Agree to disagree: The contradiction between IL-18 and IL-37 reveals shared targets in cancer.

IL-37 is a newly discovered member of the IL-1 cytokine family which plays an important role in regulating inflammation and maintaining physiological homeostasis. IL-37 showed a close relationship with IL-18, another key cytokine in inflammation regulation and cancer development. IL-37 affects the function of IL-18 either by binding to IL-18Rα, a key subunit of both IL-37 and IL-18 receptor, or by drastically neutralizing the IL-18 protein expression of IL-18 binding protein, an important natural inhibitory molecule of IL-18. Moreover, as another subunit receptor of IL-37, IL-1R8 can suppress IL-18Rα expression, functioning as a surveillance mechanism to prevent overactivation of both IL-18 and IL-37 signaling pathways. While IL-18 and IL-37 share the same receptor subunit, IL-18 would in turn interfere with IL-37 signal transduction by binding to IL-18Rα. It is also reported that IL-18 and IL-37 demonstrated opposing effects in a variety of cancers, such as glioblastoma, lung cancer, leukemia, and hepatocellular cancer. Although the mutual regulation of IL-18 and IL-37 and their diametrically opposed effects in cancers has been reported, IL-18 has not been taken into consideration when interpreting clinical findings and conducting mechanism investigations related to IL-37 in cancer. We aim to review the recent progress in IL-18 and IL-37 research in cancer and summarize the correlation between IL-18 and IL-37 in cancer based on their expression level and underlying mechanisms, which would provide new insights into elucidating the conflicting roles of IL-18 and IL-37 in cancer and bring new ideas for translational research related to IL-18 and IL-37.

Immunoregulatory and Anti-cancer Activities of Combination Treatment of Novel Four-Herb Formula and Doxorubicin in 4T1-Breast Cancer Bearing Mice.

OBJECTIVE: To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula (4HF) and doxorubicin in triple-negative breast cancer (TNBC). METHODS: Murine-derived triple-negative mammary carcinoma cell line, 4T1 cells, was cultured and inoculated into mouse mammary glands. Sixty-six mice were randomly assigned into 6 groups (n=11 in ench): naïve, control, LD 4HF (low dose 4HF), HD 4HF (high dose 4HF), LD 4HF + D (low dose and doxorubicin), and D (doxorubicin). Apart from the naïve group, each mouse received subcutaneous inoculation with 5 × 105 4T1 cells resuspended in 100 µL of normal saline in the mammary fat pads. Starting from the day of tumor cell inoculation, tumors were grown for 6 days. The LD and HD groups received daily oral gavage of 658 and 2,630 mg/kg 4HF, respectively. The LD 4HF+D group received daily oral gavage of 658 mg/kg 4HF and weekly intraperitoneal injection of doxorubicin (5 mg/kg). The D group received weekly intraperitoneal injections of doxorubicin (5 mg/kg). The treatment naïve mice received daily oral gavage of 0.2 mL double distilled water and 0.1 mL normal saline via intraperitoneal injection once a week. The control group received daily oral gavage of 0.2 mL double-distilled water. The treatment period was 30 days. At the end of treatment, mice organs were harvested to analyze immunological activities via immunophenotyping, gene and multiplex analysis, histological staining, and gut microbiota analysis. RESULTS: Mice treated with the combination of 4HF and doxorubicin resulted in significantly reduced tumor and spleen burdens (P<0.05), altered the hypoxia and overall immune lymphocyte landscape, and manipulated gut microbiota to favor the anti-tumor immunological activities. Moreover, immunosuppressive genes, cytokines, and chemokines such as C-C motif chemokine 2 and interleukin-10 of tumors were significantly downregulated (P<0.05). 4HF-doxorubicin combination treatment demonstrated synergetic activities and was most effective in activating the anti-tumor immune response (P<0.05). CONCLUSION: The above results provide evidence for evaluating the immune regulating mechanisms of 4HF in breast cancer and support its clinical significance in its potential as an adjunctive therapeutic agent or immune supplement.

Adjuvant activities of immunostimulating natural products: Astragalus membranaceus (Fisch.) Bge. and Coriolus versicolor in BNT162b2 vaccination against COVID-19 infection.

The global pandemic of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been developing all over the world for more than 3 years. In late 2020, several variants of concern of SARS-CoV-2 virus emerged, with increased viral fitness and transmissibility by mutations of the spike proteins of the viral particle, denting hopes of the use of early-generation vaccines for a widespread protective immunity against viral infection. The use of adjuvants may enhance the immune responses of the conventional application of the COVID-19 vaccine. We have shown that the water extract of 2 ß-glucan-enriched immunostimulating natural products, Astragalus membranaceus (Fisch.) Bge. (AM) and Coriolus versicolor (CV), could induce innate immunity-related cytokines from human monocytes (CCL5, interleukin [IL]-6, IL-10, and tumor necrosis factor α) and monocyte-derived dendritic cells (IL-1ß, IL-10, IL-12, and tumor necrosis factor α). Using BALB/c mice, orally administrated AM and CV (1,384 and 742 mg/kg/d) for 4 d after vaccination, respectively, could enhance (1) the immunoglobulin G binding activities of BNT162b2 vaccination against ancestral and Delta SARS-CoV-2 spike proteins by 5.8- and 4.3-fold, respectively; (2) the immunoglobulin G3 subclass production of BNT162b2 vaccination against ancestral and variant SARS-CoV-2 spike proteins; and (3) the in vitro antibody-neutralizing activities of BNT162b2 vaccinated mice. In conclusion, combining AM and CV was effective in acting as an oral adjuvant with the messenger RNA vaccine BNT162b2 to improve the antigen binding activities against SARS-CoV-2 ancestral and variant SARS-CoV-2 spike proteins, probably via trained immunity of macrophages and dendritic cells.

Natural-Product-Derived Adjunctive Treatments to Conventional Therapy and Their Immunoregulatory Activities in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an invasive and persistent subtype of breast cancer that is likely to be resistant to conventional treatments. The rise in immunotherapy has created new modalities to treat cancer, but due to high costs and unreliable efficacy, adjunctive and complementary treatments have sparked interest in enhancing the efficacy of currently available treatments. Natural products, which are bioactive compounds derived from natural sources, have historically been used to treat or ameliorate inflammatory diseases and symptoms. As TNBC patients have shown little to no response to immunotherapy, the potential of natural products as candidates for adjuvant immunotherapy is being explored, as well as their immunomodulatory effects on cancer. Due to the complexity of TNBC and the ever-changing tumor microenvironment, there are challenges in determining the feasibility of using natural products to enhance the efficacy or counteract the toxicity of conventional treatments. In view of technological advances in molecular docking, pharmaceutical networking, and new drug delivery systems, natural products show promise as potential candidates in adjunctive therapy. In this article, we summarize the mechanisms of action of selected natural-product-based bioactive compounds and analyze their roles and applications in combination treatments and immune regulation.

Mechanistic insights into the anti-tumor and anti-metastatic effects of Patrinia villosa aqueous extract in colon cancer via modulation of TGF-ß R1-smad2/3-E-cadherin and FAK-RhoA-cofilin pathways.

BACKGROUND: Patrinia villosa, a traditional medicinal herb commonly used for treating intestinal-related diseases, has been commonly prescribed by Chinese medicine practitioners as a key component herb to treat colon cancer, although its anti-tumor effect and mechanisms of action have not been fully elucidated. HYPOTHESIS/PURPOSE: This study aimed to investigate the anti-tumor and anti-metastatic effects of Patrinia villosa aqueous extract (PVW), and its underlying mechanisms. METHOD: The chemical profile of PVW was analysed by high-performance liquid chromatography with photodiode-array detection (HPLC-DAD) method. Cell-based functional assays MTT, BrdU, scratch, and transwell were conducted to evaluate the effects of PVW on human colon cancer HCT116 and murine colon26-luc cells, assessing cytotoxicity, cell proliferation, motility, and migration, respectively. Western blotting was performed to assess the effect of PVW on the expression of key intracellular signaling proteins. In vivo studies were conducted using zebrafish embryos and tumor-bearing mice to evaluate the anti-tumor, anti-angiogenesis, and anti-metastatic effects of PVW in colon cancer. RESULTS: Five chemical markers were identified and quantified in PVW. PVW exhibited significant cytotoxicity and anti-proliferative activity, as well as inhibitory effects on cell motility and migration in both HCT116 and colon 26-luc cancer cells via modulating protein expressions of TGF-ß R1, smad2/3, snail, E-cadherin, FAK, RhoA, and cofilin. PVW (0.01-0.1 mg/ml) could significantly decrease the length of subintestinal vessels of zebrafish embryos through decreasing mRNA expressions of FLT1, FLT4, KDRL, VEGFaa, VEGFc, and Tie1. PVW (> 0.05 mg/ml) also significantly suppressed colon cancer cells migration in the zebrafish embryos. Furthermore, oral administration of PVW (1.6 g/kg) significantly inhibited tumor growth by decreasing the expressions of tumor activation marker Ki-67 and CD 31 in tumor tissues of HCT116 tumor-bearing mice. PVW could also significantly inhibit lung metastasis in colon 26-luc tumor-bearing mice by modulating their tumor microenvironment, including immune cells populations (T cells and MDSCs), levels of cytokines (IL-2, IL-12, and IFN-γ), as well as increasing the relative abundance of gut microbiota. CONCLUSION: This study revealed for the first time the anti-tumor and anti-metastatic effects of PVW through regulation of TGF-ß-smad2/3-E-cadherin, and FAK-cofilin pathways in colon cancer. These findings provide scientific evidence to support the clinical use of P. villosa in patients with colon cancer.

The Potential of MSC-Based Cell-Free Therapy in Wound Healing-A Thorough Literature Review.

A wound is an interruption of the normal anatomic structure and function of the skin, which is critical in protecting against foreign pathogens, regulating body temperature and water balance. Wound healing is a complex process involving various phases, including coagulation, inflammation, angiogenesis, re-epithelialization, and re-modeling. Factors such as infection, ischemia, and chronic diseases such as diabetes can compromise wound healing, leading to chronic and refractory ulcers. Mesenchymal stem cells (MSCs) have been used to treat various wound models due to their paracrine activity (secretome) and extracellular vehicles (exosomes) that contain several molecules, including long non-coding RNAs (lncRNAs), micro-RNAs (miRNAs), proteins, and lipids. Studies have shown that MSCs-based cell-free therapy using secretome and exosomes has great potential in regenerative medicine compared to MSCs, as there are fewer safety concerns. This review provides an overview of the pathophysiology of cutaneous wounds and the potential of MSCs-based cell-free therapy in each phase of wound healing. It also discusses clinical studies of MSCs-based cell-free therapies.

The Application of Adipose Tissue-Derived Mesenchymal Stem Cells (ADMSCs) and a Twin-Herb Formula to the Rodent Wound Healing Model: Use Alone or Together?

Our previous study reported that mesenchymal stem cells (MSCs) accelerated the wound healing process through anti-inflammatory, anti-apoptotic, and pro-angiogenetic effects in a rodent skin excision model. NF3 is a twin-herb formula, which presents similar effects in promoting wound healing. Research focusing on the interaction of MSCs and Chinese medicine is limited. In this study, we applied MSCs and the twin-herb formula to the wound healing model and investigated their interactions. Wound healing was improved in all treatment groups (MSCs only, NF3 only, and MSCs + NF3). The combined therapy further enhanced the effect: more GFP-labelled ADMSCs, collagen I and collagen III expression, Sox9 positive cells, and CD31 positive cells, along with less ED-1 positive cells, were detected; the expressions of proinflammatory cytokine IL-6 and TNF-α were downregulated; and the expression of anti-inflammatory cytokine IL-10 was upregulated. In vitro, NF3 promoted the cell viability and proliferation ability of MSCs, and a higher concentration of protein was detected in the NF3-treated supernatant. A proteomic analysis showed there were 15 and 22 proteins in the supernatants of normal ADMSCs and NF3-treated ADMSCs, respectively. After PCR validation, the expressions of 11 related genes were upregulated. The results of a western blot suggested that the TGFß/Smad and Wnt pathways were related to the therapeutic effects of the combined treatment. Our study suggests for the first time that NF3 enhanced the therapeutic effect of MSCs in the wound healing model and the TGFß/Smad and Wnt pathways were related to the procedure.

The Extracts of Dendrobium Alleviate Dry Eye Disease in Rat Model by Regulating Aquaporin Expression and MAPKs/NF-κB Signalling.

Dry eye is one of the most common ocular surface diseases caused by tear film instability and ocular surface damage due to an abnormal quality or quantity of tears. Inflammatory factors can initiate relevant transduction signalling pathways and trigger the inflammatory cascade response, resulting in ocular surface inflammation. It has been shown that the active ingredients in Dendrobium, such as polysaccharides, alkaloids and phenols, have anti-inflammatory, anti-tumour and immunity-boosting effects, and Dendrobium officinale extract can improve glandular secretion function, increase salivary secretion and increase the expression level of water channel protein in salivary glands in patients with dry eye syndromes. We investigated the in vitro cytoprotective effect of Dendrobium extracts in sodium chloride induced hyperosmotic conditions in human cornea keratocytes (HKs). Results showed that Dendrobium officinale Kimura et Migo water extract (DOW) and Dendrobium loddigesii Rolfe water extract (DLW) could upregulate the expression of aquaporins (AQP)5 protein, thus exerting a repairing effect by promoting cell migration. Furthermore, oral administration of DOW and DLW enhanced tear production in rats and exerted a protective effect on ocular surface damage. DOW and DLW could upregulate the expression of AQP5 and mucin (muc)5ac proteins in the lacrimal gland and reduce the inflammatory response. DOW and DLW inhibited the activation of the corresponding mitogen-activated protein kinases (MAPK) and NF-KB pathway, thereby playing a role in improving dry eye symptoms. This study provides a new perspective on dry eye treatment, and DOW and DLW may be potential therapeutic agents for dry eye.

Anti-metastatic effects of 1,2,3,4,6-Penta-O-galloyl-ß-D-glucose in colorectal cancer: Regulation of cathepsin B-mediated extracellular matrix dynamics and epithelial-to-mesenchymal transition.

Despite significant advances in the diagnosis and treatment of colorectal cancer (CRC), metastatic colorectal cancer still poses serious threat to CRC patients. The natural gallotannin 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (PGG) has been shown to possess anti-tumor effects on colon cancer cells, but its anti-metastatic effect is yet to be investigated. In this study, the effects of PGG on cell proliferation, colony formation ability, motility, migration were investigated in colon cancer cells using BrdU, colony formation, scratch, and transwell assays, respectively. Western blot assay was used for assessing protein expression. The orthotopic colon tumor-bearing mouse model and human colon cancer metastatic mouse model were employed to evaluate the anti-metastatic effects of PGG. Results showed that PGG exhibited not only anti-proliferative and colony formation inhibitory effects, but also inhibition on cell adhesion, motility, and migration in both HCT116 and colon 26-M01 cells via modulating protein expression of cathepsin B, FAK, cofilin, and epithelial-to-mesenchymal transition related proteins. In addition, PGG (10 or 15 mg/kg, i.p.) could significantly inhibit liver and lung metastasis in colon cancer metastatic mice models. Furthermore, PGG could regulate the populations of T cells, macrophages, and MDSCs, while the levels of IL-2, IL-6, IL-10, IFN-γ, and TNF-α were altered after PGG treatment in metastatic CRC mice. This is the first report of the anti-metastatic effects of PGG by regulating cathepsin B-mediated extracellular matrix dynamics and epithelial-to-mesenchymal transition process in CRC. Our findings suggested that PGG has great potential to be developed as an anti-metastatic agent for metastatic CRC.

Human mast cells induce osteoclastogenesis through cell surface RANKL.

OBJECTIVES: We employed the co-culture of CD34+ stem cell-derived human mast cells (HMC) and human monocyte-derived osteoclast precursors to evaluate if mast cells contribute to the pathogenesis of osteoporosis through regulation of osteoclast proliferation and activation. METHODS: Mature HMC and osteoclast precursors were cultured from monocytes isolated from human buffy coat. The osteoclast precursors were incubated with HMC or receptor activator of nuclear factor kappa-B ligand (RANKL) for a week prior to determination of osteoclast maturation through characterization by their morphology and tartrate resistant acid phosphatase (TRAP) expression. The bone absorption activity was determined by pit formation on osteo-assay plate. RESULTS: Mature osteoclasts were identified following co-culture of osteoclast precursors with HMC for one week in the absence of RANKL and they were capable of bone resorption. These actions of HMC on osteoclasts were not affected by mast cell activators such anti-IgE or substance P but could be reversed by osteoprotegerin (OPG) in the co-culture system suggesting the involvement of RANKL. The expression of RANKL on the cell surface of HMC was confirmed by flow cytometry and the density was not affected by activation of HMC. CONCLUSION: Our study provided direct evidence confirming the initiation of osteoclast proliferation and activation by mast cells through cell surface RANKL suggesting that mast cells may contribute to bone destruction in pathological conditions such as osteoporosis.

The Efficacy of Herbal Supplement Danggui Buxue Tang for Relieving Menopausal Symptoms.

OBJECTIVES: This study aimed to further explore the efficacy and safety of Danggui Buxue Tang (DBT), a simple herbal formula, for improving the quality of life of women suffering from menopausal symptoms. METHODS: A third clinical trial to determine the clinical efficacy of high-dose DBT for a period of 12 weeks was carried out. The standard Menopause-Specific Quality of Life (MENQOL) assessment chart was used for the evaluation. Safety was defined as an absence of direct estrogenic effects, serum inflammatory cytokines. Notably, interleukin IL-6, IL-8 and tumor necrosis factor TNF-α, known to be directly related to estrogenic reactions in menopause studies, were monitored. RESULTS: The third clinical trial indicated an overall improvement in the four domains of MENQOL, offering further proof of the efficacy of DBT demonstrated in the two previous trials. The serial checks of the three cytokines related to estrogen activities did not show either upward or downward trends. The haphazard behavior reactions of the three cytokines offered indirect indications that DBT improved the MENQOL independently from estrogen activities. CONCLUSIONS: The three clinical trials using DBT to relieve menopausal syndrome have offered solid evidence for its efficacy. The uncertainty regarding whether the "phytoestrogen" contained in DBT had bioactivities similar to estrogen was alleviated through the confirmation that no strict estrogenic bioactivities were observed. The issue of safety was further clarified via laboratory platform studies on DBT, which not only showed the lack of similarity with estrogen actions but also confirmed the value of combining the two herbs in the classic formula.

'Healthier Chinese spine': an update of osteoporotic fractures in men (MrOS) and in women (MsOS) Hong Kong spine radiograph studies.

For the MrOS (Hong Kong) and MsOS (Hong Kong) baseline (BL) studies, community-dwelling 2,000 Chinese men (mean age: 72.3 years) and 2,000 Chinese women (mean age: 72.5 years) were recruited from 2001 to 2003. These two studies have spanned two decades till now. This review summarizes our spine radiograph results. Senile and post-menopausal osteoporosis were associated with intervertebral disc volume reduction; and in women, menopause accelerates disc degeneration. Elderly women's osteoporotic vertebral fracture (OVF) prevalence was double of that of elderly men. For year-4 follow-up (FU), male participants with BL OVF had little increased risk for further OVF. In our study comparing OVF rates in age-matched Hong Kong Chinese women and Italian Caucasian women (mean age: 74.1 years), endplate and/or cortex fracture (ECF) prevalence was 26% for Chinese and 47% for Italian. OVF with ≥40% vertebral height loss was recorded among 9.5% of the Chinese subjects while among 26% of the Italian subjects. OVFs in Italian subjects were more likely to be multiple and generally severer. Clinical spine fractures were recorded 133 cases/100,000 person-years in MrOS (Hong Kong) participants and 273 cases/100,000 person-years in MsOS (Hong Kong) participants. Literature review suggests the clinical vertebral fracture rates among elderly Hong Kong Chinese subjects are approximately half of those of American, Australian, and Canadian subjects. Data synthesis suggests elderly Caucasians have a higher degenerative spondylolisthesis prevalence, being approximately 70% higher than that of elderly Hong Kong Chinese. Literature review of other authors' publications shows, compared with Caucasians, Chinese have a much lower incident rate of back pain. We conclude that elderly Chinese have a generally healthier spine relative to elderly Caucasians.

A review on the molecular mechanisms, the therapeutic treatment including the potential of herbs and natural products, and target prediction of obesity-associated colorectal cancer.

Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. Obesity has been proven to be closely related to colorectal carcinogenesis. This review summarized the potential underlying mechanisms linking obesity to CRC in different aspects, including energy metabolism, inflammation, activities of adipokines and hormones. Furthermore, the potential therapeutic targets of obesity-associated CRC were predicted using network-based target analysis, with total predicted pathways not only containing previously reported pathways, but also putative signaling pathways pending for investigation. In addition, the current conventional therapeutic treatment options, plus the potential use of herbs and natural products in the management of obesity-associated CRC were also discussed. Taken together, the aim of this review article is to provide strong theoretical basis for future drug development, particularly herbs and natural products, in obesity-associated CRC.

Integrated Network Pharmacology Analysis and In Vitro Validation Revealed the Potential Active Components and Underlying Mechanistic Pathways of Herba Patriniae in Colorectal Cancer.

Herba Patriniae (HP) are medicinal plants commonly used in colorectal cancer (CRC) patients. In this study, network pharmacology was used to predict the active components and key signaling pathways of HP in CRC. Patrinia heterophylla, one type of HP, was chosen for validation of the network pharmacology analysis. The phytochemical profile of Patrinia heterophylla water extract (PHW) was determined by UHPLC-MS. MTT, RT-PCR, and Western blot assays were performed to evaluate the bioactivities of PHW in colon cancer cells. Results showed that 15 potentially active components of HP interacted with 28 putative targets of CRC in the compound-target network, of which asperglaucide had the highest degree. Furthermore, the ErbB signaling pathway was identified as the pathway mediated by HP with the most potential against CRC. Both RT-PCR and Western blot results showed that PHW significantly downregulated the mRNA and protein levels of EGFR, PI3K, and AKT in HCT116 cells. Asperglaucide, present in PHW, exhibited an anti-migratory effect in HCT116 cells, suggesting that it could be an active component of PHW in CRC treatment. In conclusion, this study has provided the first scientific evidence to support the use of PHW in CRC and paved the way for further research into the underlying mechanisms of PHW against CRC.

Effects of topical application of a tri-herb formula on inflammatory dry-skin condition in mice with oxazolone-induced atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing inflammatory and pruritic skin disease, affecting 10-20% of the population worldwide. Paeonia suffruticosa Andrews (Paeoniaceae) (Cortex Moutan) and Mentha haplocalyx Briq. (Labiatae) (Herba Menthae) have shown beneficial effects on AD. Calendula officinalis L. (Asteraceae) is commonly used for treating skin rashes and wounds. PURPOSE: In the present study, a three-herbs formula including Cortex Moutan and Herba Menthae, together with C. officinalis at 1:1:1 weight ratio was used as a topical agent and its therapeutic effects on AD was investigated. METHODS: In vitro effects of individual herbs and three-herbs formula (0.125-1 mg/ml) were examined using cytokine release assay on human mast HMC-1 cells, inflammation test on murine macrophage RAW cells and human keratinocyte (HaCaT) cells, and migration scratch assay on human umbilical vein endothelial cells (HUVEC). The contributing functional pathway of three-herbs formula in AD was explored using Western Blot assay in HMC-1 cells. Oxazolone-induced AD-like mice model was also used to investigate the in vivo therapeutic effect of the topical application of the three-herbs formula. RESULTS: Herba Menthae, Cortex Moutan, and three-herbs formula significantly reduced the production of IL-6 and tumor necrosis factor (TNF)-α in HMC-1 cells, inhibited the expression of IL-6, IL-8 and CCL2 in TNF-α/IFN-γ stimulated HaCaT cells, and suppressed the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cells. Moreover, Herba Menthae and three-herbs formula significantly suppressed CCL2 and TNF-α production in LPS-induced RAW 264.7 cells. C. officinalis and three-herbs formula promoted wound healing in HUVEC. For intracellular mechanisms, three-herbs formula inhibited the expressions of molecules in STAT1 and STAT3-dependent pathways. In vivo model showed that topical application of three-herbs formula on challenged ear reduced ear swelling and mice scratching frequencies. H&E and toluidine blue staining of the challenged ear tissue demonstrated that three-herbs formula reduced the epidermal thickness and mast cell infiltration, respectively. CONCLUSION: The three-herbs formula of Cortex Moutan, Herba Menthae and C. officinalis at 1:1:1 (w/w) exhibited anti-inflammatory effect and promotion of cell migration in vitro. It also alleviated ear redness, swelling, epidermal thickness and inflammation of the OXA-induced AD mice. These findings suggest a potential beneficial role of the topical application of the three-herbs formula for treatment of AD.

Adipose Tissue-Derived Mesenchymal Stem Cells (ADMSCs) and ADMSC-Derived Secretome Expedited Wound Healing in a Rodent Model - A Preliminary Study.

INTRODUCTION: The biological role of mesenchymal stem cells (MSCs) in wound healing has been demonstrated. However, there were limited studies on the healing effect of secretome which consists of many biological factors secreted by MSCs. In this study, we aimed to compare the therapeutic effects of secretome with MSCs on facilitating wound healing. METHODS: Green fluorescent protein labelled adipose-derived MSCs (GFP-ADMSCs) or secretome was injected in the full-thickness skin excision model on SD rats. The wound healing process was evaluated by calculating the healing rate and the histological examinations on skin biopsy. The cell viability, proliferation and mobility of the rat dermal fibroblasts were compared after different treatments. The inflammatory response in macrophages was indicated by the level of nitric oxide (NO) and inflammatory cytokines through NO assay and ELISA. RESULTS: On day 5 and day 14, both MSCs and secretome accelerated the wound healing, secretome further enhanced the process. GFP-MSCs were detected 10 days after transplantation. The level of IL-6 and TNF-α in blood was reduced after MSCs and secretome treatments. The expressions of VEGF and PCNA were increased after treatment, higher intensity of VEGF was observed in secretome-injected tissue. The concentrations of total protein and VEGF in secretome were 2.2 ± 0.5 mg/mL and 882.0 ± 72.7 pg/mL, respectively. The cell viability and proliferation of FR were promoted significantly after the treatment. The scratch test showed that secretome accelerated the wound healing speed. Secretome reduced the metabolism of macrophages remarkably, but it did not decrease the level of macrophage-secreted NO. The expression of the pro-inflammatory cytokines (IL-6, MCP-1 and TNF-α) was downregulated significantly. CONCLUSION: Our study indicated both MSCs and MSCs-derived secretome enhanced the wound healing process in early phase. Secretome further promoted the healing effects through promoting the fibroblast proliferation and migration and suppressing the inflammatory response.

Evidence on Efficacy and Safety of Chinese Medicines Combined Western Medicines Treatment for Breast Cancer With Endocrine Therapy.

BACKGROUND: Breast cancer, a malignant disorder, occurs in epithelial tissue of the breast glands and ducts. Endocrine therapy is commonly applied as an important adjuvant treatment for breast cancer, but it usually induces a variety of side effects. Chinese Medicines (CM) has therapeutic effect on reducing adverse effects of the endocrine therapy in many clinical studies. But strong evidence is still limited on the efficacy and safety of CM combined western medicines (CM-WM) for breast cancer. OBJECTIVE: To study the efficacy and safety of CM-WM as an adjuvant treatment for reducing side effects induced by endocrine therapy in breast cancer patients. METHOD: We searched relevant clinical studies in PubMed and the Chinese National Knowledge Infrastructure (CNKI) databases up to February 28, 2021 and only Randomized Controlled Trials (RCTs) were included. There were no limitations on the languages. We extracted data from the included RCTs, assessed study quality, conducted meta-analyses by RevMan 5.4 and compared the pooled Risk Ratios (RR) or Mean Difference (MD) with 95% CIs. RESULTS: In total 28 trials involving 1,926 participants were included. Six RCTs compared CM-WM with CM placebo-WM, while 22 RCTs compared CM-WM with WM alone. No study compared CM-WM with no treatment. Meta-analysis showed that CM-WM treatment significantly improved quality of life (MD = 0.73, 95% CI = 0.11-1.35, P = 0.02) when compared with CM placebo-WM treatment. When compared with WM treatment alone, CM-WM treatment significantly improved bone mineral density (MD = 0.24, 95% CI = 0.13-0.35, P <0.0001), TCM syndrome score (MD = -5.39, 95% CI = -8.81 to -1.97, P = 0.0002), Kupperman Scale (MD = 0.24, 95% CI = -2.76 to -1.94, P <0.0001), Karnofsky Performance Scale (MD = 3.76, 95% CI = 1.64-5.88, P = 0.0005), quality of life (MD = 3.01, 95% CI = 1.00-5.02, P = 0.003), and pain relief (MD = 2.10, 95% CI = 0.72-3.48, P <0.0001). Compared with WM, CM-WM significantly decreased incidence of TCM symptoms (nausea, vomiting, fatigue, etc.) (RR = 1.60, 95% CI = 1.40-1.84, P <0.0001). For safety, serum calcium, estradiol, ALP, and blood CD3, CD4 and CD8 counts were not significantly difference between two treatments (P >0.05). Serious side effects or reactions were not reported in all included studies. CONCLUSION: The adjunctive use of CM reduced the endocrine therapy associated adverse events, including bone mineral density loss, perimenopausal symptoms, poor quality of life, pain and impaired immune function. But large-scale and high quality RCTs are needed to support the application of CM-WM therapy.

Medicinal Plants and Mushrooms with Immunomodulatory and Anticancer Properties-A Review on Hong Kong's Experience.

The immune modulating effects of selected herbs deserve careful studies to gain evidence-based support for their further development. We have been working hard on many items of medicinal herbs to gain insight into their immunomodulatory effects relevant to cancer treatment in particular, while infection control is not excluded. Nine of them have been selected to give the results of our exploration on their biological, particularly immunomodulatory activities. Since Hong Kong people especially favor one medicinal mushroom, viz. Coriolus versicolor, a number of clinical trials using Coriolus for cancer-related studies are included in this review. While immune modulation platforms are being built for relevant studies, a brief account on the research targets and related procedures are given.

The Immuno-Modulatory Activities of Pentaherbs Formula on Ovalbumin-Induced Allergic Rhinitis Mice via the Activation of Th1 and Treg Cells and Inhibition of Th2 and Th17 Cells.

Allergic rhinitis (AR) is a highly prevalent allergic disease induced by immunoglobulin (Ig) E-mediated hypersensitivity reaction at the nasal epithelium against inhaled allergens. Previous studies have demonstrated that Pentaherbs formula (PHF), a modified herbal formula comprising five herbal medicines (Flos Lonicerae, Herba Menthae, Cortex Phellodendri, Cortex Moutan and Rhizoma Atractylodis), could suppress various immune effector cells to exert anti-inflammatory and anti-allergic effects in allergic asthma and atopic dermatitis. The present study aimed to further determine the anti-inflammatory activities of PHF in an ovalbumin (OVA)-induced AR BALB/c mouse model. Nasal symptoms such as sneezing and nose rubbing were recorded and the serum total IgE and OVA-specific IgG1, as well as interleukin (IL)-4, IL-5, IL-10, IL-13, chemokines CXCL9 CXCL10, and tumor necrosis factor (TNF)-α concentrations in nasal lavage fluid (NALF) were measured during different treatments. Effects of PHF on the expression of inflammatory mediators in the sinonasal mucosa were quantified using real-time QPCR. PHF was found to suppress allergic symptoms, infiltration of inflammatory cells, and hyperplasia of goblet cells in the nasal epithelium of the OVA-induced AR mice. PHF could reduce OVA-specific IgG1 level in serum, and TNF-α and IL-10 in nasal lavage fluid (NALF), significantly up-regulate the splenic regulatory T (Treg) cell level, increase the Type 1 helper T cell (Th1)/Type 2 helper T cell (Th2) ratio, and reduce the Th17 cells (all p < 0.05). PHF could also alleviate in situ inflammation in sinonasal mucosa of OVA-induced AR mice. In conclusion, oral treatment of PHF showed immuno-modulatory activities in the OVA-induced AR mice by regulating the splenic T cell population to suppress the nasal allergy symptoms and modulating inflammatory mediators, implicating that PHF could be a therapeutic strategy for allergic rhinitis.

Rubinoboletus ballouii polysaccharides exhibited immunostimulatory activities through toll-like receptor-4 via NF-κB pathway.

The biological activities of water-soluble components of edible mushroom Rubinoboletus ballouii (RB) were seldom reported. Polysaccharides of RB (RBP) were prepared and well-characterized using chemical analyses. The immunomodulatory properties of RBP were investigated using human monocyte-derived dendritic cells (moDC) in vitro, and cyclophosphamide (CTX)-induced immunosuppressive mouse model. Results showed that RBP was found to contain 80.6% (w/w) of neutral sugars including D-fucose, D-mannose, D-glucose and D-galactose (1.7:1.4:1.0:1.8), and 12.5% (w/w) of proteins, which composed of glutamine, threonine, serine, etc. RBP could promote the maturation of moDC and increase the secretion of IL-12p40, IL-10, and TNF-α. Furthermore, the stimulation of IL-12p40 production was inhibited by pretreatment with toll-like receptor (TLR)-4 blocker or NF-κB pathway blocker, suggesting that the activation of moDC by RBP was mediated through NF-κB pathway via TLR-4 receptor. On the other hand, in CTX-treated mice, RBP restored the loss of CD34bright CD45dim hematopoietic stem cells and increased IL-2 production in sera and splenocytes culture supernatant, as well as up-regulated the percentage of CD4+ T helper lymphocyte in mice splenocytes. These findings strongly suggested that RBP are the active ingredients of RB responsible for its immunostimulatory actions and deserved to be further investigated as cancer supplements.