioma treatment.

The molecular mechanism of chronic stress affecting the occurrence and development of breast cancer and potential drug therapy.

According to the 2020 data released by the International Agency for Research on Cancer, breast cancer has surpassed lung cancer as the world's most newly diagnosed first-time cancer. Compared with patients with other types of cancer, those with breast cancer experience greater mental stress and more severe psychological impacts because of the life-threatening diagnosis, physical changes, treatment side effects, and family and social life dysfunctions. These usually manifest as anxiety, depression, nervousness, and insomnia, all of which elicit stress responses. Particularly under chronic stress, the continuous release of neurotransmitters from the neuroendocrine system can have a highly profound impact on the occurrence and prognosis of breast cancer. However, because of the complex mechanisms underlying chronic stress and the variability in individual tolerance, evidence of the role of chronic stress in the occurrence and evolution of breast cancer remains unclear. This article reviewed previous research on the correlation between chronic stress and the occurrence and development of breast cancer, particularly the molecular mechanism through which chronic stress promotes breast cancer via neurotransmitters secreted by the nervous system. We also review the progress in the development of potential drugs or blockers for the treatment of breast cancer by targeting the neuroendocrine system.

Microemulsion of Cinnamon Essential Oil Formulated with Tea Polyphenols, Gallic Acid, and Tween 80: Antimicrobial Properties, Stability and Mechanism of Action.

The objective of this article was to combine tea polyphenols, gallic acid, and cinnamon essential oil to construct a natural extract-complex microemulsion system (NMs) with good antibacterial activity, antioxidant activity, and stability, as well as low irritation. NMs were characterized by particle size distribution, electrical conductivity, and light transmittance. The stability, as well as the antimicrobial, antioxidant, irritation, and antimicrobial mechanisms, of NMs were also studied. The results showed that NMs had a significant antimicrobial function against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Aspergillus brasiliensis. The minimum inhibitory concentrations were 156 µg/mL, 62.5 µg/mL, 125 µg/mL, 250 µg/mL, and 125 µg/mL, respectively. Through the cell membrane permeability test and growth curve test of bacteria and fungi, we concluded that the NMs' mechanism of action on bacteria and fungi could be interpreted as NMs mainly altering the permeability of cell membranes to inhibit the growth of bacteria and fungi. The results of this study have important implications for utilizing plant extracts as natural preservatives for food and cosmetics.