Xianglian Pill combined with 5-fluorouracil enhances antitumor activity and reduces gastrointestinal toxicity in gastric cancer by regulating the p38 MAPK/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Perioperative or postoperative adjuvant chemotherapy based on 5-fluorouracil (5-FU) is a common first-line adjuvant therapy for gastric cancer (GC). However, drug resistance and the side effects of 5-FU have reduced its efficacy. Among these side effects, gastrointestinal (GI) toxicity is one of the most common. Xianglian Pill (XLP) is a Chinese patent medicine that is commonly used for the treatment of diarrhoea. It can reduce inflammation and has a protective effect on the intestinal mucosa. Recent studies have shown that many components of XLP can inhibite tumor cell growth. However, the therapeutic effect of XLP in combination with 5-FU on GC is unclear. AIM OF THE STUDY: To investigate whether the combination of XLP and 5-FU can enhance anti-GC activity while reducing GI toxicity. MATERIALS AND METHODS: XLP was administered orally during intraperitoneal injection of 5-FU in GC mice model. Mice were continuously monitored for diarrhea and xenograft tumor growth. After 2 weeks, the mice were sacrificed and serum was collected to determine interleukin-6 levels. Pathological changes, the expression of pro-inflammatory factors and p38 mitogen-activated protein kinase (MAPK) in GI tissue were determined by Western blot analysis. Pathological changes, apoptosis levels and p38 MAPK expression levels in xenograft tissues were also determined. RESULTS: The results showed that XLP could alleviate GI mucosal injury caused by 5-FU, alleviated diarrhea, and inhibited the expression of nuclear factor (NF)-κB and myeloid differentiation primary response-88. Besides, XLP could promote the 5-FU-induced apoptosis of GC cells and enhance the inhibitory effect of 5-FU on tumor xenografts. Further study showed that XLP administration could regulate the expression of p38 MAPK. CONCLUSIONS: XLP in combination with 5-FU could alleviate its GI side effects and enhance its inhibitory effect on xenograft tumor. Moreover, these effects were found to be related to the regulation of the p38 MAPK/NF-κB pathway.

A novel phthalein component ameliorates neuroinflammation and cognitive dysfunction by suppressing the CXCL12/CXCR4 axis in rats with vascular dementia.

ETHNOPHARMACOLOGICAL RELEVANCE: Chuanxiong, a plant of the Umbelliferae family, is a genuine medicinal herb from Sichuan Province. Phthalides are one of its main active components and exhibit good protective effect against cerebrovascular diseases. However, the mechanism by which phthalides exert neuroprotective effects is still largely unclear. AIM OF THE STUDY: In this study, we extracted a phthalein component (named as QBT) from Ligusticum Chuanxiong, and investigated its neuroprotective effects against vascular dementia (VaD) rats and the underlying mechanism, focusing on the chemokine 12 (CXCL12)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis. METHODS: A rat model of VaD was established, and treated with QBT. Cognitive dysfunction in VaD rats was assessed using the Y-maze, new object recognition, and Morris water maze tests. Neuronal damage and inflammatory response in VaD rats were examined through Nissl staining, immunofluorescence, enzyme-linked immunospecific assay, and western blotting analysis. Furthermore, the effects of QBT on CXCL12/CXCR4 axis and its downstream signaling pathways, Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/nuclear factor-κB (NF-κB), were investigated in VaD rats and BV2 microglial cells exposed to oxygen glucose deprivation. RESULTS: QBT significantly alleviated cognitive dysfunction and neuronal damage in VaD rats, along with inhibition of VaD-induced over-activation of microglia and astrocytes and inflammatory response. Moreover, QBT exhibited anti-inflammatory effects by inhibiting the CXCL12/CXCR4 axis and its downstream JAK2/STAT3 and PI3K/AKT/NF-κB pathways, thereby attenuating the neuroinflammatory response both in vivo and in vitro. CONCLUSION: QBT effectively mitigated neuronal damage and cognitive dysfunction in VaD rats, exerting neuroprotective effects by suppressing neuroinflammatory response through inhibition of the CXCL12/CXCR4 axis.

Isobavachalcone, a natural sirtuin 2 inhibitor, exhibits anti-triple-negative breast cancer efficacy in vitro and in vivo.

Triple-negative breast cancer (TNBC) is the most aggressive and lethal clinical subtype and lacks effective targeted therapies at present. Isobavachalcone (IBC), the main active component of Psoralea corylifolia L., has potential anticancer effects. Herein, we identified IBC as a natural sirtuin 2 (SIRT2) inhibitor and characterized the potential mechanisms underlying the inhibition of TNBC. Molecular dynamics analysis, enzyme activity assay, and cellular thermal shift assay were performed to evaluate the combination of IBC and SIRT2. The therapeutic effects, mechanism, and safety of IBC were analyzed in vitro and in vivo using cellular and xenograft models. IBC effectively inhibited SIRT2 enzyme activity with an IC50 value of 0.84 ± 0.22 µM by forming hydrogen bonds with VAL233 and ALA135 within its catalytic domain. In the cellular environment, IBC bound to and stabilized SIRT2, consequently inhibiting cellular proliferation and migration, and inducing apoptosis and cell cycle arrest by disrupting the SIRT2/α-tubulin interaction and inhibiting the downstream Snail/MMP and STAT3/c-Myc pathways. In the in vivo model, 30 mg/kg IBC markedly inhibited tumor growth by targeting the SIRT2/α-tubulin interaction. Furthermore, IBC exerted its effects by inducing apoptosis in tumor tissues and was well-tolerated. IBC alleviated TNBC by targeting SIRT2 and triggering the reactive oxygen species ROS/ß-catenin/CDK2 axis. It is a promising natural lead compound for future development of SIRT2-targeting drugs.

Investigation of polysaccharide from Radix Aconiti Lateralis Preparata (Fuzi) cardio protective effect on doxorubicin-induced chronic cardiotoxicity.

OBJECTIVES: Doxorubicin (DOX) is a chemotherapy drug for treating malignant tumours. However, its cardiotoxicity has limited its clinical application. The Radix Aconiti Lateralis Preparata, also known as Fuzi, has been used for treating heart failure. Nevertheless, there is still a deficiency of claeity as to whether the Fuzi polysaccharide (FPS) may prevent the side effects of DOX. METHODS: Mice were intraperitoneally administered DOX (15 mg/kg) to establish a mouse model of DOX-induced chronic cardiotoxicity (DICC). The mice were then administered different doses of FPS or enalapril intragastrically. KEY FINDINGS: In the DOX group, the activity of CK-MB and LDH and the content of NT-proBNP in serum of mice were increased. Myocardial infiltration of inflammatory cells and cytoplasmic vacuolation occurred. Levels of NLRP3, ASC, Caspase-1, IL-1ß, IL-18, IL-6, and Bax increased, whereas levels of Bcl-2, STAT3, and p-STAT3 decreased. After administering FPS (100 mg/kg and 200 mg/kg), there were reductions in CK-MB activity and NT-proBNP levels. Cytoplasmic vacuolation, interstitial infiltration of blood, and infiltration of inflammatory cells were alleviated. The changes in protein expression mentioned above were reversed. CONCLUSIONS: FPS can protect heart function and structure in DICC mice by inhibiting NLRP3 inflammasome-mediated pyroptosis and IL-6/STAT3 pathway-induced apoptosis.

Antimicrobial Activity of Stilbenes from Bletilla striata against Cutibacterium acnes and Its Effect on Cell Membrane.

The abnormal proliferation of Cutibacterium acnes is the main cause of acne vulgaris. Natural antibacterial plant extracts have gained great interest due to the efficacy and safety of their use in skin care products. Bletilla striata is a common externally used traditional Chinese medicine, and several of its isolated stilbenes were reported to exhibit good antibacterial activity. In this study, the antimicrobial activity of stilbenes from B. striata (BSS) against C. acnes and its potential effect on cell membrane were elucidated by determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), bacterial growth curve, adenosine triphosphate (ATP) levels, membrane potential (MP), and the expression of genes related to fatty acid biosynthesis in the cell membrane. In addition, the morphological changes in C. acnes by BSS were observed using transmission electron microscopy (TEM). Experimentally, we verified that BSS possessed significant antibacterial activity against C. acnes, with an MIC and MBC of 15.62 µg/mL and 62.5 µg/mL, respectively. The growth curve indicated that BSS at 2 MIC, MIC, 1/2 MIC, and 1/4 MIC concentrations inhibited the growth of C. acnes. TEM images demonstrated that BSS at an MIC concentration disrupted the morphological structure and cell membrane in C. acnes. Furthermore, the BSS at the 2 MIC, MIC, and 1/2 MIC concentrations caused a decrease in the intracellular ATP levels and the depolarization of the cell membrane as well as BSS at an MIC concentration inhibited the expression of fatty acid biosynthesis-associated genes. In conclusion, BSS could exert good antimicrobial activity by interfering with cell membrane in C. acnes, which have the potential to be developed as a natural antiacne additive.

Galangin: A food-derived flavonoid with therapeutic potential against a wide spectrum of diseases.

Galangin is an important flavonoid with natural activity, that is abundant in galangal and propolis. Currently, various biological activities of galangin have been disclosed, including anti-inflammation, antibacterial effect, anti-oxidative stress and aging, anti-fibrosis, and antihypertensive effect. Based on the above bioactivities, more and more attention has been paid to the role of galangin in neurodegenerative diseases, rheumatoid arthritis, osteoarthritis, osteoporosis, skin diseases, and cancer. In this paper, the natural sources, pharmacokinetics, bioactivities, and therapeutic potential of galangin against various diseases were systematically reviewed by collecting and summarizing relevant literature. In addition, the molecular mechanism and new preparation of galangin in the treatment of related diseases are also discussed, to broaden the application prospect and provide reference for its clinical application. Furthermore, it should be noted that current toxicity and clinical studies of galangin are insufficient, and more evidence is needed to support its possibility as a functional food.

Potential mechanism of Taohong Siwu Decoction in uterine fibroid treatment based on integrated strategy of network pharmacology and experimental verification.

BACKGROUND: Taohong Siwu Decoction (THSWD) is a widely prescribed Traditional Chinese Medicine (TCM) for treating gynecological diseases. It is used to treat uterine fibroids (UF) in China, while its potential therapeutic effects and mechanism are unknown. METHODS: The present study used network pharmacology to identify PI3K/AKT as one of the main THSWD signaling pathways that can be targeted to treat UF. The potential binding sites of miR-21-5p to PTEN were predicted using online databases. We were able to establish a UF rat model successfully. We selected the 15% THSWD serum after preparing THSWD drug-containing serum to culture tumor tissue-derived cells. These studies enabled us to assess the role of THSWD in UF improvement. RESULTS: In vivo, we observed that low, medium, and high doses of THSWD improved histological changes in UF rats by increasing the expression levels of PTEN and miR-21-5p in their uterus while decreasing the expression levels of p-PI3K, p-AKT, and miR-21-5p. Treatment with THSWD medicated serum (15%) effectively inhibited the proliferation of cells derived from human UF and promoted apoptosis in vitro. PI3K phosphorylation, Akt phosphorylation, and miR-21-5p expression were decreased, while PTEN and cleaved caspase-3 were increased. These findings were reversed by administering 740 Y-P (a PI3K/Akt pathway agonist) and a miR-21-5p mimic. In addition, the double luciferase reporter gene assay confirmed the targeted binding relationship between miR-21-5p and PTEN. CONCLUSIONS: THSWD inhibited the expression and activation of the PI3K/AKT and miR-21-5p/PTEN pathways, resulting in anti-UF activity in leiomyoma cell models. Our findings suggest that THSWD could be used to treat UF.

The mechanism of action of safflower total flavonoids in the treatment of endometritis caused by incomplete abortion based on network pharmacology and 16S rDNA sequencing.

ETHNOPHARMACOLOGICAL RELEVANCE: Safflower is a traditional Chinese medicine used for treating gynaecological diseases. However, its material basis and mechanism of action in the treatment of endometritis induced by incomplete abortion are still unclear. AIM OF THE STUDY: This study aimed to reveal the material basis and mechanism of action of safflower in the treatment of endometritis induced by incomplete abortion through comprehensive methods, including network pharmacology and 16S rDNA sequencing. MATERIALS AND METHODS: Network pharmacology and molecular docking methods were used to screen the main active components and potential mechanisms of action of safflower in the treatment of endometritis induced by incomplete abortion in rats. A rat model of endometrial inflammation by incomplete abortion was established. The rats were treated with safflower total flavonoids (STF) based on forecasting results, serum levels of inflammatory cytokines were analysed, and immunohistochemistry, Western blots, and 16S rDNA sequencing were performed to investigate the effects of the active ingredient and the treatment mechanism. RESULTS: The network pharmacology prediction results showed 20 active components with 260 targets in safflower, 1007 targets related to endometritis caused by incomplete abortion, and 114 drug-disease intersecting targets, including TNF, IL6, TP53, AKT1, JUN, VEGFA, CASP3 and other core targets, PI3K/AKT, MAPK and other signalling pathways may be closely related to incomplete abortion leading to endometritis. The animal experiment results showed that STF could significantly repair uterine damage and reduce the amount of bleeding. Compared with the model group, STF significantly down-regulated the levels of pro-inflammatory factors (IL-6, IL-1ß, NO, TNF-α) and the expression of JNK, ASK1, Bax, caspase3, and caspase11 proteins. At the same time, the levels of anti-inflammatory factors (TGF-ß and PGE2) and the protein expression of ERα, PI3K, AKT, and Bcl2 were up-regulated. Significant differences in the intestinal flora were seen between the normal group and the model group, and the intestinal flora of the rats was closer to the normal group after the administration of STF. CONCLUSIONS: The characteristics of STF used in the treatment of endometritis induced by incomplete abortion were multi-targeted and involved multiple pathways. The mechanism may be related to the activation of the ERα/PI3K/AKT signalling pathway by regulating the composition and ratio of the gut microbiota.

Bioactive compounds and mechanism of Xianglian pill in the treatment of gastric cancer: Network pharmacology analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Gastric cancer (GC) affects people's quality of life because of its high incidence rate and mortality. The Xianglian Pill (XLP) is a traditional Chinese medicine (TCM) prescription used to treat gastrointestinal (GI） diseases. Its anti-tumor effect has been found in recent years, but it's bioactive compounds and mechanism of action in treating GC are remain unknown. AIM OF THE STUDY: This study reveals the bioactive compounds and mechanisms of XLP in the treatment of GC through network pharmacology analysis and experimental verification. MATERIALS AND METHODS: The main compounds in XLP were searched and the active compounds with anti-GC activity were selected. Compounds targets and GC- related targets were predicted, and common targets were obtained. Subsequently, a protein-protein interaction (PPI) network of common targets is constructed, while GO and KEGG enrichment analyses were performed on common targets. Finally, the anti-GC effects of active compounds in XLP were verified in GC cell lines MGC-803 and HGC-27 by wound healing assay, cell cycle assay, cell apoptosis assay and western blotting (WB) assay. RESULTS: A total of 33 active compounds of XLP were obtained. MTT assay showed that dehydrocostus lactone (DHL) and berberrubine (BRB) had lower IC50 value in GC cells HGC-27 and MGC-803, and has a less inhibitory effect on normal gastric epithelial cells. Further, 73 common targets were obtained after the total target of DHL and BRB intersected with GC. Among them, CASP3, AKT1, SRC, STAT3,and CASP9 were the most associated genes in the PPI network. GO and KEGG enrichment analyses indicated that apoptosis played a major role in the biological processes and signaling pathways involved. Moreover, the in vitro experiment revealed that DHL and BRB inhibited GC cell viability via inducing cell cycle arrest at G2/M phase, and promoting cell apoptosis by up-regulating the caspase3 expression and down-regulating the expression of Bcl2/Bax. CONCLUSIONS: DHL and BRB are the two main anti-GC active compounds in XLP, and their mechanism is mainly to inhibit cell cycle and promote cell apoptosis.

Update on the sources, pharmacokinetics, pharmacological action, and clinical application of anisodamine.

Anisodamine is an anticholinergic drug extracted and isolated from the Anisodus tanguticus (Maxim.) Pascher of the Solanaceae family which is also a muscarinic receptor antagonist. Owing to the lack of natural sources of anisodamine, synthetic products are now used. Using ornithine and arginine as precursor compounds, putrescine is catalyzed by different enzymes and then undergoes a series of reactions to produce anisodamine. It has been used clinically to protect cardiac function and treat septic shock, acute pancreatitis, calculous renal colic, bronchial asthma, blood circulation disturbances, jaundice, analgesia, vertigo, acute poisoning, and other conditions.This review describes the relevant pharmacokinetic parameters. Anisodamine is poorly absorbed in the gastrointestinal tract, and it is not as effective as intravenous administration. For clinical medication, intravenous infusion should be used rather than rapid intravenous injection. With the advancement of research in recent years, the application scope of anisodamine has expanded, with significant developments and application values surging.This review systematically describes the sources, pharmacokinetics, pharmacological effects and clinical application of anisodamine, in order to provide a basis for clinical use.

Neoprzewaquinone A Inhibits Breast Cancer Cell Migration and Promotes Smooth Muscle Relaxation by Targeting PIM1 to Block ROCK2/STAT3 Pathway.

Salvia miltiorrhiza Bunge (Danshen) has been widely used to treat cancer and cardiovascular diseases in Chinese traditional medicine. Here, we found that Neoprzewaquinone A (NEO), an active component of S. miltiorrhiza, selectively inhibits PIM1. We showed that NEO potently inhibits PIM1 kinase at nanomolar concentrations and significantly suppresses the growth, migration, and Epithelial-Mesenchymal Transition (EMT) in the triple-negative breast cancer cell line, MDA-MB-231 in vitro. Molecular docking simulations revealed that NEO enters the PIM1 pocket, thereby triggering multiple interaction effects. Western blot analysis revealed that both NEO and SGI-1776 (a specific PIM1 inhibitor), inhibited ROCK2/STAT3 signaling in MDA-MB-231 cells, indicating that PIM1 kinase modulates cell migration and EMT via ROCK2 signaling. Recent studies indicated that ROCK2 plays a key role in smooth muscle contraction, and that ROCK2 inhibitors effectively control the symptoms of high intraocular pressure (IOP) in glaucoma patients. Here, we showed that NEO and SGI-1776 significantly reduce IOP in normal rabbits and relax pre-restrained thoracic aortic rings in rats. Taken together, our findings indicated that NEO inhibits TNBC cell migration and relaxes smooth muscles mainly by targeting PIM1 and inhibiting ROCK2/STAT3 signaling, and that PIM1 may be an effective target for IOP and other circulatory diseases.

Comparative Pharmacokinetic Investigation on Multiple Active Aminoalcohol-Diterpenoid Alkaloids after Single Oral Administrations of Monomers and Aqueous Extract of Fuzi (Aconiti Lateralis Radix Praeparata) by UFLC-MS/MS.

To further study the aminoalcohol-diterpenoid alkaloids (ADAs) in Fuzi (Aconiti Lateralis Radix Praeparata), a simple and sensitive UFLC-MS/MS method was established and validated for the determination of five ADAs, aconine, mesaconine, hypaconine, deoxyaconine and fuziline, in rat plasma to compare the pharmacokinetic characteristics of pure ADAs and Fuzi decoction. After precipitating protein with methanol, plasma samples were isolated at 0.5 mL/min flow rate on Waters Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 µm). The mobile phase was composed of 0.1% formic acid-water and methanol with gradient elution. Mass spectrometric inspection was conducted on a 5500 UFLC-MS/MS system with an electrospray ionization source in patterns of positive ion and multiple reaction-monitoring (MRM). All calibration curves were proved to have acceptable linearity (r2 > 0.99) in linear ranges. Intra-day and inter-day precision and the accuracy met the requirements. The matrix effects of all analytes were between 85% and 115% of three concentration levels. This method has been under verification for comparative pharmacokinetic research after oral administration between aqueous extract of Fuzi and single pure ADAs. The results demonstrated that there are evident pharmacokinetic discrepancies between them, and administration in the extract form instead of pure form may contribute to higher absorption.

Inhibition of SLC7A11-GPX4 signal pathway is involved in aconitine-induced ferroptosis in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum species, with a long history of traditional application, were applied to treat rheumatism, arthritis, stroke, and pain in Chinese medical practice. However, misuse of Aconitum species may induce central nervous toxic effects, such as numbness, vomiting, and even coma. Aconitine has been proved to be the main toxic component of Aconitum plants. Neurotoxicity is the main toxic effect of aconitine, while the underlying mechanism of aconitine remains unclear. AIM OF THE STUDY: The purpose of the study is to explore the effects and molecular mechanism of ferroptosis caused by aconitine in vivo and in vitro. MATERIALS AND METHODS: Six-dpf zebrafish larvae and SH-SY5Y cells were treated with different concentrations of aconitine for 24 h. Inhibitors treatment, e.g. pretreatment with Necrostain-1 (Nec-1) and Z-VZD-FMK for 12 h, or with Ferrostain-1 (Fer-1) for 4 h, were involved in the identification of aconitine-induced ferroptosis. Transient transfection experiment was conducted to explore the effects of SLC7A11 in the process of aconitine-induced ferroptosis. The effects of aconitine on morphological changes, lipid peroxidation, ferrous ion, and ferroptosis were detected by transmission electron microscope, flow cytometry, confocal microscopy, enzyme-linked immunosorbent assay and western blotting. RESULTS: In SH-SY5Y cells, morphological changes including shrunken mitochondria, increased mitochondrial membranes density and ruptured mitochondrial membranes were captured in aconitine-treated group. The cell viability and GSH content dose-dependently declined, levels of lipid reactive oxygen species (ROS), malondialdehyde (MDA), and ferrous ion significantly increased after aconitine exposure for 24 h. Ferroptosis inhibitor Fer-1 pretreatment effectively increased cell viability, GSH content, and decreased levels of MDA and lipid peroxidation, suggesting that aconitine induced ferroptosis. In addition, the protein expression of SLC7A11 and GPX4 were improved after Fer-1 preincubation, which indicated that aconitine triggered ferroptosis via the inhibition of SLC7A11 and the inactivation of GPX4. Ferroptotic characteristics, including GSH depletion and lipid peroxidation accumulation, were alleviated via overexpression of SLC7A11 to increase protein expression of GPX4. In zebrafish experiment, GSH depletion, lipid peroxidation accumulation, iron overload, and the decreased protein expression of SLC7A11 and GPX4 were also induced in zebrafish larvae after aconitine exposure. Taken together, aconitine triggered ferroptotic cell death via inhibiting SLC7A11/GPX4 signal pathway in vivo and in vitro. CONCLUSION: All results indicated that aconitine triggered ferroptosis of SH-SY5Y cells and zebrafish larvae nerve cells, which involved the inhibition of SLC7A11/GPX4 signal pathway mediated by lipid peroxidation damage and iron overload.

Therapeutic potential of Curcuma oil and its terpenoids in gynecological cancers.

BACKGROUND: Gynecological cancers encompass all uncontrolled and aberrant cell growth in the female reproductive system, therapeutic interventions are constantly evolving, but there is still a high death rate, significant side effects and medication resistance, making the task of treatment challenging and complex. The essential oil extracted from the rhizome of Curcuma longa is a promising natural drug, which has excellent biological activity on cancer cells and is to be developed as a new type of anti-gynecological tumor therapeutic agent. PURPOSE: To systematically summarize the available evidence for the efficacy of Curcuma oil and its terpenoids (ß-elemene, curcumol, furanodiene, and germacrone) in gynecological cancers, primarily malignancies of the reproductive system, involving ovarian, cervical, and endometrial cancers, explain the underlying mechanisms of preventing and treating gynecological cancers, and assess the shortcomings of existing work. RESULTS: Through several signaling channels, Curcuma oil and its terpenoids can not only stop the growth of ovarian cancer, cervical cancer, and endometrial cancer cells, limit the formation of tumors, but also raise the effectiveness of chemotherapy drugs and improve the quality of life for patients. CONCLUSION: It provides a preclinical basis for the efficacy of Curcuma oil as a broad-spectrum anti-tumor agent for the prevention and treatment of gynecological cancers. Even so, further efforts are still needed to improve the bioavailability of Curcuma oil and upgrade related experiments.

The antibacterial activity of berberine against Cutibacterium acnes: its therapeutic potential in inflammatory acne.

Cutibacterium acnes (C. acnes) is a major pathogen implicated in the evolution of acne inflammation. Inhibition of C. acnes-induced inflammation is a prospective acne therapy strategy. Berberine (BBR), a safe and effective natural ingredient, has been proven to exhibit powerful antimicrobial and anti-inflammatory properties. However, the antimicrobial effect of BBR against C. acnes and its role in C. acnes-mediated inflammatory acne have not been explored. The objective of this investigation was to assess the antibacterial activity of BBR against C. acnes and its inhibitory effect on the inflammatory response. The results of in vitro experiments showed that BBR exhibited significant inhibition zones against four C. acnes strains, with the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) in the range of 6.25-12.5 µg/mL and 12.5-25 µg/mL, respectively. On the bacterial growth curve, the BBR-treated C. acnes exhibited obvious growth inhibition. Transmission electron microscopy (TEM) images indicated that BBR treatment resulted in significant morphological changes in C. acnes. High-content imaging analysis further confirmed that BBR could effectively inhibit the proliferation of C. acnes. The disruption of cell wall and cell membrane structure by BBR treatment was preliminary confirmed according to the leakage of cellular contents such as potassium (K+), magnesium (Mg2+), and alkaline phosphatase (AKP). Furthermore, we found that BBR could reduce the transcript levels of genes associated with peptidoglycan synthesis (murC, murD, mraY, and murG). Meanwhile, we investigated the modulatory ability of BBR on C. acnes-induced skin inflammation in mice. The results showed that BBR effectively reduced the number of C. acnes colonized in mice's ears, thereby alleviating ear swelling and erythema and significantly decreasing ear thickness and weight. In addition, BBR significantly decreased the levels of pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α in auricular tissues. These results suggest that BBR has the potential to treat inflammatory acne induced by C. acnes.

Genotoxicity and 28-day repeated dose oral toxicity study of garlic essential oil in mice.

Background and aim: Garlic essential oil (GEO) isolated from Garlic (Allium sativum L.) exerts biological activities in disease prevention, particularly in metabolic and liver diseases, and is used for a dietary therapy for centuries. However, due to the side effects associated with the excessive consumption of GEO, there is a need to evaluate the safety of the GEO. Experimental procedure: Ames test using five Salmonella typhimurium strains (TA98, TA100, TA102, TA1535, and TA1537) and Chinese hamster ovary (CHO-K1) cells with or without metabolic activation (S9 system), and mammalian erythrocyte micronucleus test were used to assess the genotoxicity and clastogenic effects of GEO. A repeated dose of GEO (15, 25, and 50 mg/kg body weight, p.o.) were administrated to ICR mice for 28 days to ascertain the subacute toxicity of GEO. Results and conclusions: The results of the Ames test with or without S9 system indicated that GEO did not induce mutagenicity nor have clastogenic effects in CHO-K1 cells with or without S9 activation. Furthermore, GEO did not affect the ratio of immature to total erythrocytes or the number of micronuclei in immature erythrocytes of ICR mice after 24 and 48 h. In a 28-day oral toxicity assessment, GEO (15, 25, and 50 mg/kg body weight, p.o.)-fed ICR mice exhibited normal behaviors, mortality, body weight, daily intake, hematology, clinical biochemistry, and organ weight. GEO shows no genotoxicity, and the no-observed-adverse-effect level (NOAEL) for GEO is considered to be greater than 50 mg/kg bw/day orally for 28 days in mice.

The synergistic compatibility mechanisms of fuzi against chronic heart failure in animals: A systematic review and meta-analysis.

Background: Fuzi's compatibilities with other medicines are effective treatments for chronic heart failure. Pre-clinical animal experiments have indicated many possible synergistic compatibility mechanisms of it, but the results were not reliable and reproducible enough. Therefore, we performed this systematic review and meta-analysis of pre-clinical animal studies to integrate evidence, conducted both qualitative and quantitative evaluations of the compatibility and summarized potential synergistic mechanisms. Method: An exhaustive search was conducted for potentially relevant studies in nine online databases. The selection criteria were based on the Participants, Interventions, Control, Outcomes, and Study designs strategy. The SYRCLE risk of bias tool for animal trials was used to perform the methodological quality assessment. RevMan V.5.3 and STATA/SE 15.1 were used to perform the meta-analysis following the Cochrane Handbook for Systematic Reviews of Interventions. Result: 24 studies were included in the systematic review and meta-analysis. 12 outcomes were evaluated in the meta-analysis, including BNP, HR, HWI, ALD, LVEDP, LVSP, EF, FS, +dP/dtmax, -dP/dtmax, TNF-α and the activity of Na + -K + -ATPase. Subgroup analyses were performed depending on the modeling methods and duration. Conclusion: The synergistic Fuzi compatibility therapeutic effects against CHF animals were superior to those of Fuzi alone, as shown by improvements in cardiac function, resistance to ventricular remodeling and cardiac damage, regulation of myocardial energy metabolism disorder and RAAS, alleviation of inflammation, the metabolic process in vivo, and inhibition of cardiomyocyte apoptosis. Variations in CHF modeling methods and medication duration brought out possible model-effect and time-effect relationships.

Exploring the mechanisms of neurotoxicity caused by fuzi using network pharmacology and molecular docking.

Safety has always been an important issue affecting the development of traditional Chinese medicine industry, especially for toxic medicinal materials, the establishment of risk prevention and control measures for toxic herbs is of great significance to improving the use of traditional Chinese medicine in clinical. Fuzi is a kind of traditional Chinese medicine and its toxicity has become the most important obstacle of limit in clinical using. In this paper, network pharmacology and molecular docking technology were used to analyze the main toxic components of Fuzi, the key targets and the mechanism of neurotoxicity. We carried out CCK-8 and WB assays, and detected LDH release and SDH activity. It was verified that aconitine caused neurotoxicity through a variety of pathways, including MAPK signaling pathway, pathways related to Akt protein, destruction of cell membrane integrity, damage of mitochondrial function affecting energy metabolism and apoptosis. What's more, this study confirmed that aconitine could produce neurotoxicity by promoting apoptosis of hippocampus neuron and decreasing its quantity through Nissl Staining and TUNEL assay. This paper found and confirmed multiple targets and various pathways causing neurotoxicity of Fuzi, in order to provide reference for clinical application and related research.

MicroRNAs, Key Regulators in Glioma Progression as Potential Therapeutic Targets for Chinese Medicine.

Gliomas are tumors of the primary central nervous system associated with poor prognosis and high mortality. The 5-year survival rate of patients with gliomas received surgery combined with chemotherapy or radiotherapy does not exceed 5%. Although temozolomide is commonly used in the treatment of gliomas, the development of resistance limits its use. MicroRNAs are non-coding RNAs involved in numerous processes of glioma cells, such as proliferation, migration and apoptosis. MicroRNAs regulate cell cycle, PI3K/AKT signal pathway, and target apoptosis-related genes (e.g., BCL6), angiogenesis-related genes (e.g., VEGF) and other related genes to suppress gliomas. Evidence illustrates that microRNAs can regulate the sensitivity of gliomas to temozolomide, cisplatin, and carmustine, thereby enhancing the efficacy of these agents. Moreover, traditional Chinese medicine (e.g., tanshinone IIA, xanthohumol, and curcumin) exert antiglioma effects by regulating the expression of microRNAs, and then microRNAs inhibit gliomas through influencing the process of tumors by targeting certain genes. In this paper, the mechanisms through which microRNAs regulate the sensitivity of gliomas to therapeutic drugs are described, and traditional Chinese medicine that can suppress gliomas through microRNAs are discussed. This review aims to provide new insights into the traditional Chinese medicine treatment of gliomas.