[Research progress in pharmacotherapy of insomnia].

Insomnia is extremely common and is a risk factor for a variety of physical and psychological disorders in addition to contributing to the reduced quality of life of patients and the burden of healthcare costs. Although cognitive behavioral therapy is the first-line treatment for insomnia, its difficulty of access and high cost have hindered its application. Therefore, pharmacotherapy remains the common treatment choice for patients and clinicians. Existing chemical drugs including benzodiazepine receptor agonists, dual orexin receptor antagonists, melatonin and its receptor agonists, histamine antagonists, antidepressants, and antipsychotics are able to induce and/or maintain sleep and have good therapeutic effects on acute insomnia, but their efficacy on chronic insomnia is indefinite. Furthermore, they have several side effects and affect sleep structure and physiological function. Under the guiding principle of holistic view and treatment based on syndrome differentiation, traditional Chinese medicine(TCM) has shown a good effect in clinical practice, but with little high-grade clinical evidence. The mechanism, dose, half-life period, adjustment of sleep structure, and side effects of hypnotic drugs are key factors to be considered for clinical use. This paper analyzed and summarized the drugs for insomnia from the above aspects, and is expected to provide references for the application and development of sedative and hypnotic drugs.

Neobaicalein Inhibits Th17 Cell Differentiation Resulting in Recovery of Th17/Treg Ratio through Blocking STAT3 Signaling Activation.

Huangqin is the dried root of Scutellaria baicalensis Georgi, which has been widely utilized for heat-clearing (Qingre) and dewetting (Zaoshi), heat-killed (Xiehuo) and detoxifying (Jiedu) in the concept of Traditional Chinese Medicine and is used for treating inflammation and cancer in clinical formulas. Neobaicalein (NEO) is of flavonoid isolated from Huangqin and has been reported to possess prominent anti-inflammatory effects in published work. Th17/Treg balance shift to Th17 cells is an essential reason for autoimmune inflammatory diseases. However, the role NEO plays in Th17 and Treg and the underlying mechanism has not been elucidated yet. Network pharmacology-based study revealed that NEO predominantly regulated IL-17 signaling pathway. Moreover, our result shown that NEO (3-30 µmol/L) down-regulated Th17 differentiation and cellular supernatant and intracellular IL-17A level and tumor necrosis factor α production in a concentration-dependent manner. The further mechanism research revealed that NEO also specifically inhibited phosphorylation of STAT3(Tyr725) and STAT4 (Y693) without influence on activation of STAT5 and STAT6 in splenocytes. Immunofluorescence results illuminated that NEO effectively blocked STAT3 translocated into nucleus. Interestingly, NEO at appreciated dose could only inhibit Th17 cell differentiation and have no effect on Treg differentiation. The present study revealed that NEO effectively inhibited Th17 cell differentiation through specifically blocking the activation of STAT3 signaling without inactivation of STAT5 and STAT6. Additional inhibitory effect on activation of STAT4 by NEO also suggested the potential for antagonism against Th1 differentiation. All work suggested that NEO may be a potential candidate for immunoregulation and treating autoimmune inflammatory diseases through inhibiting immune cell viability and T cell differentiation.

Arabidopsis cyclic nucleotide-gated channel 6 is negatively modulated by multiple calmodulin isoforms during heat shock.

An increased concentration of cytosolic Ca2+ is an early response of plant cells to heat shock. Arabidopsis cyclic nucleotide-gated ion channel 6 (CNGC6) mediates heat-induced Ca2+ influx and is activated by cAMP. However, it remains unclear how the Ca2+ conductivity of CNGC6 is negatively regulated under the elevated cytosolic Ca2+ concentration. In this study, Arabidopsis calmodulin isoforms CaM1/4, CaM2/3/5, CaM6, and CaM7 were found to bind to CNGC6 to varying degrees, and this binding was dependent on the presence of Ca2+ and IQ6, an atypical isoleucine-glutamine motif in CNGC6. Knockout of CaM2, CaM3, CaM5, and CaM7 genes led to a marked increase in plasma membrane inward Ca2+ current under heat shock conditions; however, knockout of CaM1, CaM4, and CaM6 genes had no significant effect on plasma membrane Ca2+ current. Moreover, the deletion of IQ6 from CNGC6 led to a marked increase in plasma membrane Ca2+ current under heat shock conditions. Taken together, the data suggest that CNGC6-mediated Ca2+ influx is likely to be negatively regulated by CaM2/3/5 and CaM7 isoforms under heat shock conditions, and that IQ6 plays an important role in CaM binding and the feedback regulation of the channel.

Arabidopsis mtHSC70-1 plays important roles in the establishment of COX-dependent respiration and redox homeostasis.

The 70 kDa heat shock proteins function as molecular chaperones and are involved in diverse cellular processes. However, the functions of the plant mitochondrial HSP70s (mtHSC70s) remain unclear. Severe growth defects were observed in the Arabidopsis thaliana mtHSC70-1 knockout lines, mthsc70-1a and mthsc70-1b. Conversely, the introduction of the mtHSC70-1 gene into the mthsc70-1a background fully reversed the phenotypes, indicating that mtHSC70-1 is essential for plant growth. The loss of mtHSC70-1 functions resulted in abnormal mitochondria and alterations to respiration because of an inhibition of the cytochrome c oxidase (COX) pathway and the activation of the alternative respiratory pathway. Defects in COX assembly were observed in the mtHSC70-1 knockout lines, leading to decreased COX activity. The mtHSC70-1 knockout plants have increased levels of reactive oxygen species (ROS). The introduction of the Mn-superoxide dismutase 1 (MSD1) or the catalase 1 (CAT1) gene into the mthsc70-1a plants decreased ROS levels, reduced the expression of alternative oxidase, and partially rescued growth. Taken together, our data suggest that mtHSC70-1 plays important roles in the establishment of COX-dependent respiration.

Ciliatasecones A-C, three rearranged limonoids from Toona ciliata var. yunnanensis.

Ciliatasecones A-C (1-3), three rearranged limonoids with a novel ring-seco model and an unprecedented cycle system, were isolated from the root bark of Toona ciliata var. yunnanensis. Ciliatasecones A-B (1-2) share a novel cyclopenta[b]furan ring C/D system through C-9/11-seco and C-11/14 ether linkage. Ciliatasecone C (3) was found to possess a rare rearranged six-membered lactone ring B between C-7 and C-9. Plausible biogenetic pathway speculation indicated that C-9/11 cleavage and oxygen bridge formation played the key roles in the framework rearrangement of 1-3.

Chronic Hepatitis B Infection is Associated with Decreased Risk of Preeclampsia: A Meta-Analysis of Observational Studies.

BACKGROUND/AIMS: Preeclampsia is a complex multi-system obstetric syndrome and remains one of the leading causes contributing to maternal and perinatal mortality and morbidity. Previous epidemiological studies regarding the association between chronic hepatitis B virus (CHB) infection and the risk of preeclampsia have reported inconsistent results. Therefore, we conducted a meta-analysis to investigate the association between CHB infection and preeclampsia. METHODS: The electronic database was searched until January 1st, 2016. Relevant studies reporting the association between CHB infection and the risk of preeclampsia were included and for further evaluation. Statistical analysis was performed using Stata 10.0 (Stata Corp). RESULTS: Three observational cohort studies and eight case-control studies, including 11566 preeclampsia patients, were identified. A significant negative association between CHB infection and preeclampsia was observed (odds ratio = 0.77, 95% confidence interval, 0.65- 0.90, P=0.002, fixed-effect model). CONCLUSIONS: Findings from our meta-analysis indicate that CHB infection may decrease the risk of preeclampsia in Asian population. Future prospective cohorts in different countries with larger sample sizes are warranted to ascertain the causality and pathophysiological studies are required to explore the possible biological mechanisms involved.

The J-protein AtDjB1 is required for mitochondrial complex I activity and regulates growth and development through ROS-mediated auxin signalling.

AtDjB1 is a mitochondria-located J-protein in Arabidopsis thaliana It is involved in the regulation of plant growth and development; however, the exact mechanisms remain to be determined. We performed comparison analyses of phenotypes, auxin signalling, redox status, mitochondrial structure and function using wild-type plants, AtDjB1 mutants, rescued AtDjB1 mutants by AtDjB1 or YUCCA2 (an auxin synthesis gene), and AtDjB1 overexpression plants. AtDjB1 mutants (atj1-1 or atj1-4) exhibited inhibition of growth and development and reductions in the level of IAA and the expression of YUCCA genes compared to wild-type plants. The introduction of AtDjB1 or YUCCA2 into atj1-1 largely rescued phenotypic defects and the IAA level, indicating that AtDjB1 probably regulates growth and development via auxin. Furthermore, atj1-1 plants displayed a significant reduction in amount/activity of mitochondrial complex I compared to wild-type plants; this resulted in the accumulation of reactive oxygen species (ROS). Moreover, exogenous H2O2 markedly inhibited the expression of YUCCA genes in wild-type plants. In contrast, the reducing agent ascorbate increased the expression of YUCCA genes and IAA level in atj1-1 plants, indicating that the low auxin level observed in atj1-1 was probably due to the high oxidation status. Overall, the data presented here suggest that AtDjB1 is required for mitochondrial complex I activity and regulates growth and development through ROS-mediated auxin signalling in Arabidopsis.

Sesquiterpenes and α-pyrones from an endophytic fungus Xylaria curta YSJ-5.

Chemical investigation of the culture extract of an endophyte Xylaria curta YSJ-5 from Alpinia zerumbet (Pers.) Burtt. et Smith resulted in the isolation of eight previously undescribed compounds including five eremophilane sesquiterpenes xylarcurenes A-E, one norsesquiterpene xylarcurene F, and two α-pyrone derivatives xylarpyrones A-B together with eight known related derivatives. Their chemical structures were extensively established based on the 1D- and 2D-NMR spectroscopic analysis, modified Mosher's method, electronic circular dichroism calculations, single-crystal X-ray diffraction experiments, and the comparison with previous literature data. All these compounds were tested for in vitro cytotoxic, anti-inflammatory, α-glucosidase inhibitory, and antibacterial activities. As a result, 6-pentyl-4-methoxy-pyran-2-one was disclosed to display significant antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus with minimal inhibitory concentration value of 6.3 µg/mL.

Magnolol as STAT3 inhibitor for treating multiple sclerosis by restricting Th17 cells.

OBJECTIVE: Multiple sclerosis (MS) is an immune disease in the central nervous system (CNS) associated with Th17 cells. Moreover, STAT3 initiates Th17 cell differentiation and IL-17A expression through facilitating RORγt in MS. Here, we reported that magnolol, isolated from Magnolia officinalis Rehd. Et Wils, was regarded as a candidate for MS treatment verified by both in vitro and in vivo studies. METHODS: In vivo, experimental autoimmune encephalomyelitis (EAE) model in mice was employed to evaluate the alleviation of magnolol on myeloencephalitis. In vitro, FACS assay was employed to evaluate the effect of magnolol on Th17 and Treg cell differentiation and IL-17A expression; network pharmacology-based study was applied to probe the involved mechanisms; western blotting, immunocytochemistry, and luciferase reporter assay was used to further confirm the regulation of magnolol on JAK/STATs signaling pathway; surface plasmon resonance (SPR) assay and molecular docking were applied to manifest affinity with STAT3 and binding sites; overexpression of STAT3 was employed to verify whether magnolol attenuates IL-17A through STAT3 signaling pathway. RESULTS: In vivo, magnolol alleviated loss of body weight and severity of EAE mice; magnolol improved lesions in spinal cords and attenuated CD45 infiltration, and serum cytokines levels; correspondingly, magnolol focused on inhibiting Th17 differentiation and IL-17A expression in splenocyte of EAE mice; moreover, magnolol selectively inhibited p-STAT3(Y705) and p-STAT4(Y693) of both CD4+ and CD8+ T cells in splenocyte of EAE mice. In vitro, magnolol selectively inhibited Th17 differentiation and IL-17A expression without impact on Treg cells; network pharmacology-based study revealed that magnolol perhaps diminished Th17 cell differentiation through regulating STAT family members; western blotting further confirmed that magnolol inhibited p-JAK2(Y1007) and selectively antagonized p-STAT3(Y705) and slightly decreased p-STAT4(Y693); magnolol antagonized both STAT3 nucleus location and transcription activity; magnolol had a high affinity with STAT3 and the specific binding site perhaps to be at SH2 domain; overexpression of STAT3 resulted in failed inhibition of magnolol on IL-17A. CONCLUSION: Magnolol selectively inhibited Th17 differentiation and cytokine expression through selectively blocking of STAT3 resulting in decreased the ratio of Th17/Treg cells for treating MS, suggesting that the potential of magnolol for treating MS as novel STAT3 inhibitor.

Metabolomic characteristics of spontaneously hypertensive rats under chronic stress and the treatment effect of Danzhi Xiaoyao Powder, a traditional Chinese medicine formula.

OBJECTIVE: Numerous studies have demonstrated the close relationship between chronic stress and blood pressure (BP). Hypertensive subjects exhibit exaggerated reactions to stress, especially higher BP. The mechanisms by which stress affects pre-existing hypertension still need to be explored. Danzhi Xiaoyao Powder (DP), a historical traditional Chinese medicine formula, is a promising treatment for BP control in hypertensive patients under stress. The present study investigated the metabolomic disruption caused by chronic stress and the treatment effect and mechanism of DP. METHODS: Spontaneously hypertensive rats (SHRs) were subjected to chronic restraint stress (CRS) for 4 weeks. BP was measured via the tail-cuff method, and anxiety-like behavior was quantified using the elevated-plus-maze test. Meanwhile, DP was administered intragastrically, and its effects were observed. Global metabolomic analysis was performed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, followed by multivariate statistical analysis to detect differential metabolites and pathways. RESULTS: DP alleviated the CRS-induced increase in BP and anxiety-like behavior. Systematic metabolic differences were found among the three study groups. A total of 29 differential plasma metabolites were identified in both positive- and negative-ion modes. These metabolites were involved in triglyceride metabolism, amino acid (phenylalanine, tryptophan, and glycine) metabolism, and steroid hormone pathways. CONCLUSION: These findings expose the metabolomic disturbances induced by chronic stress in SHRs and suggest an innovative treatment for this disorder.

Perspectives of herbs and their natural compounds, and herb formulas on treating diverse diseases through regulating complicated JAK/STAT signaling.

JAK/STAT signaling pathways are closely associated with multiple biological processes involved in cell proliferation, apoptosis, inflammation, differentiation, immune response, and epigenetics. Abnormal activation of the STAT pathway can contribute to disease progressions under various conditions. Moreover, tofacitinib and baricitinib as the JAK/STAT inhibitors have been recently approved by the FDA for rheumatology disease treatment. Therefore, influences on the STAT signaling pathway have potential and perspective approaches for diverse diseases. Chinese herbs in traditional Chinese medicine (TCM), which are widespread throughout China, are the gold resources of China and have been extensively used for treating multiple diseases for thousands of years. However, Chinese herbs and herb formulas are characterized by complicated components, resulting in various targets and pathways in treating diseases, which limits their approval and applications. With the development of chemistry and pharmacology, active ingredients of TCM and herbs and underlying mechanisms have been further identified and confirmed by pharmacists and chemists, which improved, to some extent, awkward limitations, approval, and applications regarding TCM and herbs. In this review, we summarized various herbs, herb formulas, natural compounds, and phytochemicals isolated from herbs that have the potential for regulating multiple biological processes via modulation of the JAK/STAT signaling pathway based on the published work. Our study will provide support for revealing TCM, their active compounds that treat diseases, and the underlying mechanism, further improving the rapid spread of TCM to the world.

Arabidopsis mtHSC70-1 physically interacts with the Cox2 subunit of cytochrome c oxidase.

The 70-kD heat shock proteins (HSP70s or HSC70s) function as molecular chaperones and are involved in diverse cellular processes. We recently demonstrated the roles of mitochondrial HSC70-1 (mtHSC70-1) in the establishment of cytochrome c oxidase (COX)-dependent respiration and redox homeostasis in Arabidopsis thaliana. Defects in COX assembly were observed in the mtHSC70-1 knockout lines. The levels of Cox2 (COX subunit 2) proteins in COX complex were markedly lower in the mutants than in wild-type plants; however, the levels of total Cox2 proteins in the mutants were not obviously different from those in wild-type plants, suggesting that the stability of COX or the availability of Cox2 was impaired in the mtHSC70-1 mutants. Here, we further detected the interaction between mtHSC70-1 and Cox2 proteins through co-immunoprecipitation, pull-down and firefly luciferase complementation imaging assays. The results showed that mtHSC70-1 could directly combine Cox2 in vivo and in vitro, providing supporting evidence for the role of mtHSC70-1 in COX assembly.

Effects of Eimeria tenella infection on the barrier damage and microbiota diversity of chicken cecum.

The symbiosis of host and intestinal microbiota constitutes a microecosystem and plays an important role in maintaining intestinal homeostasis and regulating the host's immune system. Eimeria tenella, an obligate intracellular apicomplexan parasite, can cause coccidiosis, a serious intestinal disease. In this study, the effects of E. tenella infection on development parameters (villus height, crypt depth, mucosa thickness, muscularis thickness, and serosa thickness) and microbiota in chicken cecum were investigated. Fourteen-day-old male Hy-Line Variety Brown layer chickens were inoculated with sporulated oocysts of E. tenella. Cecal tissues were collected 7 d after inoculation. Relative density of goblet cells and glycoproteins were determined by Alcian blue periodic acid-Schiff staining and periodic acid-Schiff staining, respectively. Intestinal development parameters were also evaluated. Cecal contents were extracted, and the composition of cecal microflora was examined by Illumine sequencing in the V3-V4 region of the 16S rRNA gene. Results indicated that E. tenella infection destroyed the structure of cecal tissue and reduced the relative density of goblet cells and glycoproteins. Sequencing analysis indicated that E. tenella infection altered the diversity and composition of cecal microbiota. The populations of Proteobacteria, Enterococcus, Incertae, and Escherichia-Shigella decreased, and those of Bacteroidales and Rikenella significantly increased in the infected group compared with those in the control group. Hence, the pathological damage caused by E. tenella infection is associated with cecal microbiota dysbiosis, and this finding may be used to develop an alternative measure for alleviating the effect of coccidiosis on the poultry industry.

Mitochondrial respiratory chain damage and mitochondrial fusion disorder are involved in liver dysfunction of fluoride-induced mice.

Our previous study showed that excessive fluoride (F) intake can induce liver dysfunction. The aim of this study was to investigate the mechanisms of F-induced mitochondrial damage resulting in liver dysfunction. Damaged mitochondrial ultrastructure and state of liver cells were estimated by TEM, TUNEL staining and BrdU measurement. The ROS level and ATP content in the liver tissue were measured by ELISA kit. Meanwhile, optic atrophy (OPA1), mitofusin-1 (Mfn1), NDUFV2, SDHA, CYC1, and COX Ⅳ expression levels were measured through real-time PCR and Western-blot. Results showed that the ROS level increased, thereby resulting in mitochondrial ultrastructure damage and abundant liver cells presented evident apoptotic characteristics after F treatment. Decreased ATP content and the abnormal expression of OPA1, Mfn1, NDUFV2, SDHA, CYC1, and COX Ⅳ of the liver tissue were observed. In conclusion, excessive F-induced mitochondrial respiratory chain damaged and mitochondrial fusion disorder resulted in liver dysfunction.

Drp1/Mff signaling pathway is involved in fluoride-induced abnormal fission of hepatocyte mitochondria in mice.

Fluoride, a toxic substance, is widely distributed in the environment and causes serious damage to the body. This study was performed to investigate the effects of fluoride on mitochondrial fission in mouse hepatocytes. A total of 48 mice were equally divided into four groups and admisnistered with NaF in drinking water at fluorine ion concentrations of 0, 25, 50 and 100 mg/L for 70 days. The pathomorphology and ultrastructurre of hepatocytes were then observed. The mitochondrial lesion parameters (number, length, width and vacuolization area) are evaluated. The expression of Drp1, Mff, Fis1, MiD49, MiD51 and Dyn2, which are associated with mitochondrial fission, was determined by quantitative real-time PCR and Western blot analysis. Apoptosis was detected by using TUNEL assay. Results showed that fluoride causes notable changes in the pathological morphology of liver tissues and severely damages the ultrastructure of hepatocytes. Damage manifested as nuclear condensation, nuclear membrane breakdown, mitochondrial vacuolation, increased fragmentation, and mitochondrial fission. Moreover, mRNA and protein expression levels were significantly upregulated in the Drp1/Mff signaling pathway. The mRNA expression levels of Cyt c, caspase 9 and 3 markedly increased in the fluoride treated groups in a dose-dependent manner. The percentage of TUNEL-positive nuclei in the liver remarkably increased after fluoride treatment. Overall, the results indicate that excessive fluoride exposure can increase mitochondrial fission via the Drp1/Mff signaling pathway, severely damage the mitochondrial structure, and lead to apoptosis of hepatocytes.

Effects of Differential Food Patterns on the Pharmacokinetics of Enteric-Coated Mesalazine Tablets in the Same Cohort of Healthy Chinese Volunteers.

This study aimed to simultaneously determine mesalazine (5-ASA) and its major metabolite N-Ac-5-ASA in the plasma and to evaluate the impact of different food patterns on the relative bioavailability and pharmacokinetics of a single oral dose of 5-ASA in healthy subjects. In this single-dose, open-label, 3-period, 3-treatment crossover study, the subjects received a single, oral dose of 500-mg enteric-coated mesalazine tablet together with either a low-fat or a high-fat breakfast or under fasting condition (reference). The pharmacokinetic parameters were determined by noncompartmental methods and analyzed with a linear mixed-effect model. The geometric least squares mean ratio for the area under the plasma concentration-time curve from zero to infinity of N-Ac-5-ASA was 1.05 (90% confidence interval [CI], 0.70-1.58) for high-fat/fasted condition and 1.06 (90%CI, 0.82-1.36) for low-fat/fasted condition. The least squares mean ratio of 5-ASA was 0.86 (90%CI, 0.65-1.14) for high-fat/fasted condition and 0.78 (90%CI, 0.60-1.02) for low-fat/fasted condition. All P values were >.05. The mean maximum plasma concentration and the time to reach the maximum plasma concentration of N-Ac-5-ASA were 2084 ng/mL, 8 hours; 2639 ng/mL, 11 hours, and 2409 ng/mL, 9 hours for fasted, high-fat, and low-fat, respectively. The values of 5-ASA were 1950 ng/mL, 7 hours; 2869 ng/mL, 9 hours; and 2837 ng/mL, 8 hours for fasted, high-fat, and low-fat condition. 5-ASA was well tolerated under all 3 conditions. Food delayed the absorption of 5-ASA, especially a high-fat meal. Therefore, enteric-coated mesalazine tablets should be taken before meals to avoid causing patients slow response and any effect of food on its efficacy.

Withaminimas A-F, six withanolides with potential anti-inflammatory activity from Physalis minima.

Withaminimas A-F (1-6), six new withaphysalin-type withanolides were isolated from the aerial parts of Physalis minima L.. The structures of these compounds were elucidated through a variety of spectroscopic techniques including HR-MS, NMR, and ECD. Compound 1 belongs to rare 18-norwithanolides, and 2-3 were 13/14-secowithanolides. According to the traditional usage of P. minima, inhibitory effects on nitric oxide (NO) production in lipopolysaccaride-activated RAW264.7 macrophages were evaluated, and compounds 1-4 exhibited significant inhibitory effects with IC50 values among 3.91-18.46 µmol·L-1.

Hyperbeanols F-Q, diverse monoterpenoid polyprenylated acylphloroglucinols from the flowers of Hypericum beanii.

Hyperbeanols F-Q, which are twelve undescribed monoterpenoid polyprenylated acylphloroglucinols, and four known analogues were isolated from the dried flowers of Hypericum beanii. Their structures were elucidated by detailed HRESIMS and 1D and 2D NMR data analyses. The absolute configurations of hyperbeanols FH were established by the circular dichroism (CD) exciton chirality method. The plausible biosynthetic pathway speculation of hyperbeanols F-Q indicated that diverse reactions, including prenylation, 1,6-ene reaction, rearrangement, epoxidation and dehydration, contributed to their diverse skeletons. Hyperbeanols FI, O and hypercalin B exhibited moderate nitric oxide (NO) inhibitory activities in LPS-induced RAW 264.7 macrophages, with IC50 values in the range of 17.11-28.74 µM.

Calcitonin gene-related peptide inhibits the cardiac fibroblasts senescence in cardiac fibrosis via up-regulating klotho expression.

It has been documented cardiac fibroblasts as the predominant cell population undergoing senescence in heart. Calcitonin gene-related peptide (CGRP) exhibits a wide range of cardiovascular protective effects. Whether CGRP protects against cardiac fibroblasts senescence in cardiac fibrosis remains unknown. Here, we detected the down-regulation of CGRP concomitant with senescence in fibrotic myocardium, both hypertension- induced left ventricular fibrosis in SHR rats and hypoxia-induced right ventricular fibrosis in pulmonary artery hypertension rats. Exogenous CGRP inhibited the cardiac fibroblasts senescence and senescence-associated secretory phenotype (SASP) induced by TGF-ß1, which was abolished by CGRP8-37, a selective CGRP receptor antagonist. Moreover, the expression of klotho, an anti-senescence protein, was down-regulated in fibrotic myocardium, and CGRP up-regulated the klotho expression in TGF-ß1-treated cardiac fibroblasts. Klotho knockdown by siRNA reversed the inhibition of CGRP on senescence and SASP induced by TGF-ß1 in cardiac fibroblasts. These results suggested that CGRP inhibited the cardiac fibroblasts senescence and SASP in cardiac fibrosis via up-regulating klotho expression.

Anticancer Activity and Mechanism of Xanthohumol: A Prenylated Flavonoid From Hops (Humulus lupulus L.).

It has been observed that many phytochemicals, frequently present in foods or beverages, show potent chemopreventive or therapeutic properties that selectively affect cancer cells. Numerous studies have demonstrated the anticancer activity of xanthohumol (Xn), a prenylated flavonoid isolated from hops (Humulus lupulus L.), with a concentration up to 0.96 mg/L in beer. This review aims to summarize the existing studies focusing on the anticancer activity of Xn and its effects on key signaling molecules. Furthermore, the limitations of current studies and challenges for the clinical use of Xn are discussed.