Search

Summary: Mucosal tissues contain distinct microbial communities that differ drastically depending on the barrier site, and as such, mucosal immune responses have evolved to be tailored specifically for their location. Whether protective or regulatory immune responses against invading pathogens or the commensal microbiota occur is controlled by local mononuclear phagocytes (MNPs). Comprising macrophages and dendritic cells (DCs), the functions of these cells are highly dependent on the local environment. For example, the intestine contains the greatest bacterial load of any site in the body, and hence, intestinal MNPs are hyporesponsive to bacterial stimulation. This is thought to be one of the major mechanisms by which harmful immune responses directed against the trillions of harmless bacteria that line the gut lumen are avoided. Regulation of MNP function by the microbiota has been characterized in the most depth in the intestine but there are several mucosal sites that also contain their own microbiota. In this review, we present an overview of how MNP function is regulated by the microbiota at mucosal sites, highlighting recent novel pathways by which this occurs in the intestine, and new studies elucidating these interactions at mucosal sites that have been characterized in less depth, including the urogenital tract. [ABSTRACT FROM AUTHOR]

iMOLSDOCK is an induced-fit docking algorithm that uses the mutually orthogonal Latin squares (MOLS) sampling technique. Here, we describe the updates made to iMOLSDOCK in order to increase receptor flexibility, improve the scoring system, and speed up calculation. With a dataset of 35 peptide-protein complexes, the PepSet benchmark dataset of 80 peptide-protein complexes, and the Astex Diverse set, which uses nonpeptide small molecules as ligands, iMOLSDOCK has been benchmarked and validated. Flexible residues are now able to deviate from the starting position by a maximum of 3.0 Å due to the increased receptor flexibility. The ranking effectiveness of iMOLSDOCK has increased by 24% once the scoring system was improved. Additionally, iMOLSDOCK has been compared to Gold v5.2.1, HPEPDOCK, AutoDock CrankPep v1.0, AutoDock Vina, HADDOCK, PatchDock, and RosettaLigand. For induced-fit peptide-protein docking, iMOLSDOCK achieved success rates of 6%, 37%, and 89% at the top 1, 10, and 100 levels. At the top 1, 10, and 100 levels, iMOLSDOCK had success rates for small molecule-protein docking of 14%, 31%, and 49%. The computation time for peptide docking was lowered by two orders of magnitude, and for nonpeptide small molecule docking, it was roughly 14 times faster due to code optimization in the iMOLSDOCK docking tool. Source code and binary of iMOLSDOCK could be obtained from https://sourceforge.net/projects/mols2-0/files/ ., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/Aims: Bile acids have recently been associated with the pathogenesis of irritable bowel syndrome (IBS). We therefore evaluated the expression of bile acid receptors in the intestinal mucosa of IBS patients as well as the effects of bile acids on small intestinal epithelial cells. Methods: Intestinal biopsy specimens were obtained from 15 IBS patients and 15 healthy controls. The effects of bile acid stimulation on trans-epithelial electrical resistance (TEER) and permeability in differentiated Caco-2 cells were measured. Proinflammatory cytokines were measured by enzyme-linked immunosorbent assay. mRNA levels of bile acid receptors, including farnesoid X receptor (FXR), and cytokines were determined by real-time reverse transcription-PCR. Caco-2 cells were pre-incubated with the FXR antagonist guggulsterone. Results: FXR mRNA expression at the terminal ileum was increased in IBS patients. Chenodeoxycholic acid (CDCA) significantly decreased TEER, increased permeability, and increased interleukin-8 (IL-8) release from Caco-2 cells. Pre-incubation with guggulsterone blocked CDCA-mediated IL-8 release; however, the decrease in TEER was not reversed. CDCA-induced IL-6 and IL-8 mRNA levels were blocked by guggulsterone. CDCA increased IL-6, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor release, whereas guggulsterone significantly blocked IL-6 and TNF-α release. Conclusions: FXR expression was elevated at the terminal ileum in IBS patients. CDCA increased proinflammatory cytokines, while guggulsterone blocked these increases. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel diseases are immunologically mediated disorders of gastrointestinal tract, characterized by dysregulated immune responses that result in a chronic intestinal inflammation. The antiplatelet cilostazol (CS), a phosphodiesterase‐III inhibitor, exerted a beneficial effect on several models of gastrointestinal diseases; however, the full mechanism of action in this context has not been unveiled. Aim: The current study aimed to elucidate the potential role of CS in a 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis model. Methods: Male Wistar rats were divided into a sham group and groups treated with sulfasalazine (500 mg/kg), CS (50 and 100 mg/kg), and a combination (sulfasalazine/CS 50 mg/kg). All treatments were administered orally 15 days, with TNBS rectal administration on the 11th day. Results: TNBS‐produced colitis manifested as a decrease in the epithelial junctional adhesion molecule‐A (JAM‐A) and as an increase in trefoil factor‐3, ulcerative area, and colon mass index, parameters that collaborate with the gross macroscopic changes in colon tissue. In addition, TNBS increased hemeoxygenase‐1, nuclear factor‐kappa B, P‐selectin, and myeloperoxidase, as well as the apoptotic ratio of Bax/Bcl‐2. Administration of CS alone, especially at the high dose level, attenuated the severity of TNBS‐induced colitis in a sulfasalazine‐comparable manner. In addition, a better effect was mediated by the combination regimen, which succeeded in normalizing most of the measured parameters. Conclusion: CS protected the colon against TNBS through its anti‐inflammatory and antiapoptotic effects along with maintaining cellular tight junctions (TJs). Furthermore, CS can be beneficial as an add‐on drug with the conventional treatments of colitis. [ABSTRACT FROM AUTHOR]

A reduction in intestinal barrier function is currently believed to play an important role in pathogenesis of many diseases, as it facilitates passage of injurious factors such as lipopolysaccharide, peptidoglycan, whole bacteria, and other toxins to traverse the barrier to damage the intestine or enter the portal circulation. Currently available evidence in animal models and in vitro systems has shown that certain dietary interventions can be used to reinforce the intestinal barrier to prevent the development of disease. The relevance of these studies to human health is unknown. Herein, we define the components of the intestinal barrier, review available modalities to assess its structure and function in humans, and review the available evidence in model systems or perturbations in humans that diet can be used to fortify intestinal barrier function. Acknowledging the technical challenges and the present gaps in knowledge, we provide a conceptual framework by which evidence could be developed to support the notion that diet can reinforce human intestinal barrier function to restore normal function and potentially reduce the risk for disease. Such evidence would provide information on the development of healthier diets and serve to provide a framework by which federal agencies such as the US Food and Drug Administration can evaluate evidence linking diet with normal human structure/function claims focused on reducing risk of disease in the general public. [ABSTRACT FROM AUTHOR]

Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and nonalcoholic fatty liver disease. Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5. Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size. Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity. Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

A total of 175 abietane quinone diterpenes with ortho- or para-quinone chromophore, namely 11,12-ortho-quinone abietane, 11,14-para-quinone abietane, seco-abietane and abeo-abietanes quinones were surveyed from 130 species of Salvia of central Asia/Mediterranean area, eastern Asia, and Central and South America. An organized information on the phytochemistry and the biological activities, i.e. anti-cancer, antioxidant, anxiolytic and antidepressant, anti-obesity, antinflammatory, as well as antimicrobial and toxicological aspects of these compounds was provided. Due to the many nomenclatural mistakes caused by the abundance of data, and the need to provide the plant knowledge for further chemotaxonomic studies, the results about the botany and the taxonomy of the plant source of these compounds were also summarized. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. Approximately 30% of patients do not respond to therapy with ursodeoxycholic acid (UDCA). Previous studies have implicated increased senescence of cholangiocytes in patients who do not respond to UDCA. This may increase the release of cytokines which drive pathogenic T cell polarization. As FXR agonists are beneficial in treating UDCA non‐responsive patients, the current study was designed to model the interactions between cholangiocytes and CD4+ T cells to investigate potential immunomodulatory mechanisms of bile acid receptor agonists. Human cholangiocytes were co‐cultured with CD4+ T cells to model the biliary stress response. Senescent cholangiocytes were able to polarize T cells toward a Th17 phenotype and suppressed expression of FoxP3 (P = 0.0043). Whilst FXR and TGR5 receptor agonists were unable directly to alter cholangiocyte cytokine expression, FGF19 was capable of significantly reducing IL‐6 release (P = 0.044). Bile acid receptor expression was assessed in PBC patients with well‐characterized responsiveness to UDCA therapy. A reduction in FXR staining was observed in both cholangiocytes and hepatocytes in PBC patients without adequate response to UDCA. Increased IL‐6 expression by senescent cholangiocytes represents a potential mechanism by which biliary damage in PBC could contribute to excessive inflammation. [ABSTRACT FROM AUTHOR]

Background and Aims: Bariatric surgery, such as vertical sleeve gastrectomy (VSG), is the most effective long-term treatment for obesity. However, there are conflicting reports on the effect of bariatric surgery on inflammatory bowel disease (IBD). Bariatric surgery increases bile acid concentrations, which can decrease inflammation by signaling through the bile acid receptor, TGR5. TGR5 signaling protects against chemically induced colitis in mice. VSG increases circulating bile acid concentrations to increase TGR5 signaling, which contributes to improved metabolic regulation after VSG. Therefore, we investigated the effect of VSG on chemically induced colitis development and the role of TGR5 in this context. Methods: VSG or sham surgery was performed in high fat diet-fed male Tgr5+/+ and Tgr5−/− littermates. Sham-operated mice were food restricted to match their body weight to VSG-operated mice. Colitis was induced with 2.5% dextran sodium sulfate (DSS) in water post-operatively. Body weight, energy intake, fecal scoring, colon histopathology, colonic markers of inflammation, goblet cell counts, and colonic microRNA-21 levels were assessed. Results: VSG decreased body weight independently of genotype. Consistent with previous work, genetic ablation of TGR5 increased the severity of DSS-induced colitis. Notably, despite the effect of VSG to decrease body weight and increase TGR5 signaling, VSG increased the severity of DSS-induced colitis. VSG-induced increases in colitis were associated with increased colonic expression of TNF-α, IL-6, MCP-1, and microRNA-21. Conclusions: While our data demonstrate that TGR5 protects against colitis, they also demonstrate that VSG potentiates chemically induced colitis in mice. These data suggest that individuals undergoing VSG may be at increased risk for developing colitis; however, further study is needed. [ABSTRACT FROM AUTHOR]

Diepoxy-containing compounds are widely distributed in nature. These metabolites are found in plants and marine organisms and are also produced by many microorganisms, fungi, or fungal endophytes. Many of these metabolites are antibiotics and exhibit a wide variety of biological activities. More than 80 α,β-diepoxy-containing compounds are presented in this article, which belong to different classes of chemical compounds including lipids, terpenoids, alkaloids, quinones, hydroquinones, and pyrones. The main activities that characterize α,β-diepoxy-containing compounds are antineoplastic with confidence up to 99%, antifungal with confidence up to 94%, antiinflammatory with confidence up to 92%, or antibacterial with confidence up to 78%. In addition, these metabolites can be used as a lipid metabolism regulator with a certainty of up to 81%, antiviral (Arbovirus) activity with a certainty of up to 71%, or antiallergic activity with confidence up to 69%. These data on the biological activity of diepoxy-containing compounds are of considerable interest to pharmacologists, chemists, and medical professionals who are involved in phytomedicine and related areas of science and industry. [ABSTRACT FROM AUTHOR]

Fecal microbiota transplantation (FMT) is a well-established treatment for recurrent Clostridioides difficile infection. FMT has become a more readily available and useful new treatment option as a result of stool banks. The current state of knowledge indicates that dysbiosis of the gut microbiota is implicated in several disorders in addition to C. difficile infection. Randomized controlled studies have shown FMT to be somewhat effective in treating ulcerative colitis, irritable bowel syndrome, and hepatic encephalopathy. In addition, FMT has been beneficial in treating several other conditions, such as the eradication of multidrug-resistant organisms and graft-versus-host disease. We expect that FMT will soon be implemented as a treatment strategy for several new indications, although further studies are needed. [ABSTRACT FROM AUTHOR]

The pathological characteristics of Alzheimer's disease (AD) include formation of senile plaques resulting from amyloid-β (Aβ) deposition and neurofibrillary tangles caused by tau hyperphosphorylation. Reducing tau hyperphosphorylation is crucial for treatment of AD. Network pharmacology analysis showed that CTS may reduce tau hyperphosphorylation by regulating the phosphatidylinositol 3 kinases/protein kinase B/ glycogen synthase kinase-3β (PI3K/Akt/GSK3β) pathway. We investigated the ability of cryptotanshinone (CTS) to reduce Aβ-induced tau hyperphosphorylation and characterized the underlying mechanisms. Amyloid-β 42 oligomers (AβO) were used to establish an AD model in HT22 cells. The expression levels of tau and related proteins in PI3K/Akt/GSK3β pathway were measured using western blot and immunofluorescence staining. The above-mentioned proteins were then evaluated in an okadaic acid (OKA)-induced AD cell model to verify the results. Synapse-associated proteins including post-synaptic density protein-95 (PSD95) and synaptophysin were also evaluated. We found that CTS significantly reduced tau hyperphosphorylation at Ser202, Ser404, Thr181, and Thr231 in AβO- and OKA-induced cell models. Moreover, we also found that CTS reversed AβO-induced reductions in the levels of PSD95 and synaptophysin. We used LY294002 to block PI3K and the results showed that CTS exerted neuroprotective effects through regulation of the PI3K/Akt/GSK3β signaling pathway. In summary, we showed for the first time that CTS inhibited AD-related tau hyperphosphorylation and reduced the effects of AβO on the expression levels of PSD95 and synaptophysin via the PI3K/Akt/GSK3β pathway in HT22 cells., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Parenteral nutrition (PN) provides nutrition intravenously; however, this life-saving therapy is associated with significant liver disease. Recent evidence indicates improvement in PN-associated injury in animals with intact gut treated with enteral bile acid (BA), chenodeoxycholic acid (CDCA), and a gut farnesoid X receptor (FXR) agonist, which drives the gut-liver cross talk (GLCT). We hypothesized that similar improvement could be translated in animals with short bowel syndrome (SBS).Methods: Using piglets, we developed a novel 90% gut-resected SBS model. Fifteen SBS piglets receiving PN were given CDCA or control (vehicle control) for 2 weeks. Tissue and serum were analyzed posteuthanasia.Results: CDCA increased gut FXR (quantitative polymerase chain reaction; P = .008), but not downstream FXR targets. No difference in gut fibroblast growth factor 19 (FGF19; P = .28) or hepatic FXR (P = .75), FGF19 (P = .86), FGFR4 (P = .53), or Cholesterol 7 α-hydroxylase (P = .61) was noted. PN resulted in cholestasis; however, no improvement was noted with CDCA. Hepatic fibrosis or immunostaining for Ki67, CD3, or Cytokeratin 7 was not different with CDCA. PN resulted in gut atrophy. CDCA preserved (P = .04 vs control) gut mass and villous/crypt ratio. The median (interquartile range) for gut mass for control was 0.28 (0.17-0.34) and for CDCA was 0.33 (0.26-0.46).Conclusions: We note that, unlike in animals with intact gut, in an SBS animal model there is inadequate CDCA-induced activation of gut-derived signaling to cause liver improvement. Thus, it appears that activation of GLCT is critically dependent on the presence of adequate gut. This is clinically relevant because it suggests that BA therapy may not be as effective for patients with SBS. [ABSTRACT FROM AUTHOR]

A new series of triheterocycles containing indole-benzimidazole-based 1,2,3-triazole hybrids have been synthesized in good yields via a microwave-assisted click reaction. All the compounds were characterized by IR, 1H NMR, 13C NMR and mass spectroscopy and were evaluated for their in vitro antitubercular activity against the Mycobacterium tuberculosis H37Rv strain. Compounds 4b, 4h and 4i displayed highly potent antitubercular activity with MIC 3.125-6.25 μg/mL. The antioxidant potential was evaluated using 2,2-diphenyl-1-picryl hydrazine and H2O2 radical scavenging activity, and compounds 4e,4f and 4g showed excellent radical scavenging activity with IC50 values in the range of 08.50-10.05 μg/mL. Furthermore, the compounds were evaluated for antimicrobial activity against numerous bacterial and fungal strains, and compounds 4b, 4c and 4h were found to be the most promising potential antimicrobial molecules with MIC 3.125-6.25 μg/mL. [ABSTRACT FROM AUTHOR]

Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer’s and Parkinson’s diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases. [ABSTRACT FROM AUTHOR]

Introduction: Chronic idiopathic constipation (CC) is highly prevalent worldwide. A subset of patients with CC have reduced fecal (and by inference, intra-colonic) bile acids (BA). Elobixibat, a locally-acting ileal bile acid transporter (IBAT) inhibitor, leads to increased BA delivery to the colon and represents a new class of treatment for CC. BAs accelerate colonic transit and increase colonic secretion. Therefore, IBAT inhibitors have potential to treat patients with CC. Areas covered: Rationale for IBAT inhibitor in therapeutics, and preclinical and clinical pharmacology of elobixibat: In vitro, elobixibat is a highly potent, selective IBAT inhibitor. In humans, elobixibat accelerated colonic transit. In phase 2A, 2B and 3 studies in CC, elobixibat was efficacious, well tolerated and safe. An open-label, phase 3 trial (52 weeks) confirmed the safety of elobixibat. Elobixibat reduces LDL cholesterol, increases serum GLP-1, and has potential in metabolic syndrome. Expert commentary: Uniquely among current treatments of CC, elobixibat stimulates both motor and secretory functions in the colon. These dual effects suggest that, when approved, elobixibat may be a first-line choice for constipation associated with colonic BA deficiency and a second-line treatment for all patients with CC and constipation-predominant irritable bowel syndrome. Further studies are required to confirm efficacy for relief of CC. Once approved, elobixibat will likely become a second-line choice for treatment of CC. [ABSTRACT FROM AUTHOR]

Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention. [ABSTRACT FROM AUTHOR]

A series of novel 2-(2-cyanophenyl)-N-phenylacetamide derivatives 3(a-u) were designed and synthesized via selective amidation of methyl-2-(2-cyanophenyl)acetates over amidine formation by using AlMe3 as catalyst in good yields. All the newly synthesized derivatives were well characterized by 1H NMR, 13C NMR, FTIR and HRMS spectral techniques. All the synthesized title compounds were evaluated for their in vitro anticancer activity against three cancer cell lines. Among all compounds, 3i (IC50 = 1.20 μM, IC50 = 1.10 μM), 3j (IC50 = 0.11 μM, IC50 = 0.18 μM), 3o (IC50 = 0.98 μM, IC50 = 2.76 μM) showed excellent inhibitory activity than the standard Etoposide (IC50 = 2.11 μM, IC50 = 3.08 μM) against MCF-7 and A-549 cell lines, respectively. Docking analysis of all the compounds with the human topoisomerase II revealed that the compound 3j fitted well in the active site pocket, showing the best docking score of 158.072 kcal/mol. [ABSTRACT FROM AUTHOR]

Seized samples of illegally produced cocaine have a very large variability in composition; a fact that may result in a challenge to their analysis. We demonstrate here a simple and fast method to detect the presence of cocaine in both hydrochloride and free-base forms in illicit drug samples by nuclear magnetic resonance (NMR) spectroscopy. This is achieved by combining the commonly used 1D spectra and diffusion-ordered spectroscopy and introducing the 2D maximum-quantum NMR approach to forensic analysis. The protocol allows the facile determination of the cocaine forms even in the presence of multiple adulterants. By relying on non-uniform sampling acceleration of 2D spectroscopy, the identification can be obtained in less than 3 min for 10 mg of product. Moreover, we show that intermolecular interactions of the sample constituents, while affecting the analysis result, do not interfere with the quality of the detection of the proposed protocol. [ABSTRACT FROM AUTHOR]

Once known exclusively for their role in nutrients absorption, primary bile acids, chenodeoxycholic and cholic acid, and secondary bile acids, deoxycholic and lithocholic acid, are signaling molecules, generated from cholesterol breakdown by the interaction of the host and intestinal microbiota, acting on several receptors including the G proteincoupled bile acid receptor 1 (GPBAR1 or Takeda G-protein receptor 5) and the Farnesoid-X-Receptor (FXR). Both receptors are placed at the interface of the host immune system with the intestinal microbiota and are highly represented in cells of innate immunity such as intestinal and liver macrophages, dendritic cells and natural killer T cells. Here, we review how GPBAR1 and FXR modulate the intestinal and liver innate immune system and contribute to the maintenance of a tolerogenic phenotype in entero-hepatic tissues, and how regulation of innate immunity might help to explain beneficial effects exerted by GPBAR1 and FXR ligands in immune and metabolic disorders. [ABSTRACT FROM AUTHOR]

Cedrela P. Browne is a genus of trees, strictly related to Toona, in the Meliaceae, a family of flowering plants in the order Sapindales, which is among the most diverse sources of secondary metabolites in the Angiospermae. The most abundant metabolites in these genera are limonoids, tetranortriterpenes possessing diverse structural features, apotirucallanes, tirucallanes, and other triterpenes. The chemical constituents isolated from the genera Cedrela and Toona over the past decades, together with their biological activities, have been compiled in this article. The allelochemical and the phytotoxic activity of limonoids and triterpenoids seem to play a crucial role in the ecological function of these metabolites. While, the most promising use in human field seems related to their antimalarial and anti-inflammatory effects, even that further investigation are still needed. [ABSTRACT FROM AUTHOR]

Introduction: Pain is an unpleasant sensation triggered by noxious stimulation. It is one of the most prevalent conditions, limiting productivity and diminishing quality of life. Non steroidal anti inflammatory drugs (NSAIDs) are widely used as pain relievers in present day practice as pain is mostly initiated due to inflammation. However, due to potentially serious side effects, long term use of these antihyperalgesic drugs raises concern. Therefore there is a demand to search novel medicines with least side effects. Herbal products have been used for centuries to reduce pain and inflammation, and phytochemicals are known to cause fewer side effects. However, identification of active phytochemicals of herbal medicines and clear understanding of the molecular mechanism of their action is needed for clinical acceptance.Materials and methods: In this review, we have briefly discussed the cellular and molecular changes during hyperalgesia via inflammatory mediators and neuro-modulatory action involved therein. The review includes 54 recently reported phytochemicals with antihyperalgesic action, as per the literature available with PubMed, Google Scholar and Scopus.Conclusion: Compounds of high interest as potential antihyperalgesic agents are: curcumin, resveratrol, capsaicin, quercetin, eugenol, naringenin and epigallocatechin gallate (EGCG). Current knowledge about molecular targets of pain and their regulation by these phytochemicals is elaborated and the scope of further research is discussed. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate whether ginsenoside Rb1 (G-Rb1) attenuates spinal cord injury-associated oxidative stress in rats by regulating the endothelial nitric oxide synthase eNOS/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 signaling pathway. Sprague Dawley rats were randomly divided into the sham operation group (S group), spinal cord injury group (SCI group), G-Rb1 treatment group (G-Rb1 group) and SCI+G-Rb1+Inhibitor L-name group (L-name group). The posterior limb function was evaluated via the Basso, Beattie and Bresnahan scoring method. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) and glutathione (GSH) in serum were measured by ELISA. The pathological changes in the spinal cord were observed by H&E staining. Reverse transcription-quantitative polymerase chain reaction and western blot analyses were used to detect eNOS, phosphorylated (p)-eNOS, heat shock protein (HSP)90, Nrf2 and NAD(P)H quinone dehydrogenase 1 (Nqo1) at the mRNA and protein level. Immunohistochemistry was used to detect the expression of Nrf2 and p-eNOS. Compared with the S group, the scores of spinal cord function in the SCI group were significantly lower, and the levels of MDA were significantly increased, while the levels of SOD, CAT and GSH protein in spinal cord were significantly decreased (P<0.05). The spinal cord tissue exhibited hemorrhage, neuronal degeneration/necrosis, as well as mononuclear cell and lymphocyte infiltration. The eNOS, HSP90, Nrf2, Nqo1 and HO-1 mRNA levels were decreased (P<0.05). Compared with those in the SCI group, the spinal cord function score in the G-Rb1 group were significantly higher and the serum MDA content was significantly decreased, while the activity of SOD, CAT and GSH was significantly increased (P<0.05). The degeneration/necrosis of spinal cord neurons was attenuated, inflammatory cell infiltration was significantly reduced and the levels of eNOS, HSP90, Nrf2, Nqo1 and HO-1 were significantly upregulated (P<0.05). In the group that was administered the eNOS inhibitor L-name, the levels of eNOS, HSP90, Nrf2, Nqo1 and HO-1 were significantly decreased. In conclusion, G-Rb1 attenuates oxidative stress in injured spinal cords. The mechanism may at least in part involve the eNOS/Nrf2/HO-1 pathway. [ABSTRACT FROM AUTHOR]

Background/Aims: Intrahepatic cholangiocarcinoma (ICC) is a complicated condition, with difficult diagnosis and poor prognosis. The expression and clinical significance of the farnesoid X receptor (FXR), an endogenous receptor of bile acids, in ICC is not well understood. Methods: Western blotting and immunochemical analyses were used to determine the levels of FXR in 4 cholangiocarcinoma cell lines, a human intrahepatic biliary epithelial cell line (HIBEpic) and 322 ICC specimens, respectively, while quantitative reverse transcription polymerase chain reaction was used to detect the mRNA levels of FXR in cholangiocarcinoma cell lines. We evaluated the prognostic value of FXR expression and its association with clinical parameters. We determined the biological significance of FXR in ICC cell lines by agonist-mediated activation and lentivirus-mediated silence. IL-6 expression was tested by an enzyme-linked immunosorbent assay and flow cytometry. In vitro, cell proliferation was examined by Cell Counting Kit-8, migration and invasion were examined by wound healing and transwell assays; in vivo, tumor migration and invasion were explored in NOD-SCID mice. Results: FXR was downregulated in ICC cell lines and clinical ICC specimens. Loss of FXR was markedly correlated with aggressive tumor phenotypes and poor prognosis in patients with ICC. Moreover, FXR expression also had significant prognostic value in carbohydrate antigen 19-9 (CA19-9) negative patients. The expression of FXR was negatively correlated with IL-6 levels in clinical ICC tissues. FXR inhibited the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) of ICC cells via suppression of IL-6 in vitro. Obeticholic acid, an agonist of FXR, inhibited IL-6 production, tumor growth and lung metastasis of ICC in vivo. Conclusions: FXR could be a promising ICC prognostic biomarker, especially in CA19-9 negative patients with ICC. FXR inhibits the tumor growth and metastasis of ICC via IL-6 suppression. [ABSTRACT FROM AUTHOR]

The clinical manifestations of variant angina is unevenly distributed during the 24 h, thus the in vivo performance of drugs should be tailored according to the angina circadian rhythm. Cryptotanshinone (CTN) is one of the representative bioactive lipid-soluble components of Danshen which has been commonly used for cardiovascular diseases such as angina pectoris. The aim of this study was to develop a novel CTN sustained-released pellets (CTN-SRPs) to precisely synchronize the CTN plasma concentrations with predicted occurrence of angina pectoris for angina chronotherapy. A deconvolution-based method was applied to develop and optimize the CTN-SRPs. The plasma concentration-time curve of CTN immediate-released formulation after oral administration in rats was used as the weight function. The predicted plasma concentration-time curve of CTN-SRPs simulated according to the incidence of variant angina during 24 h was used as the response function. Then the desired drug release profile of CTN-SRPs was calculated based on deconvolution using weight function and response function, and subsequently used for guiding the formulation optimization. CTN-SRPs were prepared with the combinations of PVP, poloxamer 127 and EC as matrix using fluidized bed technology. An orthogonal design was employed to obtain the optimal formulation with its release profile similar with the desired one. Pharmacokinetic studies validated that the actual plasma concentration-time curve of these optimized CTN-SRPs was similar with the predicted one. In addition, the percent errors (%PE) of CTN plasma concentrations in 8-12 h were less than 10%. In conclusion, this deconvolution-based method could be applied to adjust the in vivo performance of drugs for angina chronotherapy. [ABSTRACT FROM AUTHOR]

Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders. [ABSTRACT FROM AUTHOR]

The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial restitution. Wound healing in T84 cell monolayers grown on transparent, permeable supports was assessed over 48 h with or without bile acids. Cell migration was measured in Boyden chambers. mRNA and protein expression were measured by RT-PCR and Western blotting. DCA (50–150 µM) significantly inhibited wound closure in cultured epithelial monolayers and attenuated cell migration in Boyden chamber assays. DCA also induced nuclear accumulation of the farnesoid X receptor (FXR), whereas an FXR agonist, GW4064 (10 µM), inhibited wound closure. Both DCA and GW4064 attenuated the expression of CFTR Cl− channels, whereas inhibition of CFTR activity with either CFTR-inh-172 (10 µM) or GlyH-101 (25 µM) also prevented wound healing. Promoter/reporter assays revealed that FXR-induced downregulation of CFTR is mediated at the transcriptional level. In contrast, UDCA (50–150 µM) enhanced wound healing in vitro and prevented the effects of DCA. Finally, DCA inhibited and UDCA promoted mucosal healing in an in vivo mouse model. In conclusion, these studies suggest bile acids are important regulators of epithelial wound healing and are therefore good targets for development of new drugs to modulate intestinal barrier function in disease treatment. NEW & NOTEWORTHY The secondary bile acid, deoxycholic acid, inhibits colonic epithelial wound healing, an effect which appears to be mediated by activation of the nuclear bile acid receptor, FXR, with subsequent downregulation of CFTR expression and activity. In contrast, ursodeoxycholic acid promotes wound healing, suggesting it may provide an alternative approach to prevent the losses of barrier function that are associated with mucosal inflammation in IBD patients. [ABSTRACT FROM AUTHOR]

Carnosic acid (CA) is a phenolic diterpene obtained from Rosmarinus officinalis L. and has demonstrated cytoprotective properties in several experimental models. CA exerts antioxidant effects by upregulating the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which controls the expression of antioxidant and phase II detoxification enzymes. Heme oxygenase-1 (HO-1) expression is modulated by Nrf2 and has been demonstrated as part of the mechanism underlying the CA-induced cytoprotection. Nonetheless, it remains to be studied whether and how HO-1 would mediate CA-elicited anti-inflammatory effects. Therefore, we have investigated here whether and how CA would prevent paraquat (PQ)-induced inflammation-related alterations in human neuroblastoma SH-SY5Y cells. SH-SY5Y cells were pretreated for 12 h with CA at 1 μM before exposure to PQ for further 24 h. CA suppressed the PQ-induced alterations on the levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) through a mechanism involving the activation of the Nrf2/HO-1 axis. Furthermore, we observed a crosstalk between the Nrf2/HO-1 signaling pathway and the activation of the nuclear factor-κB (NF-κB) transcription factor, since administration of ZnPP IX (specific inhibitor of HO-1) or Nrf2 knockdown using small interfering RNA (siRNA) abolished the anti-inflammatory effects induced by CA. Moreover, administration of SN50 (specific inhibitor of NF-κB) inhibited the PQ-induced inflammation-related effects in SH-SY5Y cells. Therefore, CA exerted anti-inflammatory effects in SH-SY5Y cells through an Nrf2/HO-1 axis-dependent manner associated with downregulation of NF-κB. [ABSTRACT FROM AUTHOR]

This study investigated the anti-inflammatory effects and possible underlying mechanisms of Salvia miltiorrhiza polysaccharides (SMP) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The cytotoxicity of SMP was detected by the MTT method. The morphological change of RAW264.7 was observed by Diff-Quik staining. Enzyme-linked immunosorbent assay was used to evaluate the production of cytokines in LPS-induced RAW264.7 cells. The nitric oxide (NO) kit assay detected the NO release from LPS-induced RAW264.7 cells. Real-time polymerase chain reaction was used to detect the transcriptions of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), inducible NO synthase (iNOS), and cyclooxygenase (COX)-2 in LPS-induced RAW264.7 cells. The protein expression of nuclear NF-κB was measured by Western blot. The results showed that the safe medication range of SMP was less than 3 mg/mL. Compared with the LPS model group, SMP (2, 1, and 0.5 mg/mL) improved the degree of cell deformation and reduced the amount of pseudopodia, and statistically reduced the secretions of cytokines in cells induced by LPS ( P < 0.01) at different time points. SMP significantly inhibited the mRNA transcriptions of TNF-α, IL-6, iNOS, and COX-2 and the protein expressions of NF-κB, p-p65, and p-IκBa. In conclusion, this study preliminarily proved the protective effect of SMP on LPS-induced RAW264.7 macrophage. Its mechanism might be related to inhibition of NF-κB signal pathway and the gene expressions and secretion of cytokines. [ABSTRACT FROM AUTHOR]

The structure of the human kappa opioid receptor (KOR) in complex with the long-acting antagonist JDTic was solved crystallographically in 2012 and, along with structures of other opioid receptors, revolutionized our understanding of opioid system function and pharmacology. More recently, active state KOR structure was also determined, giving important insights into activation mechanisms of the receptor. In this review, we will discuss how the understanding of atomistic structures of KOR established a key platform for deciphering details of subtype and functional selectivity of KOR-targeting ligands and for discovery of new chemical probes with potentially beneficial pharmacological profiles., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Some new 1,4-disubstituted-sulfonyl-1,2,3-triazoles ( 3a- f, 5a- h, 7a- d, and 9a- e) were regioselectively synthesized in high yields by Cu(I) catalyzed 1,3-dipolar cycloaddition (DC) reaction of p-acetamidobenzenesulfonyl azide ( p-ABSA) with terminal alkynes. These new triazole compounds were evaluated for in vitro antibacterial activity against a panel of Gram-positive Bacillus sphericus, Staphylococcus epidermidis, and Gram-negative Klebsiella pneumonia, Escherichia coli species. Several of these compounds were found to possess comparable growth inhibition activity with the commercial standards Penicillin-G and Streptomycin. [ABSTRACT FROM AUTHOR]

The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy. [ABSTRACT FROM AUTHOR]

Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. [ABSTRACT FROM AUTHOR]

Bile acids are established signaling molecules next to their role in the intestinal emulsification and uptake of lipids. We here aimed to identify a potential interaction between bile acids and CD4+ Th cells, which are central in adaptive immune responses. We screened distinct bile acid species for their potency to affect T cell function. Primary human and mouse CD4+ Th cells as well as Jurkat T cells were used to gain insight into the mechanism underlying these effects. We found that unconjugated lithocholic acid (LCA) impedes Th1 activation as measured by i) decreased production of the Th1 cytokines IFNγ and TNFαα, ii) decreased expression of the Th1 genes T-box protein expressed in T cells (T-bet), Stat-1 and Stat4, and iii) decreased STAT1α/β phosphorylation. Importantly, we observed that LCA impairs Th1 activation at physiological relevant concentrations. Profiling of MAPK signaling pathways in Jurkat T cells uncovered an inhibition of ERK-1/2 phosphorylation upon LCA exposure, which could provide an explanation for the impaired Th1 activation. LCA induces these effects via Vitamin D receptor (VDR) signaling since VDR RNA silencing abrogated these effects. These data reveal for the first time that LCA controls adaptive immunity via inhibition of Th1 activation. Many factors influence LCA levels, including bile acid-based drugs and gut microbiota. Our data may suggest that these factors also impact on adaptive immunity via a yet unrecognized LCA-Th cell axis. [ABSTRACT FROM AUTHOR]

Background: Bile acids (BAs) are steroid molecules that are synthesized in the liver. In addition to their important role as a surfactant in solubilizing lipids and promoting the absorption of lipids in the gastrointestinal tract, they act as inflammagens. The role of BAs and their receptor farnesoid X receptor (FXR) during viral infection has not been studied in detail. Methods: By using FXR-deficient mice, we investigated the role of bile acid receptor FXR during infection with lymphocytic choriomeningitis virus (LCMV). The importance of FXR in inducing IFN-I and monocytes proliferation were investigated and viral titers and T cell exhaustion were analyzed at different time points. Results: This study shows that controlled levels of BAs activate FXR in hepatocytes and FXR in response upregulates the production of type I interferon. In turn, FXR maintains BAs within a balanced range to inhibit their toxic effects. The absence of FXR results in high levels of BAs, which inhibit the proliferation of monocytes and result in a defect in viral elimination, consequently leading to T cell exhaustion. Conclusion: We found that FXR contributes to IFN-I production in hepatocytes and balances BA levels to inhibit their toxic effects on monocytes. [ABSTRACT FROM AUTHOR]

In the present paper 5-[4′-({4-[(4-aryloxy)methyl]-1 H-1,2,3-triazol-1-yl}methyl)[1,1′-biphenyl]-2-yl]-1 H-tetrazoles ( 5a- g) and [2′-(1 H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl-substituted-1-carbodithioates ( 11h- q) have been designed and synthesized. These compounds were subjected to docking (against AT receptor protein enzyme in complex with Lisinopril), in vitro angiotensin converting enzyme inhibition, anti-proliferative, anti-inflammatory screening (through egg albumin denaturation inhibition and red blood cell membrane stabilization assay) and finally anti-fungal activity analyses. Some of the compounds have shown significant pharmacological properties. [ABSTRACT FROM AUTHOR]

Background: The herb-pair, Salviaemiltiorrhizae (Danshen, DS) and Panaxnotoginseng (Sanqi, SQ), often occurs in traditional Chinese medicine prescriptions used for the treatment of cardiovascular diseases in clinics in Asian areas. Many commercial preparations containing the DS-SQ herbpair were produced by various manufactures with the different production process. The raw materials were from different sources, which raised a challenge to control the quality of the herb-pair medicines. Objective: In this paper, a high-performance liquid chromatography (HPLC) method was developed to simultaneously determine seventeen bioactive components, including 8 phenolic acids, 4 tanshinones, and 5 saponins, for quality control of compound preparations containing DS-SQ herb-pair. The chromatographic separation was studied on an Ultimate™ XB-C18 column (150 mm × 4.6 mmi.d., 3.5 μm) with a mobile phase composed of 0.5% aqueous acetic acid and acetonitrile using a gradient elution in 70 min. Results: The optimum detection wavelength was set at 288 nm for phenolic acids and tanshinones, and 203 nm for saponins. The method was validated sufficiently by examining the precision, recoveries, linearity, range, LOD and LOQ, and was successfully applied to quantify the seventeen compounds in five commercial preparations containing DS-SQ herb-pair. Conclusions: It is the first time to report the rapid and simultaneous analysis of the seventeen compounds with the base-line separation of peaks for ginsenoside Rg1 and Re in 70 min by routine HPLC. This HPLC method could be considered as good quality criteria to control the quality of preparations containing DS-SQ herb-pair. [ABSTRACT FROM AUTHOR]

An iridoid glucoside, 10- p-hydroxybenzoyl-6 β-hydroxyiridoid 1- O- β- d-(6′- O- p-hydroxybenzoyl)-glucopyranoside ( 1), and a phenol glucoside, 4-hydroxyphenethanol 3- O- β- d-(6′- O- p-hydroxybenzoyl)-glucopyranoside ( 2), along with nine known compounds ( 3- 11) were isolated from the dried leaves of Vitex negundo var. heterophylla. Their structures were elucidated by extensive analysis of NMR spectra. All of the isolated compounds were evaluated for their inhibitory effects on nitric oxide production in RAW 264.7 macrophages. Compounds 2 and 3 exhibited obvious inhibitory effects on NO production with IC values of 30.76 and 49.89 μM, respectively. Molecular docking studies of compounds 2 and 3 with nitric oxide synthase (NOS) further confirmed the above results. [ABSTRACT FROM AUTHOR]

Bile acids are end products of cholesterol metabolism generated in the liver and released in the intestine. Primary and secondary bile acids are the result of the symbiotic relation between the host and intestinal microbiota. In addition to their role in nutrient absorption, bile acids are increasingly recognized as regulatory signals that exert their function beyond the intestine by activating a network of membrane and nuclear receptors. The best characterized of these bile acid-activated receptors, GPBAR1 (also known as TGR5) and the farnesosid-X-receptor (FXR), have also been detected in the vascular system and their activation mediates the vasodilatory effects of bile acids in the systemic and splanchnic circulation. GPBAR1, is a G protein-coupled receptor, that is preferentially activated by lithocholic acid (LCA) a secondary bile acid. GPBAR1 is expressed in endothelial cells and liver sinusoidal cells (LSECs) and responds to LCA by regulating the expression of both endothelial nitric oxide synthase (eNOS) and cystathionine-γ-lyase (CSE), an enzyme involved in generation of hydrogen sulfide (H2S). Activation of CSE by GPBAR1 ligands in LSECs is due to genomic and nongenomic effects, involves protein phosphorylation, and leads to release of H2S. Despite that speciesspecific effects have been described, vasodilation caused by GPBAR1 ligands in the liver microcirculation and aortic rings is abrogated by inhibition of CSE but not by eNOS inhibitor. Vasodilation caused by GPBAR1 (and FXR) ligands also involves large conductance calcium-activated potassium channels likely acting downstream to H2S. The identification of GPBAR1 as a vasodilatory receptor is of relevance in the treatment of complex disorders including metabolic syndrome-associated diseases, liver steatohepatitis, and portal hypertension. [ABSTRACT FROM AUTHOR]

Background: Bile acids (BAs) play a potential role in regulating the whole-body metabolic homeostasis via the interaction with gut microbiome and the signal transduction as messengers, which establish a link between the primary biliary cirrhosis (PBC) and gut microbiome in many aspects, particularly with regard to the immune system of the body. PBC, as a chronic cholestatic liver disease characterised by the destruction of small intrahepatic bile ducts, causes fibrosis and potential cirrhosis without efficient therapies. Summary: Recent researches show BAs can induce the differentiation of hepatic stellate cells, suggesting that it may serve as a novel therapy to resist, even changeover the irreversible liver cirrhosis in PBC. Key Messages: In this review, we conclude and provide information on the possible mechanism of pleiotropic BAs in homeostasis of the gut microbiome and liver regeneration, and hope to broaden the therapy of PBC and promote the relevant drugs’ development. [ABSTRACT FROM AUTHOR]

Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi-induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signaling system that could trigger and mediate this response. To account for the existence of such a response, we note that HDACi of various chemical types are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers. Also see the . [ABSTRACT FROM AUTHOR]

Bile acids are known to initiate intricate signaling events in a variety of tissues, primarily in the liver and gastrointestinal tract. Of the known bile acids, only the 7α-dihydroxy species, deoxycholic acid and chenodeoxycholic acid (CDCA), and their conjugates, activate processes that stimulate epithelial Cl− secretion. We have previously published that CDCA acts in a rapid manner to stimulate colonic ion secretion via protein kinase A (PKA)-mediated activation of the dominant Cl− channel, the cystic fibrosis transmembrane conductance regulator (CFTR) (Ao M, Sarathy J, Domingue J, Alrefai WA, and Rao MC. Am J Physiol Cell Physiol 305: C447–C456, 2013); however, PKA signaling did not account for the entire CDCA response. Here we show that in human colonic T84 cells, CDCA's induction of CFTR activity, measured as changes in short-circuit current (Isc), is dependent on epidermal growth factor receptor (EGFR) activation and does not involve the bile acid receptors TGR5 or farnesoid X receptor. CDCA activation of Cl− secretion does not require Src, mitogen-activated protein kinases, or phosphoinositide 3-kinase downstream of EGFR but does require an increase in cytosolic Ca2+. In addition to PKA signaling, we found that the CDCA response requires the novel involvement of the exchange protein directly activated by cAMP (EPAC). EPAC is a known hub for cAMP and Ca2+ cross talk. Downstream of EPAC, CDCA activates Rap2, and changes in free cytosolic Ca2+ were dependent on both EPAC and EGFR activation. This study establishes the complexity of CDCA signaling in the colonic epithelium and shows the contribution of EGFR, EPAC, and Ca2+ in CDCA-induced activation of CFTR-dependent Cl− secretion. [ABSTRACT FROM AUTHOR]

Bioactive natural products are serendipitous drug candidates, which stimulate synthetic approaches for improving and supporting drug discovery and development. Therefore, the search for bioactive metabolites from different natural sources continues to play an important role in fashioning new medicinal agents. Several cyclic peptides were produced by organisms, such as β-defensins, gramicidin S, and tyrocidine A, and exhibited a wide range of bioactivities, such as antiviral activity against HIV-1, influenza A viruses, or antibacterial activity. Cyclic tetrapeptides are a class of natural products that were found to have a broad range of biological activities, promising pharmacokinetic properties, as well as interesting conformational dynamics and ability of slow inter-conversion to several different structures. Cyclooligopeptides, particularly medium ring-sized peptides, were obtained from marine microorganisms and exhibited a wide range of pharmacological properties, including antimicrobial and anti-dinoflagellate activities, cytotoxicity, and inhibitory activity against enzyme sortase B. Most of the naturally occurring cyclotetrapeptides are obtained from fungi. Some natural cyclic tetrapeptides were found to inhibit histone deacetylase (HDAC), which regulate the expression of genes. These compounds are very useful as cancer therapeutics. Various analogues of the natural cyclotetrapeptides were successfully synthesized to find novel lead compounds for pharmacological and biotechnological applications. Therefore, in this review, previously reported novel natural cyclotetrapeptides are briefly discussed, along with their important biological activities as drug candidates, together with their promising therapeutic properties. Moreover, their future perspective in drug discovery as potential therapeutic agents will be determined. [ABSTRACT FROM AUTHOR]

Copyright of Progress in Modern Biomedicine is the property of Publishing House of Progress in Modern Biomedicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)