Gegen Qinlian decoction ameliorates TNBS-induced ulcerative colitis by regulating Th2/Th1 and Tregs/Th17 cells balance, inhibiting NLRP3 inflammasome activation and reshaping gut microbiota.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal medicine Gegen Qinlian Decoction (GQD) has been clinically shown to be an effective treatment of ulcerative colitis (UC) in China. However, the underlying mechanism of GQD's anti-ulcerative colitis properties and its effect on gut microbiota still deserve further exploration. AIM OF THE STUDY: This study observed the regulatory effects of GQD on Th2/Th1 and Tregs/Th17 cells balance, the NOD-like receptor family pyrin domain containing 3 (NLRP3) infammasome and gut microbiota in TNBS-induced UC in BALB/c mice. MATERIALS AND METHODS: 61 main chemical compounds in the GQD were determined by UPLC-Q-TOF/MS. The UC BALB/c model was established by intrarectal administration of trinitrobenzene sulfonic acid (TNBS), and GQD was orally administered at low and high dosages of 2.96 and 11.83 g/kg/day, respectively. The anti-inflammatory effects of GQD for ulcerative colitis were evaluated by survival rate, body weight, disease activity index (DAI) score, colonic weight and index, spleen index, hematoxylin-eosin (HE) staining and histopathological scores. Flow cytometry was used to detect the percentage of CD4, Th1, Th2, Th17 and Tregs cells. The levels of Th1-/Th2-/Th17-/Tregs-related inflammatory cytokines and additional proinflammatory cytokines (IL-1ß, IL-18) were detected by CBA, ELISA, and RT-PCR. The expressions of GATA3, T-bet, NLRP3, Caspase-1, IL-Iß, Occludin and Zonula occludens-1 (ZO-1) on colon tissues were detected by Western blot and RT-PCR. Transcriptome sequencing was performed using colon tissue and 16S rRNA gene sequencing was performed on intestinal contents. Fecal microbiota transplantation (FMT) was employed to assess the contribution of intestinal microbiota and its correlation with CD4 T cells and the NLRP3 inflammasome. RESULTS: GQD increased the survival rate of TNBS-induced UC in BALB/c mice, and significantly improved their body weight, DAI score, colonic weight and index, spleen index, and histological characteristics. The intestinal barrier dysfunction was repaired after GQD administration through promoting the expression of tight junction proteins (Occludin and ZO-1). GQD restored the balance of Th2/Th1 and Tregs/Th17 cells immune response of colitis mice, primarily inhibiting the increase in Th2/Th1 ratio and their transcription factor production (GATA3 and T-bet). Morever, GQD changed the secretion of Th1-/Th2-/Th17-/Tregs-related cytokines (IL-2, IL-12, IL-5, IL-13, IL-6, IL-10, and IL-17A) and reduced the expressions of IL-1ß, IL-18. Transcriptome results suggested that GQD could also remodel the immune inflammatory response of colitis by inhibiting NOD-like receptor signaling pathway, and Western blot, immunohistochemistry and RT-PCR further revealed that GQD exerted anti-inflammatory effects by inhibiting the NLRP3 inflammasome, such as down-regulating the expression of NLRP3, Caspase-1 and IL-1ß. More interestingly, GQD regulated gut microbiota dysbiosis, suppressed the overgrowth of conditional pathogenic gut bacteria like Helicobacter, Proteobacteria, and Mucispirillum, while the probiotic gut microbiota, such as Lactobacillus, Muribaculaceae, Ruminiclostridium_6, Akkermansia, and Ruminococcaceae_unclassified were increased. We further confirmed that GQD-treated gut microbiota was sufficient to relieve TNBS-induced colitis by FMT, involving the modulation of Th2/Th1 and Tregs/Th17 balance, inhibition of NLRP3 inflammasome activation, and enhancement of colonic barrier function. CONCLUSIONS: GQD might alleviate TNBS-induced UC via regulating Th2/Th1 and Tregs/Th17 cells Balance, inhibiting NLRP3 inflammasome and reshaping gut microbiota, which may provide a novel strategy for patients with colitis.

Integrated network pharmacological analysis revealed that Smilax glabra Roxb. alleviates IMQ-induced psoriatic skin inflammation through regulating T cell immune response.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is an autoimmune disease characterized by dysfunctional T cells and dysregulated immune responses. Smilax glabra Roxb. (SGR) is a formulation used in Traditional Chinese Medicine for the treatment of inflammatory skin disorders, including psoriasis. This study explores the scientific basis for its use by examining the effects of SGR on T cell differentiation and insulin receptor signaling, relevant pathways implicated in the pathophysiology of psoriasis. AIM OF THE STUDY: This study investigates the therapeutic potential of SGR (a Chinese medicine) in psoriasis and its impact on T cell differentiation. MATERIALS AND METHODS: An integrated network pharmacology and bioinformatics approach was employed to elucidate the mechanisms of SGR in regulating T cell differentiation. A psoriasis mouse model was utilized to evaluate the effects of SGR on T cell subsets. Immunohistochemistry and gene expression analyses were conducted to investigate the modulation of insulin receptor signaling pathways by SGR. RESULTS: SGR treatment effectively reset the expression of various T cell subsets in the psoriasis mouse model, suggesting its ability to regulate T cell differentiation and immune function. Furthermore, SGR treatment inhibited insulin receptor signaling and downstream pathways, including PI3K/AKT and ERK, in psoriatic skin lesions. This indicates that SGR may exert its therapeutic effects through modulation of the insulin receptor signaling pathway. CONCLUSIONS: This study provides novel insights into the therapeutic potential of SGR in psoriasis. By modulating T cell differentiation and targeting the insulin receptor signaling pathway, SGR holds promise as a potential treatment option for psoriasis.

Load-bearing columns inspired fabrication of ductile and mechanically enhanced BSA hydrogels.

Currently, protein-based hydrogels are widely applied in soft materials, tissue engineering and implantable scaffolds owing to their excellent biocompatibility, and degradability. However, most protein-based hydrogels are soft brittle. In this study, a ductile and mechanically enhanced bovine serum albumin (BSA) hydrogel is fabricated by soaking the a 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) induced BSA hydrogel in (NH4)2SO4 solution. An EDC/NHS coupling reaction induce protein coupling reactions that cause the BSA skeleton to resemble architectural load-bearing walls, protecting the integrity of the hydrogel and preventing collapse. The effects of the BSA and (NH4)2SO4 concentrations on the hydrogel mechanics are evaluated, and the possible strengthening mechanism is discussed. Besides, the highly kosmotropic ions greatly enhance the hydrophobic interaction within BSA gels and dehydration effect and their mechanical properties were significantly enhanced. The various mechanical properties of hydrogels can be regulated over a large window by soaking hydrogels into various ions. And most of them can be washed away, maintaining high biocompatibility of the protein. Importantly, the protein hydrogels prepared by this strategy could also be modified as strain sensors. In a word, this work demonstrates a new, universal method to provide multi-functional, biocompatible, strength enhanced and regulable mechanical pure protein hydrogel, combining the Hofmeister effect with -NH2/-COOH association groups.

Fabricating the multibranch carboxyl-modified cellulose for hemorrhage control.

Excessive bleeding is associated with a high mortality risk. In this study, citric acid and ascorbic acid were sequentially modified on the surface of microcrystalline cellulose (MCAA) to increase its carboxyl content, and their potential as hemostatic materials was investigated. The MCAA exhibited a carboxylic group content of 9.52 %, higher than that of citric acid grafted microcrystalline cellulose (MCA) at 4.6 %. Carboxyl functionalization of microcrystalline cellulose surfaces not only plays a fundamental role in the structure of composite materials but also aids in the absorption of plasma and stimulation of platelets. Fourier -transform infrared (FT-IR), thermogravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS) spectra confirmed that carboxyl groups were successfully introduced onto the cellulose surface. Physical properties tests indicated that the MCAA possessed higher thermal stability (Tmax = 472.2 °C) compared to microcrystalline cellulose (MCC). Additionally, in vitro hemocompatibility, cytotoxicity and hemostatic property results demonstrated that MCAA displayed good biocompatibility (hemolysis ratio <1 %), optimal cell compatibility (cell viability exceeded 100 % after 72 h incubation), and impressive hemostatic effect (BCIMCAA = 31.3 %). Based on these findings, the hemostatic effect of covering a wound with MCAA was assessed, revealing enhanced hemostatic properties using MCAA in tail-amputation and liver-injury hemorrhage models. Furthermore, exploration into hemostatic mechanisms revealed that MCAA can significantly accelerate coagulation through rapid platelet aggregation and activation of the clotting cascade. Notably, MCAA showed remarkable biocompatibility and induced minimal skin irritation. In conclusion, the results affirmed that MCAA is a safe and potentially effective hemostatic agent for hemorrhage control.

Review of Marine Cyanobacteria and the Aspects Related to Their Roles: Chemical, Biological Properties, Nitrogen Fixation and Climate Change.

Marine cyanobacteria are an ancient group of photosynthetic microbes dating back to 3.5 million years ago. They are prolific producers of bioactive secondary metabolites. Over millions of years, natural selection has optimized their metabolites to possess activities impacting various biological targets. This paper discusses the historical and existential records of cyanobacteria, and their role in understanding the evolution of marine cyanobacteria through the ages. Recent advancements have focused on isolating and screening bioactive compounds and their respective medicinal properties, and we also discuss chemical property space and clinical trials, where compounds with potential pharmacological effects, such as cytotoxicity, anticancer, and antiparasitic properties, are highlighted. The data have shown that about 43% of the compounds investigated have cytotoxic effects, and around 8% have anti-trypanosome activity. We discussed the role of different marine cyanobacteria groups in fixing nitrogen percentages on Earth and their outcomes in fish productivity by entering food webs and enhancing productivity in different agricultural and ecological fields. The role of marine cyanobacteria in the carbon cycle and their outcomes in improving the efficiency of photosynthetic CO2 fixation in the chloroplasts of crop plants, thus enhancing the crop plant's yield, was highlighted. Ultimately, climate changes have a significant impact on marine cyanobacteria where the temperature rises, and CO2 improves the cyanobacterial nitrogen fixation.

Bioactive components and molecular mechanisms of Salvia miltiorrhiza Bunge in promoting blood circulation to remove blood stasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge (SM) is an outstanding herbal medicine with various traditional effects, especially promoting blood circulation to remove blood stasis. It has been widely used for centuries to treat blood stasis syndrome (BSS)-related diseases. BSS is one of the basic pathological syndromes of diseases such as cardiovascular and cerebrovascular diseases in traditional East Asian medicine, which is characterized by disturbance of blood circulation. However, the bioactive components and mechanisms of SM in the treatment of BSS have not been systematically reviewed. Therefore, this article outlines the anti-BSS effects of bioactive components of SM, concentrating on the molecular mechanisms. AIM OF THE REVIEW: To summarize the bioactive components of SM against BSS and highlight its potential targets and signaling pathways, hoping to provide a modern biomedical perspective to understand the efficacy of SM on enhancing blood circulation to remove blood stasis. MATERIALS AND METHODS: A comprehensive literature search was performed to retrieve articles published in the last two decades on bioactive components of SM used for BSS treatment from the online electronic medical literature database (PubMed). RESULTS: Phenolic acids and tanshinones in SM are the main bioactive components in the treatment of BSS, including but not limited to salvianolic acid B, tanshinone IIA, salvianolic acid A, cryptotanshinone, Danshensu, dihydrotanshinone, rosmarinic acid, protocatechuic aldehyde, and caffeic acid. They protect vascular endothelial cells by alleviating oxidative stress and inflammatory damage and regulating of NO/ET-1 levels. They also enhance anticoagulant and fibrinolytic capacity, inhibit platelet activation and aggregation, and dilate blood vessels. Moreover, lowering blood lipids and improving blood rheological properties may be the underlying mechanisms of their anti-BSS. More notably, these compounds play an anti-BSS role by mediating multiple signaling pathways such as Nrf2/HO-1, TLR4/MyD88/NF-κB, PI3K/Akt/eNOS, MAPKs (p38, ERK, and JNK), and Ca2+/K+ channels. CONCLUSIONS: Both phenolic acids and tanshinones in SM may act synergistically to target different signaling pathways to achieve the effect of promoting blood circulation.

Injectable Zn2+ and Paeoniflorin Release Hydrogel for Promoting Wound Healing.

As more and more superbugs emerge, wounds are struggling to heal due to the inflammation that accompanies infection. Therefore, there is an urgent need to reduce the abuse of antibiotics and find nonantibiotic antimicrobial methods to counter infections to accelerate wound healing. In addition, common wound dressings struggle to cover irregular wounds, causing bacterial invasion or poor drug release, which reduces the wound healing rate. In this study, Chinese medicinal monomer paeoniflorin which can inhibit inflammation is loaded in mesoporous zinc oxide nanoparticles (mZnO), while Zn2+ released from mZnO degradation can kill bacteria and facilitate wound healing. The drug-loaded mZnO was encapsulated by a hydrogel formed from oxidized konjac glucomannan and carboxymethyl chitosan via rapid Schiff base reaction to obtain an injectable drug-releasing hydrogel wound dressing. The immediate-formation hydrogel allows the dressing to cover any wound shape. In vitro and in vivo studies have demonstrated that the dressing has good biocompatibility and superior antibacterial properties, which can promote wound healing and tissue regeneration by promoting angiogenesis and collagen production, providing a promising perspective for the further development of multifunctional wound dressings.

Gelatin nanofibers: Recent insights in synthesis, bio-medical applications and limitations.

The use of gelatin and gelatin-blend polymers as environmentally safe polymers to synthesis electrospun nanofibers, has caused a revolution in the biomedical field. The development of efficient nanofibers has played a significant role in drug delivery, and for use in advanced scaffolds in regenerative medicine. Gelatin is an exceptional biopolymer, which is highly versatile, despite variations in the processing technology. The electrospinning process is an efficient technique for the manufacture of gelatin electrospun nanofibers (GNFs), as it is simple, efficient, and cost-effective. GNFs have higher porosity with large surface area and biocompatibility, despite that there are some drawbacks. These drawbacks include rapid degradation, poor mechanical strength, and complete dissolution, which limits the use of gelatin electrospun nanofibers in this form for biomedicine. Thus, these fibers need to be cross-linked, in order to control its solubility. This modification caused an improvement in the biological properties of GNFs, which made them suitable candidates for various biomedical applications, such as wound healing, drug delivery, bone regeneration, tubular scaffolding, skin, nerve, kidney, and cardiac tissue engineering. In this review an outline of electrospinning is shown with critical summary of literature evaluated with respect to the various applications of nanofibers-derived gelatin.

Tetrastigma polysaccharide reprogramming of tumor-associated macrophages via PPARγ signaling pathway to play antitumor activity in breast cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Tetrastigma Hemsleyanum Diels et Gilg (SYQ) is a typical She ethnomedicine that has been used in anti-tumor treatment in Chinese folklore. The polysaccharide of SYQ (SYQ-PA) has been reported to have antioxidant and anti-inflammatory effects, but the effect and mechanism on antitumor is still unclear. AIM OF THE STUDY: To investigate the activity and mechanism of SYQ-PA against breast cancer in vitro and in vivo. MATERIALS AND METHODS: In this study, different stages of MMTV-PYMT mice, which at 4-week-old and 8-week-old representative the transition from hyperplasia to late carcinoma, were used to investigate the potential effect of SYQ-PA of breast cancer development in vivo. The mechanism was explored with IL4/13-induced peritoneal macrophages model. Flow cytometry assay was employed to analysis the change of tumor microenvironment and the macrophages typing. The inhibition of the condition medium from macrophages on breast cancer cells was detected with xCELLigence system detection. The inflammation factors were tested with cytometric bead array. Co-culture system was used to detect the cell migration and invasion. In addition, the underlying mechanism was investigated using RNAseq analysis, Q-PCR and Western blot, and the PPARγ inhibitor was used to verify the mechanism. RESULTS: SYQ-PA significantly attenuated the process of breast primary tumor growth and reduced the infiltration of TAMs accompanied promoting the polarization of M1 phenotype in MMTV-PyMT mice. Then in vitro studies showed that SYQ-PA promoted macrophages polarization form IL4/13 induced M2 toward to the anti-tumor M1 phenotypes, and the conditioned medium (CM) from the induced macrophages inhibited the proliferation of breast cancer cells. At the same time, SYQ-PA treated macrophages inhibited the migration and invasion of 4T1 in the co-culture system. Further results indicated that SYQ-PA suppressed the release of anti-inflammatory factors and promoted the production of inflammatory cytokines which may induce M1 macrophage polarization and inhibit breast cancer cell proliferation. Subsequently, the underlying mechanism analysis based on RNAseq and molecular assays indicated that SYQ-PA inhibited PPARγ expression and regulated downstream NF-κB in macrophages. After treated with PPARγ inhibitor, T0070907, the effect of SYQ-PA was decreased, or even disappeared. As the downstream, the expression of ß-catenin was also inhibited obviously, those above all contribute the process of SYQ-PA induced M1 macrophages polarization. CONCLUSIONS: Collectively, SYQ-PA was observed inhibited breast cancer, at least in part, via PPARγ activation- and ß-catenin-mediated M2 macrophages polarization. These data expound the antitumor effect and mechanism of SYQ-PA, and provide a possible that SYQ-PA can be used as an adjuvant drug for macrophage tumor immunotherapy in breast cancer.

Fabricating Oxidized Cellulose Sponge for Hemorrhage Control and Wound Healing.

Uncontrolled hemorrhage and infection are the main reasons for many trauma-related deaths in both clinic and battlefield. However, most hemostatic materials have various defects and side effects, such as low hemostatic efficiency, poor biocompatibility, weak degradation ability, and lack of antimicrobial properties. Herein, an oxidized cellulose (OC) sponge with antibacterial properties and biosafety was fabricated for hemorrhage control and wound healing. The as-prepared OC sponges were prone to water triggered expansion and superabsorbent capacity, which could facilitate blood component concentration effectively. Importantly, they had significant biodegradability with little irritation to the skin. This hemostat could also reduce the plasma clotting time to 53.54% in vitro and demonstrated less blood loss than commercially available hemostatic agents (GS) in a mouse model of bleeding from liver defects. Furthermore, the biocompatibility antimicrobial properties and possible hemostatic mechanism of the OC sponge were also systematically evaluated. Importantly, the potential wound healing applications have also been demonstrated. Therefore, the materials have broad clinical application prospects.

Panax notoginseng saponins normalises tumour blood vessels by inhibiting EphA2 gene expression to modulate the tumour microenvironment of breast cancer.

BACKGROUND: Panax notoginseng saponins (PNS), the main active component of Panax notoginseng, can promote vascular microcirculation. PNS exhibits antitumor effects in various cancers. However, the molecular basis of the relationship between PNS and tumor blood vessels remains unclear. PURPOSE: To study the relationship between PNS inhibiting the growth and metastasis of breast cancer and promoting the normalization of blood vessels. METHODS: We performed laser speckle imaging of tumor microvessels and observed the effects of PNS on tumor growth and metastasis of MMTV-PyMT (FVB) spontaneous breast cancer in a transgenic mouse model. Immunohistochemical staining of Ki67 and CD31 was performed for tumors, scanning electron microscopy was used to observe tumor vascular morphology, and flow cytometry was used to detect tumor tissue immune microenvironment (TME). RNA-seq analysis was performed using the main vessels of the tumor tissues of the mice. HUVECs were cultured in tumor supernatant in vitro to simulate tumor microenvironment and verify the sequencing differential key genes. RESULTS: After treatment with PNS, we observed that tumor growth was suppressed, the blood perfusion of the systemic tumor microvessels in the mice increased, and the number of lung metastases decreased. Moreover, the vascular density of the primary tumor increased, and the vascular epidermis was smoother and flatter. Moreover, the number of tumor-associated macrophages in the tumor microenvironment was reduced, and the expression levels of IL-6, IL-10, and TNF-α were reduced in the tumor tissues. PNS downregulated the expression of multiple genes associated with tumor angiogenesis, migration, and adhesion. In vitro tubule formation experiments revealed that PNS promoted the formation and connection of tumor blood vessels and normalized the vessel morphology primarily by inhibiting EphA2 expression. In addition, PNS inhibited the expression of tumor vascular marker proteins and vascular migration adhesion-related proteins in vivo. CONCLUSION: In this study, we found that PNS promoted the generation and connection of tumor vascular endothelial cells, revealing the key role of EphA2 in endothelial cell adhesion and tumor blood vessel morphology. PNS can inhibit the proliferation and metastasis of breast cancer by inhibiting EphA2, improving the immune microenvironment of breast cancer and promoting the normalization of tumor blood vessels.

Structural Diversity, LC-MS-MS Analysis and Potential Biological Activities of Brevibacillus laterosporus Extract.

Lake Mariout is Egypt's degraded coastal marine habitat that encompasses a variety of wastes. The biodiversity and hard environmental conditions allow the co-existence of organisms with high resistance and rich metabolism, making them potential candidates for screening and isolating novel microbial strains. A bacterial isolate (BF202) cultured from the marine sediments of Alexandria's Mariout Lake (Egypt) was tested for its antimicrobial and anticancer potential. The phylogenetic analysis of the isolated strain's 16S rDNA and gyrB revealed that BF202 belongs to Brevibacillus laterosporus (B. laterosporus). Antibiosis of B. laterosporus was confirmed against microbial pathogens including Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, and Staphylococcus aureus. The highest antibacterial activity was detected on glucose peptone medium after 18 h of incubation at 35 °C, and at pH of 7.0 in the presence of mannose and ammonium carbonate as carbon and nitrogen sources, respectively. The cytotoxicity of the methanolic extract against breast cancer (MCF-7) and normal Vero cell lines, using the MTT test, revealed IC50 values of 7.93 and 23.79 µg/mL, respectively. To identify apoptotic and necrotic cells, a flow cytometric analysis using annexin V-FITC/PI dual-labeling was utilized and recorded a higher number of necrotic cells compared to apoptotic ones. Similarly, the cell cycle S-phase arrest was reported. The LC-MS-MS investigation of B. laterosporus extract and the molecular networking database analysis demonstrated five strategic diketopiperazine compounds with antimicrobial and anticancer activities. Taken together, this research shows that the crude extract of B. laterosporus might be an effective agent against drug-resistant bacteria and malignant disorders due to its richness in diketopiperazines.

Catalpol ameliorates CFA-induced inflammatory pain by targeting spinal cord and peripheral inflammation.

Chronic, inflammatory pain is an international health concern that severely diminishes individuals' quality of life. Catalpol is an iridoid glycoside derived from the roots of Rehmannia glutinosa that possesses anti-inflammatory, antioxidant, and neuroprotective properties for the treating multiple kinds of disorders. Nevertheless, catalpol's impacts on inflammatory pain and its potential methods of action are still unclear. The purpose of this investigation is to determine the mechanism of catalpol to reduce the inflammatory pain behaviors in a rat model with complete Freund's adjuvant (CFA). Catwalk, Von-Frey, and open field testing were performed for behavioral assessment. Western blot analysis and real-time quantitative PCR (RT-PCR) were employed to identify variations in molecular expression, while immunofluorescence was utilized to identify cellular localization. Catalpol effectively reduced CFA-induced mechanical allodynia and thermal hyperalgesia when injected intrathecally. Moreover, catalpol can regulate the HDAC4/PPAR-γ-signaling pathway in CFA rat spinal cord neurons. Meanwhile catalpol significantly decreased the expression of the NF-κB/NLRP3 inflammatory axis in the spinal cord of CFA rats. In addition, both in vivo and in vitro research revealed that catalpol treatment inhibited astrocyte activation and increase inflammatory factor expression. Interestingly, we also found that catalpol could alleviate peripheral pain by inhibiting tissue inflammation. Taken together, the findings declared that catalpol may inhibit inflammatory pain in CFA rats by targeting spinal cord and peripheral inflammation.

Royal Jelly: Beneficial Properties and Synergistic Effects with Chemotherapeutic Drugs with Particular Emphasis in Anticancer Strategies.

Cancer is one of the major causes of death globally. Currently, various methods are used to treat cancer, including radiotherapy, surgery, and chemotherapy, all of which have serious adverse effects. A healthy lifestyle, especially a nutritional diet, plays a critical role in the treatment and prevention of many disorders, including cancer. The above notion, plus the trend in going back to nature, encourages consumers and the food industry to invest more in food products and to find potential candidates that can maintain human health. One of these agents, and a very notable food agent, is royal jelly (RJ), known to be produced by the hypopharyngeal and mandibular salivary glands of young nurse honeybees. RJ contains bioactive substances, such as carbohydrates, protein, lipids, peptides, mineral salts and polyphenols which contribute to the appreciated biological and pharmacological activities. Antioxidant, anticancer, anti-inflammatory, antidiabetic, and antibacterial impacts are among the well-recognized benefits. The combination of RJ or its constituents with anticancer drugs has synergistic effects on cancer disorders, enhancing the drug's effectiveness or reducing its side effects. The purpose of the present review is to emphasize the possible interactions between chemotherapy and RJ, or its components, in treating cancer illnesses.

Flavonoid Group of Smilax glabra Roxb. Regulates the Anti-Tumor Immune Response Through the STAT3/HIF-1 Signaling Pathway.

Background: Smilax glabra Roxb. (SGR) is a widely used traditional Chinese medicine, which has known effects of enhancing immunity. However, its anti-tumor effects and mechanism of action are still unclear. Methods: We selected MMTV-PyMT mice to determine the anti-tumor efficacy of SGR ethyl acetate (SGR-EA). First, flow cytometry was used to detect the number of immune cells in the mice tumor microenvironment. Furthermore, M2 polarization of macrophages was stimulated in vitro, and the expressions of macrophage M1/M2 surface markers and mRNA were as determined. Finally, we carried out a network pharmacology analysis on the active components of SGR-EA and in vitro experiments to verify that SGR-EA regulated the hypoxia-inducible factor (HIF)-1 signaling pathway to modulate the anti-tumor immune response by resetting M2 macrophages toward the M1 phenotype which inhibited tumor growth and lung metastasis in the mice. Result: SGR-EA inhibited tumor growth and lung metastasis in the mice. Tumor-associated macrophages switched from M2 to the tumor-killing M1 phenotype and promoted the recruitment of CD4+ and CD8+ T cells in the tumor microenvironment. In vitro, SGR-EA significantly inhibited the polarization of macrophages into M2 macrophages and increased the number of M1 macrophages. In addition, following an intervention with SGR-EA, the expression of the HIF-1 signaling pathway-related proteins stimulated by interleukin-4 in macrophages was significantly inhibited. Conclusion: SGR-EA played an anti-tumor role by inhibiting the activation of the HIF-1 signaling pathway and response by resetting tumor-associated macrophages toward the M1 phenotype.

Bee Pollen: Clinical Trials and Patent Applications.

Bee pollen is a natural cocktail of floral nectar, flower pollen, enzymes, and salivary secretions produced by honeybees. Bee pollen is one of the bee products most enriched in proteins, polysaccharides, polyphenols, lipids, minerals, and vitamins. It has a significant health and medicinal impact and provides protection against many diseases, including diabetes, cancer, infectious, and cardiovascular. Bee pollen is commonly promoted as a cost-effective functional food. In particular, bee pollen has been applied in clinical trials for allergies and prostate illnesses, with a few investigations on cancer and skin problems. However, it is involved in several patents and health recipes to combat chronic health problems. This review aimed to highlight the clinical trials and patents involving bee pollen for different cases and to present the role of bee pollen as a supplementary food and a potential product in cosmetic applications.

Total glucosides of paeony inhibit breast cancer growth by inhibiting TAMs infiltration through NF-κB/CCL2 signaling.

PURPOSE: The high density of tumor-associated macrophages (TAMs) and inflammatory factors are crucial elements leading to tumor immune tolerance. Previously, we found that total glucosides of paeony (TGP) have strong inhibitory effects on the release of various inflammatory factors; however, it is unclear whether the inhibitory effects can improve the inflammatory microenvironment of tumors. Therefore, in the present study, we investigated the mechanism via which TGP depresses tumor growth and metastasis via modulation of TAM infiltration in breast cancer. METHODS: We assessed the effects of TGP on various mouse models of tumor. Lung metastasis was detected using hematoxylin and eosin staining. T cell (CD3+CD4+ and CD3+CD8+) effector and memory subsets, and TAM (CD45+CD11b+F4/80+) populations in the tumor microenvironment (TME) were examined using flow cytometry. Lipopolysaccharide (LPS)-stimulated macrophage experiments were used to investigate the TGP anti-inflammatory effects in vitro. Furthermore, conditional medium (CM) was added to detect 4T1 breast cancer cell growth using a Real-Time Cell Analyzer (RTCA) xCELLigence system. Inflammatory cytokine and chemokine levels were measured using cytometric bead array (CBA) kits and quantitative polymerase chain reaction (qPCR). NF-κB expression in the nucleus was examined by immunofluorescence and Western blot analysis. RESULTS: TGP suppressed tumor growth and lung metastasis, decreased CD45+CD11b+F4/80+ (TAMs) population obviously, and increased CD44LowCD62LHi (T memory stem cells) and CD44HiCD62LHi (central memory cells) populations in the tumor-infiltrating CD4+ and CD8+ T cells. In addition, TGP reduced inflammatory factor levels in tumors, thus inhibiting the infiltration of TAMs to improve the inflammation immunosuppressive microenvironment. In the in vitro experiment, TGP inhibited IL-10 and C-C Motif Chemokine Ligand 2 (CCL2) secretion and mRNA expression in LPS-stimulated macrophages to inhibit 4T1 cell growth and restrain macrophages M2 polarization. In addition, TGP can directly inhibit 4T1 cell proliferation by restraining autocrine CCL2 and IL-10. Further mechanistic studies reavealed that TGP inhibited CCL2 secretion by inhibiting NF-κB accumulation in the nucleus in macrophages. CONCLUSION: TGP reduced TAM recruitment mainly through the NF-κB/CCL2 signaling pathway, thereby promoting T cell infiltration in the TME. TGP has a unique advantage in balancing the inflammatory response. Furthermore, our results present novel insights on the mechanisms underlying TAM infiltration that were inhibited by TGP, with potential application in development of novel therapies targeting CCL2 pathways.

Study on the Mechanism of Sancao Tiaowei Decoction in the Treatment of MNNG-Induced Precancerous Lesions of Gastric Carcinoma Through Hedgehog Signaling Pathway.

Sancao Tiaowei Decoction (SCTWD), a traditional Chinese medicine created by Professor Chen Weijian, has been used in the prevention and treatment of precancerous lesions of gastric carcinoma (PLGC). However, its mechanism has not been made clear. This study aimed to evaluate the therapeutic effect of SCTWD on 1-methyl-3-nitro-1-nitrosoguanidine-induced PLGC in rats and the mechanism of this effect. We found that SCTWD effectively repaired gastric mucosal injury, reversed the process of PLGC, and inhibited the occurrence of gastric cancer to some extent. In the results of hematoxylin-eosin (HE) staining, the number and arrangement of mucosal glands and the number of mononuclear cells in the lamina propria were improved in varying degrees; the enzyme-linked immunosorbent assay (ELISA) showed that the PG I and PGR of the medication treatment group were significantly higher; a Reverse Transcription-Polymerase Chain Reaction (RT-PCR) test showed that SCTWD could significantly upregulate the expression levels of Shh, Ptch, and Gli-1 in the gastric tissue of rats. The immunohistochemical method showed that SCTWD could significantly upregulate the protein expressions of Shh, Gli-1, Smo, cyclin D1, CDKN2A/p16INK4a, and NF-κBP65 and could reduce the expression of Ptch at the same time. Through the preliminary analysis of 75 compounds screened by UPLC-Q-TOF-MS, the main components, such as organic acids, esters and anhydrides, flavonoids, phenols, tanshinones, and so on, have anti-inflammatory and anti-tumor pharmacological effects. The results of KEGG enrichment analysis showed that 5 signaling pathways related to this project were found, and 33 differential genes were presented to construct the interaction network. These results suggested that SCTWD had a good regulatory effect on PLGC and thus may have a multi-targeted effect; SCTWD can not only significantly improve the pathological changes of gastric mucosa in rats with PLGC but also exert a strong effect of the regulation of the hedgehog signaling pathway.

Blood Stasis Syndrome Accelerates the Growth and Metastasis of Breast Cancer by Promoting Hypoxia and Immunosuppressive Microenvironment in Mice.

Blood stasis syndromes (BSSs) are closely related to the occurrence and development of tumors, although the mechanism is still unclear. This study was aimed at exploring the effect and mechanism underlying different BSSs on tumor growth and metastasis. We established four BSS mouse models bred with breast cancer: qi deficiency and blood stasis (QDBS), cold coagulation blood stasis (CCBS), heat toxin and blood stasis (HTBS), and qi stagnation and blood stasis (QSBS). The results showed that microcirculation in the lower limb, abdominal wall, and tumor in situ decreased by varying degrees in the BSS groups. In addition, BSS promoted tumor growth and lung metastasis. The ratio of regulatory T cells in the tumor microenvironment was downregulated. Moreover, hypoxia-inducible factor 1-α, Wnt1, ß-catenin, vascular endothelial growth factor, and Cyclin D1 levels increased in the tumors of BSS mice. In conclusion, BSS not only promoted the formation of a hypoxic and immunosuppressive microenvironment but also promoted the neovascularization.

Designing Functionally Substituted Pyridine-Carbohydrazides for Potent Antibacterial and Devouring Antifungal Effect on Multidrug Resistant (MDR) Strains.

The emergence of multidrug-resistant (MDR) pathogens and the gradual depletion of available antibiotics have exacerbated the need for novel antimicrobial agents with minimal toxicity. Herein, we report functionally substituted pyridine carbohydrazide with remarkable antimicrobial effect on multi-drug resistant strains. In the series, compound 6 had potent activity against four MDR strains of Candida spp., with minimum inhibitory concentration (MIC) values being in the range of 16-24 µg/mL and percentage inhibition up to 92.57%, which was exceptional when compared to broad-spectrum antifungal drug fluconazole (MIC = 20 µg/mL, 81.88% inhibition). Substitution of the octyl chain in 6 with a shorter butyl chain resulted in a significant anti-bacterial effect of 4 against Pseudomonas aeruginosa (ATCC 27853), the MIC value being 2-fold superior to the standard combination of ampicillin/cloxacillin. Time-kill kinetics assays were used to discern the efficacy and pharmacodynamics of the potent compounds. Further, hemolysis tests confirmed that both compounds had better safety profiles than the standard drugs. Besides, molecular docking simulations were used to further explore their mode of interaction with target proteins. Overall results suggest that these compounds have the potential to become promising antimicrobial drugs against MDR strains.