Dietary Flavonoid Intake and Carotid Calcification in Patients with Ischemic Stroke.

INTRODUCTION: Owing to the antioxidant and anti-inflammatory effects, flavonoids can influence the initiation and development of atherosclerosis, but the underlying mechanisms remain largely undetermined. This study aimed to evaluate the associations between dietary flavonoids and carotid calcification in patients with ischemic stroke. METHODS: This study screened consecutive patients with ischemic stroke via Nanjing Stroke Registry Program from February 2016 to April 2021. A semiquantitative food frequency questionnaire was used to evaluate dietary consumption of flavonoids and other nutritional components. Presence and degree of carotid calcification were determined according to Agatston scores on computer tomography angiography. Logistic regression was performed to evaluate the association between dietary flavonoids (total flavonoids, flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, and isoflavones) and carotid calcification. RESULTS: Of the 601 enrolled patients, 368 (61.2%) were detected with carotid calcification. Patients with high intake of total flavonoids (the fifth quintile) had a 52% lower carotid calcification risk than those with low intake (the first quintile; odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.26-0.90; p = 0.007 for trends) after adjusting for major confounders. Patients with high intake of flavan-3-ols (the fifth quintile) had a 51% lower carotid calcification risk than those with low intake (the first quintile; OR = 0.49; 95% CI, 0.25-0.97; p = 0.016 for trends). CONCLUSION: Dietary flavonoid intake is associated with carotid calcification, and, therefore, may influence the risk of stroke occurrence and recurrence.

Associations between dietary flavonoid intake with hepatic steatosis and fibrosis quantified by VCTE: Evidence from NHANES and FNDDS.

BACKGROUND AND AIM: Flavonoids are natural products of plant origin and have been shown to be beneficial for nonalcoholic fatty liver disease (NAFLD) in animal studies. However, relevant epidemiological evidence is still lacking, and the relationship between flavonoid and subclass intake with quantified hepatic steatosis and fibrosis has not been investigated. METHODS AND RESULTS: This study was based on the Food and Nutrient Database for Dietary Studies (FNDDS) expanded flavonoid intake database and the National Health and Nutrition Examination Survey (NHANES) 2017-2018 and included a total of 4113 participants with vibration-controlled transient elastography (VCTE) data. Multiple logistic regression was used to assess linear relationships between flavonoids and hepatic steatosis and fibrosis. Smoothed curve fit and a generalized additive model were used to investigate the non-linear relationship, and a two-tailed linear regression model was used to find potential inflection points. Of the 4113 participants, 1045 (25.41%) were diagnosed with NAFLD. After adjusting for energy and major non-dietary covariates, significant linear negative correlations were observed between total flavonoids and CAP [-1.53 (-2.59, -0.47)] and LSM [-0.17 (-0.27, -0.07)]. After adjusting for all covariates, flavones had the strongest and most significant negative association with hepatic steatosis [-1.98 (-3.79, -0.17)]. The results of smooth curve fitting and subgroup analysis demonstrated gender differences, and threshold effect analysis further identified a U-shaped relationship and inflection point between flavonoid intake and hepatic steatosis (infection point: 287.25 mg/d). CONCLUSIONS: Our findings suggest negative associations between flavonoid and subclass intake with hepatic steatosis and fibrosis.

The molecular mechanisms underlying anti-inflammatory effects of galangin in different diseases.

When used as an alternative source of drugs to treat inflammation-associated diseases, phytochemicals with anti-inflammatory properties provide beneficial impacts. Galangin is one of the most naturally occurring flavonoids. Galangin has many biological activities, such as anti-inflammatory, antioxidant, antiproliferative, antimicrobial, anti-obesity, antidiabetic, and anti-genotoxic activities. We observed that galangin was well tolerated and positively impacted disease underlying inflammation for the renal, hepatic, central nervous system, cardiovascular, gastrointestinal system, skin, and respiratory disorders, as well as ulcerative colitis, acute pancreatitis, retinopathy, osteoarthritis, osteoporosis, and rheumatoid arthritis. Galangin anti-inflammatory effects are mediated mainly by suppressing p38 mitogen-activated protein kinases, nuclear factor-kappa B, and nod-like receptor protein 3 signals. These effects are confirmed and supported by molecular docking. Clinical translational research is required to accelerate the bench-to-bedside transfer and determine whether galangin can be utilised as a safe, natural source of pharmaceutical anti-inflammatory medication for humans.

Eupatilin Ameliorates Hepatic Fibrosis and Hepatic Stellate Cell Activation by Suppressing ß-catenin/PAI-1 Pathway.

The activation of hepatic stellate cells (HSCs) has proved to be pivotal in hepatic fibrosis. Therefore, the suppression of HSC activation is an effective anti-fibrotic strategy. Although studies have indicated that eupatilin, a bioactive flavone found in Artemisia argyi, has anti-fibrotic properties, the effect of eupatilin on hepatic fibrosis is currently unclear. In this study, we used the human hepatic stellate cell line LX-2 and the classical CCl4-induced hepatic fibrosis mouse model for in vitro and vivo experiments. We found that eupatilin significantly repressed the levels of the fibrotic markers COL1α1 and α-SMA, as well as other collagens in LX-2 cells. Meanwhile, eupatilin markedly inhibited LX-2 cell proliferation, as verified by the reduced cell viability and down-regulation of c-Myc, cyclinB1, cyclinD1, and CDK6. Additionally, eupatilin decreased the level of PAI-1 in a dose-dependent manner, and knockdown of PAI-1 using PAI-1-specific shRNA significantly suppressed the levels of COL1α1, α-SMA, and the epithelial-mesenchymal transition (EMT) marker N-cadherin in LX-2 cells. Western blotting indicated that eupatilin reduced the protein level of ß-catenin and its nuclear translocation, while the transcript level of ß-catenin was not affected in LX-2 cells. Furthermore, analysis of histopathological changes in the liver and markers of liver function and fibrosis revealed that hepatic fibrosis in CCl4-treated mice was markedly alleviated by eupatilin. In conclusion, eupatilin ameliorates hepatic fibrosis and hepatic stellate cell activation by suppressing the ß-catenin/PAI-1 pathway.

Flavonoids in Amomum tsaoko Crevost et Lemarie Ameliorate Loperamide-Induced Constipation in Mice by Regulating Gut Microbiota and Related Metabolites.

Amomum tsaoko (AT) is a dietary botanical with laxative properties; however, the active ingredients and mechanisms are still unclear. The active fraction of AT aqueous extract (ATAE) for promoting defecation in slow transit constipation mice is the ethanol-soluble part (ATES). The total flavonoids of ATES (ATTF) were the main active component. ATTF significantly increased the abundance of Lactobacillus and Bacillus and reduced the dominant commensals, such as Lachnospiraceae, thereby changing the gut microbiota structure and composition. Meanwhile, ATTF changed the gut metabolites mainly enriched in pathways such as the serotonergic synapse. In addition, ATTF increased the serum serotonin (5-HT) content and mRNA expression of 5-hydroxytryptamine receptor 2A (5-HT2A), Phospholipase A2 (PLA2), and Cyclooxygenase-2 (COX2), which are involved in the serotonergic synaptic pathway. ATTF increased Transient receptor potential A1 (TRPA1), which promotes the release of 5-HT, and Myosin light chain 3(MLC3), which promotes smooth muscle motility. Notably, we established a network between gut microbiota, gut metabolites, and host parameters. The dominant gut microbiota Lactobacillus and Bacillus, prostaglandin J2 (PGJ2) and laxative phenotypes showed the most significant associations. The above results suggest that ATTF may relieve constipation by regulating the gut microbiota and serotonergic synaptic pathway and has great potential for laxative drug development in the future.

Redox Activity of Flavonoids: Impact on Human Health, Therapeutics, and Chemical Safety.

The cost-effectiveness of presently used therapies is a problem in overall redox-based management, which is posing a significant financial burden on communities across the world. As a result, sophisticated treatment models that provide notions of predictive diagnoses followed by targeted preventive therapies adapted to individual patient profiles are gaining global acclaim as being beneficial to patients, the healthcare sector, and society as a whole. In this context, natural flavonoids were considered due to their multifaceted antioxidant, anti-inflammatory, and anticancer effects as well as their low toxicity and ease of availability. The aim of this review is to focus on the capacity of flavonoids to modulate the responsiveness of various diseases and ailments associated with redox toxicity. The review will also focus on the flavonoids' pathway-based redox activity and the advancement of redox-based therapies as well as flavonoids' antioxidant characteristics and their influence on human health, therapeutics, and chemical safety. Research findings indicated that flavonoids significantly exhibit various redox-based therapeutic responses against several diseases such as inflammatory, neurodegenerative, cardiovascular, and hepatic diseases and various types of cancer by activating the Nrf2/Keap1 transcription system, suppressing the nuclear factor κB (NF-κB)/IκB kinase inflammatory pathway, abrogating the function of the Hsp90/Hsf1 complex, inhibiting the PTEN/PI3K/Akt pathway, and preventing mitochondrial dysfunction. Some flavonoids, especially genistein, apigenin, amentoflavone, baicalein, quercetin, licochalcone A, and biochanin A, play a potential role in redox regulation. Conclusions of this review on the antioxidant aspects of flavonoids highlight the medicinal and folk values of these compounds against oxidative stress and various diseases and ailments. In short, treatment with flavonoids could be a novel therapeutic invention in clinical trials, as we hope.

Brightening effect of Ziziphus jujuba (jujube) fruit extract on facial skin: A randomized, double-blind, clinical study.

Ziziphus jujuba Mill. (jujube) is an invaluable medicinal plant in traditional and modern medicine. Jujube syrup is a complex of herbal extracts including Z. jujuba, Berberis vulgaris, Rhus coriaria, Prunus domestica, and Rosa damascene. The purpose of the present study was to formulate and investigate the efficacy and safety of jujube syrup on brightening of facial skin. In this randomized, double-blind, controlled clinical study, 46 participants consumed jujube syrup or placebo (23 in each group) twice a day for 8 weeks. The number of pigments, area of pigmentation, and physician's global assessment score (PGAS) were evaluated at baseline and after 8 weeks. The results showed the amounts of total phenolics and flavonoids were 81.97 ± 0.25 and 4.98 ± 1.04 mg/ml, respectively. The amounts of organic acids (gallic acid and chlorogenic acid) were quantified at 1140 ± 17.65 and 1520 ± 25.77 µg/ml, respectively. The amounts of total phenolic and flavonoids were stable under accelerated conditions. Eight weeks after treatment, the number of pigment counts reduced to 0.545 ± 0.307 compared to the placebo group. Moreover, the pigmented area and its percentages were significantly reduced to 0.556 ± 0.285 and 0.561 ± 0.288 in jujube syrup compared with placebo, respectively. Jujube syrup is efficient and safe for treating hyperpigmentation of the face.

Exploring the Potential of ToxCast Data in Supporting Read-Across for Evaluation of Food Chemical Safety.

The intention of this study was to determine the utility of high-throughput screening (HTS) data, as exemplified by ToxCast and Tox21, for application in toxicological read-across in food-relevant chemicals. Key questions were addressed on the extent to which the HTS data could provide information enabling (1) the elucidation of underlying bioactivities associated with apical toxicological outcomes, (2) the closing of existing toxicological data gaps, and (3) the definition of the boundaries of chemical space across which bioactivity could reliably be extrapolated. Results revealed that many biological targets apparently activated within the chemical groupings lack, at this time, validated toxicity pathway associations. Therefore, as means of providing proof-of-principle, a comparatively well-characterized end point-estrogenicity-was selected for evaluation. This was facilitated through the preparation of two exploratory case studies, focusing upon groupings of paraben-gallates and pyranone-type compounds (notably flavonoids). Within both, the HTS data were seen to reflect estrogenic potencies in a manner which broadly corresponded to established structure-activity group relationships, with parabens and flavonoids displaying greater estrogen receptor affinity than benzoate esters and alternative pyranone-containing molecules, respectively. As such, utility in the identification of out-of-domain compounds was demonstrated, indicating potential for application in addressing point (3) as detailed above.

Sestrin2 protects against bavachin induced ER stress through AMPK/mTORC1 signaling pathway in HepG2 cells.

Bavachin (BV), a natural flavonoid compound derived from Psoralea corylifolia L, has been reported to be a potential hepatotoxin. Our previous studies have found that BV can induce endoplasmic reticulum (ER) stress-related cell apoptosis, but the molecular mechanism underlying BV-induced ER stress remains obscure. Sestrin2, a highly conserved stress-inducible protein, is involved in the cellular responses of various stress conditions and homeostatic regulation. However, whether Sestrin2 participated in the ER stress related hepatotoxicity against BV is still elusive. In the present study, we aim to investigate the role of BV on liver injury of mice and the impact of Sestrin2 on BV-induced ER stress in HepG2 cells. The results in mice showed that BV induced ER stress related liver injury with increased Sestrin2 expression involvement. Knockdown of Sestrin2 with siRNA aggravated BV-induced ER stress significantly in HepG2 cells. Further mechanistic study uncovered that inhibition of mTORC1 with rapamycin blocked BV-induced ER stress, and treatment with Sestrin2 siRNA blocked the inhibition effect of AMPK to mTORC1. Therefore, constant mTORC1 would lead to accumulation of misfolded or unfolded proteins and aggravated ER stress. Collectively, our study indicates that Sestrin2 confers protection against BV-induced ER stress via activating of the AMPK/mTORC1 pathway.

Icariin reduces bone loss in a Rankl-induced transgenic medaka (Oryzias latipes) model for osteoporosis.

Given the limitations and side effects of many synthetic drugs, natural products are an important alternative source for drugs and medications for many diseases. Icariin (ICA), one of the main flavonoids from plants of the Epimedium genus, has been shown to ameliorate osteoporosis and improve bone health in preclinical studies. Those studies have used different in vivo models, mostly rodents, but the underlying mechanisms remain unclear. The present study shows, for the first time, that ICA reduces bone damage in a Rankl-induced medaka fish (Oryzias latipes), a non-rodent osteoporosis model. Live imaging was previously performed in this model to characterize antiresorptive and bone-anabolic properties of drugs. Here, a new quantification method (IM ) was established based on the length of mineralized neural arches to quantify levels of bone mineralization damage and protection in early post-embryonic fish. This method was validated by quantification of three levels of bone damage in three independent Rankl fish lines, and by the determination of different degrees of severity of osteoporosis-like phenotypes in one Rankl line exposed to variable Rankl induction schemes. IM was also used to quantify the efficacy of alendronate and etidronate, two common anti-osteoporotic bisphosphonates, and revealed comparable bone protective effects for ICA and alendronate in this fish osteoporosis model. This study's data support the value of the medaka fish model for bone research and establish a method to screen for novel osteoprotective compounds.

Antioxidative and anti-inflammatory activities of Polygonum minus: a review of literature.

Inflammation and oxidative stress are involved in the pathogenesis of cardiovascular diseases such as atherosclerosis, hypertension and ischemic heart disease. Natural products play an important role as nutritional supplements with potential health benefits in cardiovascular diseases. Polygonum minus (PM) is an aromatic plant that is widely used as a flavoring agent in cooking and has been recognized as a plant with various medicinal properties including antioxidative and anti-inflammatory actions. Phytoconstituents found in PM such as phenolic and flavonoid compounds contribute to the plant's antioxidative and anti-inflammatory effects. We conducted this review to systematically identify articles related to the antioxidative and anti-inflammatory activities of PM. A computerized database search was conducted on Ovid MEDLINE, PubMed, Scopus, and ACS publication, from 1946 until May 2020, and the following keywords were used: 'Kesum OR Polygonum minus OR Persicaria minor' AND 'inflammat* OR oxida* OR antioxida*'. A total of 125 articles were obtained. Another eight additional articles were identified through Google Scholar and review articles. Altogether, 17 articles were used for data extraction, comprising 16 articles on antioxidant and one article on anti-inflammatory activity of PM. These studies consist of 14 in vitro studies, one in vivo animal study, one combined in vitro and in vivo study and one combined in vitro and ex vivo study. All the studies reported that PM exhibits antioxidative and anti-inflammatory activities which are most likely attributed to its high phenolic and flavonoid content.

Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer.

The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.

Preventative and Therapeutic Potential of Flavonoids in Peptic Ulcers.

Peptic ulcer disease is a common gastrointestinal tract disorder that affects up to 20% of the population of the world. Treatment of peptic ulcer remains challenging due to the limited effectiveness and severe side effects of the currently available drugs. Hence, natural compounds, owing to their medicinal, ecological, and other safe properties, are becoming popular potential candidates in preventing and treating peptic ulcers. Flavonoids, the most abundant polyphenols in plants, exhibit gastroprotective effects against peptic ulcer both in vivo and in vitro. In this review, we summarized the anti-ulcer functions and mechanisms, and also the bioavailability, efficacy, and safety, of flavonoid monomers in the gastrointestinal tract. Flavonoids exerted cytoprotective and rehabilitative effects by not only strengthening defense factors, such as mucus and prostaglandins, but also protecting against potentially harmful factors via their antioxidative, anti-inflammatory, and antibacterial activities. Although controlled clinical studies are limited at present, flavonoids have shown a promising preventable and therapeutic potential in peptic ulcers.

First-in-class immune-modulating small molecule Icaritin in advanced hepatocellular carcinoma: preliminary results of safety, durable survival and immune biomarkers.

BACKGROUND: With poor prognosis and limited treatment options for advanced hepatocellular carcinoma (HCC), development of novel therapeutic agents is urgently needed. This single-arm phase I study sought to assess the safety and preliminary efficacy of icaritin in human as a potential oral immunotherapy in addition to the immune-checkpoint inhibitors. METHODS: Eligible advanced HCC patients with Child-Pugh Class A or B were administered with a fixed oral dose of icaritin at either 600 or 800 mg b.i.d. The primary endpoint was safety, and the secondary endpoints included time-to-progression (TTP), overall survival (OS) and the clinical benefit rate (CBR). Icaritin treatment induced immune biomarkers and immune-modulating activities in myeloid cells were also explored. RESULTS: No drug-related adverse events ≥ Grade 3 were observed in all 20 enrolled HCC patients. Among the 15 evaluable patients, 7 (46.7%) achieved clinical benefit, representing one partial response (PR, 6.7%) and 6 stable disease (SD, 40%). The median TTP was 141 days (range: 20-343 days), and the median OS was 192 days (range: 33-1036 days). Durable survival was observed in PR/SD patients with a median OS of 488 days (range: 72-773). TTP was significantly associated with the dynamic changes of peripheral neutrophils (p = 0.0067) and lymphocytes (p = 0.0337). Icaritin treatment induced changes in immune biomarkers-and immune-suppressive myeloid cells were observed. CONCLUSIONS: Icaritin demonstrated safety profiles and preliminary durable survival benefits in advanced HCC patients, which were correlated with its immune-modulation activities and immune biomarkers. These results suggested the potential of icaritin as a novel oral immunotherapy for advanced HCC in addition to antibody-based PD-1/PD-L1 blockade therapies. TRIAL REGISTRATION: Clinicaltrial.gov identifier. NCT02496949 (retrospectively registered, July 14, 2015).

Identification of Quinone Methide Intermediate Resulting from Metabolic Activation of Icaritin in Vitro and in Vivo.

Many herbal medicines such as epimedium have been reported to cause adverse effects, and icaritin is the common aglycone of many glucosides in epimedium. Our present work aimed at the clarification of the metabolic activation of icaritin possibly responsible for the adverse effects of epimedium. A quinone methide metabolite (M1) was detected in icaritin-fortified microsomal incubations. A glutathione (GSH) conjugate (M2) and N-acetyl-l-cysteine (NAC) conjugate (M3) derived from icaritin were observed in GSH/NAC-supplemented rat/human liver microsomal incubations. CYP3A family was the predominant enzyme catalyzing the bioactivation of icaritin. In conclusion, sufficient evidence indicates the metabolic activation of icaritin to quinone methide metabolite.

A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease.

To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC). The primary objective was attainment of a complete remission (CR). A Simon two-stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S-MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%-35%), 28% in the FLAM arm (10/36, 90% CI, 16%-43%), and 16% in the S-MEC arm (3/19, 90% CI, 4%-36%). There were nine treatment-related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients.

Dual-function of Baicalin in nsPEFs-treated Hepatocytes and Hepatocellular Carcinoma cells for Different Death Pathway and Mitochondrial Response.

Nanosecond pulsed electric fields (nsPEFs) is emerged as a potential curative modality to ablate hepatocellular carcinoma (HCC). The application of local ablation is usually limited by insufficiency of liver function. While baicalin, a flavonoid isolated from Scutellaria baicalensis Georgi, has been proven to possess both anti-tumor and protective effects. Our study aimed to estimate different responses of hepatic cancer cells and hepatocytes to the combination of nsPEFs and baicalin. Cell viability, apoptosis and necrosis, mitochondrial transmembrane potential (MTP) and reactive oxygen species (ROS) were examined by CCK-8, FCM, JC-1 and fluorescent probe, respectively. After treatment by nsPEFs, most hepatocytes died by apoptosis, nevertheless, nearly all cancer cells were killed through necrosis. Low concentration of baicalin synergically enhanced nsPEFs-induced suppression and necrosis of HCC cells, nevertheless, the application of baicalin protected normal hepatocytes from the injury caused by nsPEFs, owing to elevating mitochondrial transmembrane potential and reducing ROS generation. Our work provided an advantageous therapy for HCC through the enhanced combination treatment of nsPEFs and baicalin, with which could improve the tumor-ablation effect and alleviate the injury of hepatic tissues simultaneously.

Improvement in colistin-induced reproductive damage, apoptosis, and autophagy in testes via reducing oxidative stress by chrysin.

This study aimed to investigate the effect of chrysin on colistin-induced reproductive toxicity. Twenty-eight adult male Sprague-Dawley rats were divided into four groups of seven rats each. Group I received physiological saline for 7 days. Group II received 50 mg/kg/day chrysin for 7 days. Group III received a total dose of 73 mg/kg colistin for 7 days. Group IV received 50 mg/kg/day chrysin by an oral gavage after the colistin treatment. Colistin causes an increase in oxidative stress (OS) in the testis. Chrysin treatment significantly decreased the OS in the chrysin + colistin group compared with the colistin group. The highest caspase-3 and LC3B expression levels were found in the colistin group and these levels were statistically lower in the chrysin + colistin group. Colistin treatment caused a decrease in sperm motility and an increase in sperm abnormality. Chrysin treatment mitigated these side effects significantly. In conclusion, chrysin treatment can be beneficial against colistin-induced reproductive toxicity.

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells.

As a traditional herbal medicine, the fruits of Psoralea corylifolia L. (Fructus Psoraleae (FP)) have been widely used for the treatment of various skin diseases for hundred years. Recently, the emerging FP-induced toxic effects, especially hepatotoxicity, in clinic are getting the public's attention. However, its exact toxic components and mechanisms underlying remain unclear. Bavachin, one of flavonoids in FP, has been documented as a hepatotoxic substance, and the present study aimed to determine the toxicity caused by bavachin and the possible toxic mechanisms involved using human hepatocellular carcinoma (HepG2) cells. Our results showed that bavachin could significantly inhibited cell proliferation and trigger the endoplasmic reticulum (ER) stress in a dose dependent manner. Downregulating ER stress using tauroursodeoxycholic acid (TUDCA) obvious attenuated bavachin-triggerd cell apoptosis. Then, small interfering RNA (siRNA) knock-down of Mitofusion2 (Mfn2) resulted in a remarkable aggravation of ER stress through the inhibition of the phosphorylation of protein kinase B (Akt). Additionally, suppression of reactive oxygen species (ROS) by ROS Scavenger (N-acetyl-l-cystein (NAC)) also reduced bavachin-induced ER stress. Taken together, our study demonstrated that bavachin-induced ER stress caused cell apoptosis by Mfn2-Akt pathway, and that ROS may participate upstream in this mechanism. Here, we not only provide a new understanding of ROS/Mfn2/Akt pathway in bavachin-induced cytotoxicity via the ER stress, but also identify a new specific intervention to prevent FP-induced hepatotoxicity in the future.

Antiangiogenic Activity and Cytotoxicity of Triterpenoids and Homoisoflavonoids from Massonia pustulata and Massonia bifolia.

The Hyacinthaceae family (sensu APGII), with approximately 900 species in around 70 genera, plays a significant role in traditional medicine in Africa as well as across Europe and the Middle and Far East. The dichloromethane extract of the bulbs of Massonia pustulata (Hyacinthaceae sensu APGII) yielded two known homoisoflavonoids, (R)-5-hydroxy-3-(4-hydroxybenzyl)-7-methoxy-4-chromanone 1: and 5-hydroxy-3-(4-hydroxybenzyl)-7-methoxy-4-chromone 2: and four spirocyclic nortriterpenoids, eucosterol 3: , 28-hydroxyeucosterol 4: and two previously unreported triterpenoid derivatives, (17S,23S)-17α,23-epoxy-3ß,22ß,29-trihydroxylanost-8-en-27,23-olide 5: , and (17S, 23S)-17α,23-epoxy-28,29-dihydroxylanost-8-en-3-on-27,23-olide 6: . Compounds 1, 2, 3: , and 5: were assessed for cytotoxicity against CaCo-2 cells using a neutral red uptake assay. Compounds 1, 2: , and 5: reduced cell viability by 70% at concentrations of 30, 100, and 100 µM, respectively. Massonia bifolia yielded three known homoisoflavonoids, (R)-(4'-hydroxy)-5-hydroxy-7-methoxy-4-chromanone 1: , (R)-(4'-hydroxy)-5,7-dihydroxy-4-chromanone 7: and (R)-(3'-hydroxy-4'-methoxy)-5,7-dihydroxy-4-chromanone 9: , two previously unreported homoisoflavonoids, (E)-3-benzylidene-(3',4'-dihydroxy)-5-hydroxy-7-methoxy-4-chromanone 8: and (R)-(3',4'-dihydroxy)-5-hydroxy-7-methoxy-4-chromanone 10,: and a spirocyclic nortriterpenoid, 15-deoxoeucosterol 11: . Compounds 1, 1AC, 7, 8, 9,: and 10: were screened for antiangiogenic activity against human retinal microvascular endothelial cells. Some compounds showed dose-dependent antiproliferative activity and blocked endothelial tube formation, suggestive of antiangiogenic activity.