CXCL6: A potential therapeutic target for inflammation and cancer.

Chemokines were originally defined as cytokines that affect the movement of immune cells. In recent years, due to the increasing importance of immune cells in the tumor microenvironment (TME), the role of chemokines has changed from a single "chemotactic agent" to a key factor that can regulate TME and affect the tumor phenotype. CXCL6, also known as granulocyte chemoattractant protein-2 (GCP-2), can recruit neutrophils to complete non-specific immunity in the process of inflammation. Cancer-related genes and interleukin family can promote the abnormal secretion of CXCL6, which promotes tumor growth, metastasis, epithelial mesenchymal transformation (EMT) and angiogenesis in the TME. CXCL6 also has a role in promoting fibrosis and tissue damage repair. In this review, we focus on the regulatory network affecting CXCL6 expression, its role in the progress of inflammation and how it affects tumorigenesis and progression based on the TME, in an attempt to provide a potential target for the treatment of diseases such as inflammation and cancer.

Cinobufagin: a promising therapeutic agent for cancer.

OBJECTIVES: Cinobufagin is a natural active ingredient isolated from the traditional Chinese medicine Venenum Bufonis (Chinese: Chansu), which is the dried secretion of the postauricular gland or skin gland of the Bufo gargarizans Cantor or Bufo melanostictus Schneider. There is increasing evidence indicating that cinobufagin plays an important role in the treatment of cancer. This article is to review and discuss the antitumor pharmacological effects and mechanisms of cinobufagin, along with a description of its toxicity and pharmacokinetics. METHODS: The public databases including PubMed, China National Knowledge Infrastructure and Elsevier were referenced, and 'cinobufagin', 'Chansu', 'Venenum Bufonis', 'anticancer', 'cancer', 'carcinoma', and 'apoptosis' were used as keywords to summarize the comprehensive research and applications of cinobufagin published up to date. KEY FINDINGS: Cinobufagin can induce tumour cell apoptosis and cycle arrest, inhibit tumour cell proliferation, migration, invasion and autophagy, reduce angiogenesis and reverse tumour cell multidrug resistance, through triggering DNA damage and activating the mitochondrial pathway and the death receptor pathway. CONCLUSIONS: Cinobufagin has the potential to be further developed as a new drug against cancer.

An endophytic fungus Schizophyllum commune isolated from Panax ginseng enhances hairy roots growth and ginsenoside biosynthesis.

Using endophytic fungal elicitors to increase the accumulation of valuable secondary metabolites in plant tissue culture is an effective biotechnology strategy. In this study, a collection of 56 strains of endophytic fungi were isolated from different organs of cultivated Panax ginseng, of which seven strains can be symbiotically co-cultured with the hairy roots of P. ginseng. Further experiments observed that strain 3R-2, identified as endophytic fungus Schizophyllum commune, can not only infect hairy roots but also promote the accumulation of specific ginsenosides. This was further verified because S. commune colonization significantly affected the overall metabolic profile of ginseng hairy roots. By comparing the effects of S. commune mycelia and its mycelia extract (EM) on ginsenoside production in P. ginseng hairy roots, the EM was confirmed to be a relatively better stimulus elicitor. Additionally, the introduction of EM elicitor can significantly enhance the expressions of key enzyme genes of pgHMGR, pgSS, pgSE, and pgSD involved in the biosynthetic pathway of ginsenosides, which was deemed the most relevant factor for promoting ginsenosides production during the elicitation period. In conclusion, this study is the first to show that the EM of endophytic fungus S. commune can be considered as an effective endophytic fungal elicitor for increasing the biosynthesis of ginsenosides in hairy root cultures of P. ginseng.

The Pathological Effects of Circulating Hydrophobic Bile Acids in Alzheimer's Disease.

Recent clinical studies have revealed that the serum levels of toxic hydrophobic bile acids (deoxy cholic acid, lithocholic acid [LCA], and glycoursodeoxycholic acid) are significantly higher in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) when compared to control subjects. The elevated serum bile acids may be the result of hepatic peroxisomal dysfunction. Circulating hydrophobic bile acids are able to disrupt the blood-brain barrier and promote the formation of amyloid-ß plaques through enhancing the oxidation of docosahexaenoic acid. Hydrophobic bile acid may find their ways into the neurons via the apical sodium-dependent bile acid transporter. It has been shown that hydrophobic bile acids impose their pathological effects by activating farnesoid X receptor and suppressing bile acid synthesis in the brain, blocking NMDA receptors, lowering brain oxysterol levels, and interfering with 17ß-estradiol actions such as LCA by binding to E2 receptors (molecular modelling data exclusive to this paper). Hydrophobic bile acids may interfere with the sonic hedgehog signaling through alteration of cell membrane rafts and reducing brain 24(S)-hydroxycholesterol. This article will 1) analyze the pathological roles of circulating hydrophobic bile acids in the brain, 2) propose therapeutic approaches, and 3) conclude that consideration be given to reducing/monitoring toxic bile acid levels in patients with AD or aMCI, prior/in combination with other treatments.

Natural products targeting macrophages in tumor microenvironment are a source of potential antitumor agents.

BACKGROUND: Macrophages are one of the major cell types in the immune system and are closely related to tumor development, which can be polarized into M1 type with anti-tumor activity or M2 type with pro-tumor activity. The infiltration of more macrophages into tumor predicts poorer prognosis due to their more exhibition of M2 phenotype under the influence of many factors in the tumor microenvironment (TME). Therefore, reverse of M2 macrophage polarization in TME is conducive to the suppression of tumor deterioration and understanding the influencing factors of macrophage polarization is helpful to provide new ideas for the subsequent targeting macrophages for tumor therapy. PURPOSE: This review summarizes the effects of TME on macrophage polarization and natural products against M2 macrophage polarization, which may provide some directions for tumor therapy. METHODS: The search of relevant literature was conducted using the PubMed, Science Direct, CNKI and Web of Science databases with the search terms "macrophage", "tumor microenvironment", "natural product" and "tumor". RESULTS: The mutual transformation of M1 and M2 phenotypes in macrophages is influenced by many factors. Tumor cells affect the polarization of macrophages by regulating the expression of genes and proteins and the secretion of cytokines. The expression of some genes or proteins in macrophages is also related to their own polarization. Many natural products can reverse M2 polarization of macrophages which has been summarized in this review. CONCLUSION: Regulation of macrophage polarization in TME can inhibit tumor development, and natural products have the potential to impede tumor development by regulating macrophage polarization.

Herbal medicines for insomnia through regulating 5-hydroxytryptamine receptors: a systematic review / 中国天然药物

Insomnia is a common sleep disorder without effective therapy and can affect a person's life. The mechanism of the disease is not completely understood. Hence, there is a need to understand the targets related to insomnia, in order to develop innovative therapies and new compounds. Recently, increasing interest has been focused on complementary and alternative medicines for treating or preventing insomnia. Research into their molecular components has revealed that their sedative and sleep-promoting properties rely on the interactions with various neurotransmitter systems in the brain. In this review, the role of 5-hydroxytryptamine (5-HT) in insomnia development is summarized, while a systematic analysis of studies is conducted to assess the mechanisms of herbal medicines on different 5-HT receptors subtypes, in order to provide reference for subsequent research.

Fabrication of Low-Cost Resistance Temperature Detectors and Micro-Heaters by Electrohydrodynamic Printing.

EHD printing is an advanced deposition technology that is commonly utilized for the direct manufacture of electrical devices. In this study, meander-type resistive electrodes consisting of silver nanoparticles were printed directly on rigid glass and flexible polyethylene terephthalate (PET) substrates. High-resolution patterns of ≈50 µm linewidth were successfully printed on untreated surfaces utilizing a bigger nozzle of 100 µm inner diameter after improving the experimental settings. The manufactured electrodes were evaluated and used as Resistance Temperature Detectors (RTDs) and micro-heaters in a systematic manner. The temperature sensors performed well, with a Temperature Coefficient of Resistivity (TCRs) of 11.5 ×10-3/°C and 13.3 ×10-3/°C, for glass and PET substrates, respectively, throughout a wide temperature range of 100 °C and 90 °C. Furthermore, the RTDs had a quick response and recovery time, as well as minimal hysteresis. The electrodes' measured sensitivities as micro-heaters were 3.3 °C/V for glass and 6.8 °C/V for PET substrates, respectively. The RTDs were utilized for signal conditioning in a Wheatstone bridge circuit with a self-heating temperature of less than 1 °C as a practical demonstration. The micro-heaters have a lot of potential in the field of soft wearable electronics for biomedical applications, while the extremely sensitive RTDs have a lot of potential in industrial situations for temperature monitoring.

Bie-Jia-Ruan-Mai-Tang, a Chinese Medicine Formula, Inhibits Retinal Neovascularization in Diabetic Mice Through Inducing the Apoptosis of Retinal Vascular Endothelial Cells.

Proliferative diabetic retinopathy (PDR) is one of the main complications of diabetes, mainly caused by the aberrant proliferation of retinal vascular endothelial cells and the formation of new blood vessels. Traditional Chinese medicines possess great potential in the prevention and treatment of PDR. Bie-Jia-Ruan-Mai-Tang (BJ), a Chinese medicine formula, has a good therapeutic effect on PDR clinically; however, the mechanism of action involved remains unclear. Therefore, we investigated the effect of BJ on PDR through in vitro and in vivo experiments. A diabetic mouse model with PDR was established by feeding a high-fat-high-glucose diet combined with an intraperitoneal injection of streptozotocin (STZ), while high-glucose-exposed human retinal capillary endothelial cells (HRCECs) were employed to mimic PDR in vitro. The in vivo experiments indicated that BJ inhibited the formation of acellular capillaries, decreased the expression of VEGF, and increased the level of ZO-1 in diabetic mice retina. In vitro experiments showed that high glucose significantly promoted cell viability and proliferation. However, BJ inhibited cell proliferation by cycle arrest in the S phase, thus leading to apoptosis; it also increased the production of ROS, decreased the mitochondrial membrane potential, reduced the ATP production, and also reduced the expressions of p-PI3K, p-AKT, and Bcl-xL, but increased the expressions of Bax and p-NF-κB. These results suggest that BJ induces the apoptosis of HRCECs exposed to high glucose through activating the mitochondrial death pathway by decreasing the PI3K/AKT signaling and increasing the NF-κB signaling to inhibit the formation of acellular capillaries in the retina, thus impeding the development of PDR.

Transcriptome sequencing and signal transduction for the enhanced tanshinone production in Salvia miltiorrhiza hairy roots induced by Trichoderma atroviride D16 polysaccharide fraction.

Salvia miltiorrhiza Bunge. is commonly used to treat vascular diseases because of its activity ingredients, phenolic acids, and tanshinones. Polysaccharide fraction (PSF) extracted from Trichoderma atroviride D16 could promote tanshinone accumulation in S. miltiorrhiza hairy roots. Transcriptome sequencing was conducted to describe the global gene expression of PSF-treatment hairy roots, and data analyses showed enzymes of tanshinone biosynthetic pathways were up-regulated, and genes associated to signal molecules and transcription factors were responsive. Endogenous H2O2, abscisic acid, and nitric oxide contents were measured after PSF treatment, while tanshinone accumulations were measured with treatment of exogenous H2O2 or H2O2 inhibitor on PSF-treatment S. miltiorrhiza hairy roots. The results showed H2O2 was important in tanshinone biosynthesis caused by PSF and nitric oxide might be the downstream molecules of H2O2. Taken together, the study indicates that D16 PSF enhances the accumulation of tanshinones through enzymes of tanshinone biosynthetic pathways, signal molecules, and transcription factors.

Corrigendum: ErHuang Formula Improves Renal Fibrosis in Diabetic Nephropathy Rats by Inhibiting CXCL6/JAK/STAT3 Signaling Pathway.

[This corrects the article DOI: 10.3389/fphar.2019.01596.].

Transcription Factor: A Powerful Tool to Regulate Biosynthesis of Active Ingredients in Salvia miltiorrhiza.

Salvia miltiorrhiza Bunge is a common Chinese herbal medicine, and its major active ingredients are phenolic acids and tanshinones, which are widely used to treat vascular diseases. However, the wild form of S. miltiorrhiza possess low levels of these important pharmaceutical agents; thus, improving their levels is an active area of research. Transcription factors, which promote or inhibit the expressions of multiple genes involved in one or more biosynthetic pathways, are powerful tools for controlling gene expression in biosynthesis. Several families of transcription factors have been reported to participate in regulating phenolic acid and tanshinone biosynthesis and influence their accumulation. This review summarizes the current status in this field, with focus on the transcription factors which have been identified in recent years and their functions in the biosynthetic regulation of phenolic acids and tanshinones. Otherwise, the new insight for further research is provided. Finally, the application of the biosynthetic regulation of active ingredients by the transcription factors in S. miltiorrhiza are discussed, and new insights for future research are explored.

Isatis indigotica: a review of phytochemistry, pharmacological activities and clinical applications.

OBJECTIVES: Isatis indigotica Fort. (I. indigotica) is an herbaceous plant belonging to Cruciferae family. Its leaf (IIL) and root (IIR) are commonly used in traditional Chinese medicines (TCMs) with good clinical efficacies such as clearing away heat and detoxification, cooling blood and reducing swelling. This review aimed to provide a systematic summary on the phytochemistry, pharmacology and clinical applications of I. indigotica. KEY FINDINGS: This plant contains alkaloids, organic acids, flavonoids, lignans, nucleosides, amino acids, and steroids. Previous pharmacological researches indicated that I. indigotica possesses promising antivirus, antibacterial, immunoregulatory, anti-inflammation, and cholagogic effects. Importantly, it can inhibit various viruses, such as influenza, hepatitis B, mumps, herpes simplex, cytomegalovirus, and coxsachievirus. Clinically, it is frequently used to treat various viral diseases like viral influenza, parotitis and viral hepatitis. Consequently, I. indigotica may be beneficial for the prevention and treatment of coronavirus disease 2019 (COVID-19). SUMMARY: This paper reviewed the chemical constituents, pharmacological effects and clinical applications of I. indigotica which may guide further research and application of this plant.

Mesoporous silica nanoparticles: facile surface functionalization and versatile biomedical applications in oncology.

Mesoporous silica nanoparticles (MSNs) have received increasing interest due to their tunable particle size, large surface area, stable framework, and easy surface modification. They are increasingly being used in varying applications as delivery vehicles including bio-imaging, drug delivery, biosensors and tissue engineering etc. Precise structure control and the ability to modify surface properties of MSNs are important for their applications. This review summarises the different synthetic methods for the preparation of well-ordered MSNs with tunable pore volume as well as the approaches of drugs loading, especially highlighting the facile surface functionalization for various purposes and versatile biomedical applications in oncology. Finally, the challenges of clinical transformation of MSNs-based nanomedicines are further discussed.

The Effect of Cellular Coenzyme Q10 Deficiency on Lysosomal Acidification.

Coenzyme Q10 (CoQ10) deficiency currently represents the only treatable mitochondrial disorder, however, little is known about how it may affect other organelles. The lysosome has been found to have a large concentration of CoQ10 localised at its membrane; additionally, it has been suggested that it plays a role in the normal acidification of the lysosomal lumen. As a result, in this study we assessed the effect of CoQ10 deficiency on lysosomal acidification. In order to investigate this, a neuronal cell model of CoQ10 deficiency was established via the treatment of SH-SY5Y cells with para-aminobenzoic acid (PABA). This method works through the competitive inhibition of the CoQ10 biosynthetic pathway enzyme, CoQ2. A single 1 mM (5 days) treatment with PABA resulted in a decrease of up to 58% in cellular CoQ10 (p < 0.05). It was found that this resulted in a significant decrease in fluorescence of both the LysoSensor (23%) and LysoTracker (35%) probes used to measure lysosomal pH (p < 0.05). It was found that subsequent treatment with CoQ10 (5 µM, 3 days) was able to restore cellular CoQ10 concentration (p < 0.005), which was associated with an increase in fluorescence from both probes to around 90% of controls (p < 0.05), suggesting a restoration of lysosomal pH. This study provides insights into the association between lysosomal pH and cellular CoQ10 status and the possibility that a deficit in the status of this isoprenoid may result in an impairment of lysosomal acidification.

Isorhamnetin: A review of pharmacological effects.

Isorhamnetin is one of the most important active ingredients in the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L., which possesses extensive pharmacological activities. At present, there have been numerous investigations on isorhamnetin, which has the effects of cardiovascular and cerebrovascular protection, anti-tumor, anti-inflammatory, anti-oxidation, organ protection, prevention of obesity, etc. The related mechanisms involve the regulation of PI3K/AKT/PKB, NF-κB, MAPK and other signaling pathways as well as the expression of related cytokines and kinases. Isorhamnetin has a high value of development and application. However, the investigations on its mechanism of action are limited and lack of detailed scientific validation. The manuscript reviewed the pharmacological effects of isorhamnetin and related mechanisms of action for the development of its medicinal properties further.

Beneficial Effects of Endophytic Fungi from the Anoectochilus and Ludisia Species on the Growth and Secondary Metabolism of Anoectochilus roxburghii.

Endophytic fungi possess favorable effects on their host plants, including disease-resistance improvement, secondary metabolite induction, and growth promotion. It is therefore a promising and sustainable strategy to utilize endophytic fungi for the quality improvement of medicinal herbs or important crops. In our study, a collection of 277 strains of endophytic fungi were isolated from Anoectochilus and Ludisia orchids. Two strains J162 and J211 can be symbiotically cocultured with the tissue culture seedlings of Anoectochilus roxburghii, a popular medicinal and edible plant in southern China. Both strains can significantly enhance the biomass of A. roxburghii and induce the biosynthesis and accumulation of its active ingredients, including flavonoids, kinsenoside, and polysaccharides. J162 and J211 were further identified as Chaetomium globosum and Colletotrichum gloeosporioides based on multilocus phylogenetic analysis. Immunocytochemical staining indicated that J162 and J211 mainly colonized the intercellular gap of xylem parenchyma cells of A. roxburghii roots without obvious harm. In addition, quantitative real-time polymerase chain reaction showed that the expression of three growth-related genes, namely, uracil phosphoribosyl transferase, amino acid transmembrane transporter, and maturase K, were significantly altered in A. roxburghii plants when treated with J162 and J211. In conclusion, the two strains are highly beneficial microbial resources for the growth and accumulation of active ingredients of A. roxburghii in agricultural cultivation.

Compound-based Chinese medicine formula: From discovery to compatibility mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese medicine formula (CMF) has a long history of clinical use in the treatment of various diseases under the guidance of traditional Chinese medicine (TCM) theory. The application of CMF can be divided into three levels, crude extracts, homologous compounds mixture, and specific compounds. However, the modern scientific connotation of the CMF theory has not been clarified. AIM OF THE REVIEW: To critically evaluate the research strategy for the investigation of compound-based CMF (CCMF). MATERIALS AND METHODS: The related information was collected from the scientific databases, including CNKI, Elsevier, ScienceDirect, PubMed, SpringerLink, Web of Science, and Wiley Online. RESULTS: The research design including discovery, screening, optimization, pharmacodynamics models, and target research techniques including the targets for compatibility compounds were evaluated. Essentially it has been evaluated that the in vitro multicellular three-dimensional culture or organoid model has been proposed for the optimization model for compatibility research of CCMF. Based on these, the traditional compatibility theory of CMF, such as Monarch-Minister-Assistant-Guide (Jun-Chen-Zuo-Shi in Chinese), can probably be elucidated by the CCMF research. CONCLUSIONS: CCMF has the clear advantage of providing the exact composition and controllable quality of modern medicines, in addition to having the characteristics of multi-ingredients and multi-targets synergistic effects of TCM. However, CCMF is still associated with challenges which need to be addressed for its future use.

Scutellaria barbata: A Review on Chemical Constituents, Pharmacological Activities and Clinical Applications.

Scutellaria barbata has a long history of medical use in Traditional Chinese Medicine for removing heat and toxic material, promoting blood circulation and removing blood stasis, and inducing diuresis to reduce edema. Recent pharmacology investigations have provided evidence for its anti-cancer, bacteriostasis, anti-virus, anti-inflammation, anti-oxidation and immunity enhancement properties. The efficacy of activating blood circulation and removing blood stasis has unique advantages in the treatment of cardiovascular and cerebrovascular diseases. A total of 84 compounds have been isolated from S. barbata and are characterized mainly as flavonoids, diterpenoids, followed by polysaccharide, volatile oil and steroids. Peer-reviewed articles published over the last few years were gathered by consulting the databases PubMed, Elsevier, Springer, and Chinese Herbal Classics. This review mainly focuses on the pharmacologically active constituents isolated from S. barbata，which have been subjected to in vitro and/or in vivo studies. Although, the chemical components, pharmacological activities, toxicology, clinical applications and mechanisms of action of S. barbata have been investigated, many constituents remain unknown. Further investigations are required to investigate the medicinal properties of S. barbata.