Genetic diversity, biofilm formation, and Vancomycin resistance of clinical Clostridium innocuum isolates.

BACKGROUND: Clostridium innocuum, previously considered a commensal microbe, is a spore-forming anaerobic bacterium. C. innocuum displays inherent resistance to vancomycin and is associated with extra-intestinal infections, antibiotic-associated diarrhea, and inflammatory bowel disease. This study seeks to establish a multilocus sequence typing (MLST) scheme to explore the correlation between C. innocuum genotyping and its potential pathogenic phenotypes. METHODS: Fifty-two C. innocuum isolates from Linkou Chang Gung Memorial Hospital (CGMH) in Taiwan and 60 sequence-available C. innocuum isolates from the National Center for Biotechnolgy Information Genome Database were included. The concentrated sequence of housekeeping genes in C. innocuum was determined by amplicon sequencing and used for MLST and phylogenetic analyses. The biofilm production activity of the C. innocuum isolates was determined by crystal violet staining. RESULTS: Of the 112 C. innocuum isolates, 58 sequence types were identified. Maximum likelihood estimation categorized 52 CGMH isolates into two phylogenetic clades. These isolates were found to be biofilm producers, with isolates in clade I exhibiting significantly higher biofilm production than isolates in clade II. The sub-inhibitory concentration of vancomycin seemed to minimally influence biofilm production by C. innocuum isolates. Nevertheless, C. innocuum embedded in the biofilm structure demonstrated resistance to vancomycin treatments at a concentration greater than 256 µg/mL. CONCLUSIONS: This study suggests that a specific genetic clade of C. innocuum produces a substantial amount of biofilm. Furthermore, this phenotype assists C. innocuum in resisting high concentrations of vancomycin, which may potentially play undefined roles in C. innocuum pathogenesis.

SPHK1 promotes bladder cancer metastasis via PD-L2/c-Src/FAK signaling cascade.

SPHK1 (sphingosine kinase type 1) is characterized as a rate-limiting enzyme in sphingolipid metabolism to phosphorylate sphingosine into sphingosine-1-phosphate (S1P) that can bind to S1P receptors (S1PRs) to initiate several signal transductions leading to cell proliferation and survival of normal cell. Many studies have indicated that SPHK1 is involved in several types of cancer development, however, a little is known in bladder cancer. The TCGA database analysis was utilized for analyzing the clinical relevance of SPHK1 in bladder cancer. Through CRISPR/Cas9 knockout (KO) and constitutive activation (CA) strategies on SPHK1 in the bladder cancer cells, we demonstrated the potential downstream target could be programmed cell death 1 ligand 2 (PD-L2). On the other hand, we demonstrated that FDA-approved SPHK1 inhibitor Gilenya® (FTY720) can successfully suppress bladder cancer metastasis by in vitro and in vivo approaches. This finding indicated that SPHK1 as a potent therapeutic target for metastatic bladder cancer by dissecting the mechanism of action, SPHK1/S1P-elicited Akt/ß-catenin activation promoted the induction of PD-L2 that is a downstream effector in facilitating bladder cancer invasion and migration. Notably, PD-L2 interacted with c-Src that further activates FAK. Here, we unveil the clinical relevance of SPHK1 in bladder cancer progression and the driver role in bladder cancer metastasis. Moreover, we demonstrated the inhibitory effect of FDA-approved SPHK1 inhibitor FTY720 on bladder cancer metastasis from both in vitro and in vivo models.

Fine particulate matter manipulates immune response to exacerbate microbial pathogenesis in the respiratory tract.

Particulate matter with a diameter ≤2.5 µm (PM2.5) poses a substantial global challenge, with a growing recognition of pathogens contributing to diseases associated with exposure to PM2.5 Recent studies have focused on PM2.5, which impairs the immune cells in response to microbial infections and potentially contributes to the development of severe diseases in the respiratory tract. Accordingly, changes in the respiratory immune function and microecology mediated by PM2.5 are important factors that enhance the risk of microbial pathogenesis. These factors have garnered significant interest. In this review, we summarise recent studies on the potential mechanisms involved in PM2.5-mediated immune system disruption and exacerbation of microbial pathogenesis in the respiratory tract. We also discuss crucial areas for future research to address the gaps in our understanding and develop effective strategies to combat the adverse health effects of PM2.5.

RAGE participates in the intracellular transport of Campylobacter jejuni cytolethal distending toxin.

BACKGROUND: Cytolethal distending toxin (CDT) belongs to the genotoxin family and is closely related to Campylobacter jejuni-associated gastroenteritis. We recently reported that CDT triggers the danger-associated molecular pattern (DAMP) signaling to exert deleterious effects on host cells. However, how CDT traffics in cells and the mechanism of CDT intoxication remain to be elucidated. METHODS: Recombinant CDT subunits (CdtA, CdtB, and CdtC) were purified, and their activity was characterized in gastrointestinal cells. Molecular approaches and image tracking were employed to analyze the delivery of CDT in host cells. RESULTS: In this study, we found that CDT interacts with the receptor of advanced glycation end products (RAGE) and high mobility group box 1 (HMGB1) to enter the cells. Our results further showed that CdtB transport in cells through the dynamin-dependent endocytic pathway and lysosome is involved in this process. Conversely, blockage of RAGE signaling resulted in a reduction in CDT-arrested cell cycles, indicating that RAGE is involved in CDT intracellular transport and its subsequent pathogenesis. CONCLUSION: Our results demonstrate that RAGE is important for CDT trafficking in the cells. These findings expand our understanding of important issues related to host cell intoxication by C. jejuni CDT.

OTUB1 contributes to the stability and function of Influenza A virus NS2.

The influenza A virus (IAV) consists of 8 single-stranded, negative-sense viral RNA (vRNA) segments. After infection, vRNA is transcribed, replicated, and wrapped by viral nucleoprotein (NP) to form viral ribonucleoprotein (vRNP). The transcription, replication, and nuclear export of the viral genome are regulated by the IAV protein, NS2, which is translated from spliced mRNA transcribed from viral NS vRNA. This splicing is inefficient, explaining why NS2 is present in low abundance after IAV infection. The levels of NS2 and its subsequent accumulation are thought to influence viral RNA replication and vRNP nuclear export. Here we show that NS2 is ubiquitinated at the K64 and K88 residues by K48-linked and K63-linked polyubiquitin (polyUb) chains, leading to the degradation of NS2 by the proteasome. Additionally, we show that a host deubiquitinase, OTUB1, can remove polyUb chains conjugated to NS2, thereby stabilizing NS2. Accordingly, knock down of OTUB1 by siRNA reduces the nuclear export of vRNP, and reduces the overall production of IAV. These results collectively demonstrate that the levels of NS2 in IAV-infected cells are regulated by a ubiquitination-deubiquitination system involving OTUB1 that is necessary for optimal IAV replication.

Nanoparticles for Augmenting Therapeutic Potential and Alleviating the Effect of Di(2-ethylhexyl) Phthalate on Gastric Cancer.

Changes in diet culture and modern lifestyle contributed to a higher incidence of gastrointestinal-related diseases, including gastritis, implicated in the pathogenesis of gastric cancer. This observation raised concerns regarding exposure to di(2-ethylhexyl) phthalate (DEHP), which is linked to adverse health effects, including reproductive and developmental problems, inflammatory response, and invasive adenocarcinoma. Research on the direct link between DEHP and gastric cancer is ongoing, and further studies are required to establish a conclusive association. In our study, extremely low concentrations of DEHP exerted significant effects on cell migration by promoting the epithelial-mesenchymal transition in gastric cancer cells. This effect was mediated by the modulation of the PI3K/AKT/mTOR and Smad2 signaling pathways. To address the DEHP challenges, our initial design of TPGS-conjugated fucoidan, delivered via pH-responsive nanoparticles, successfully demonstrated binding to the P-selectin protein. This achievement has not only enhanced the antigastric tumor efficacy but has also led to a significant reduction in the expression of malignant proteins associated with the condition. These findings underscore the promising clinical therapeutic potential of our approach.

Exploring the impact of culture techniques and patient demographics on the success rate of primary culture of human periodontal ligament stem cells.

Background/purpose: Periodontal ligament stem cells (PDLSCs) have the potential for regenerating periodontal tissue. The study aims to investigate the impact of demographics (ages, gender, disease) and culture techniques (shipping storage time and culture method) on the success of primary culture. Materials and methods: PDLSCs were collected from 51 teeth of 26 patients and cultured via outgrowth (OG) and enzymatic digestion (ED) methods. Cells characteristics were confirmed by flow cytometry, MTT, and ARS. The primary culture success rate was evaluated with a serial chi-square test to determine the relationship with culture technique (ED/OG and ≤4 h/prolonged culture) and patient demographics (Young/Old, Female/Male, and Health/Periodontitis). Results: The overall success rate of Health group (69.7%) was higher than Periodontitis (38.9%). Culturing within 4 h possessed a higher success rate (71.8%) than prolonged group (16.7%) regardless of patient demographics, and using OG method (81.5%) revealed more promising. Subgroup analysis of 39 cases (culture within 4 h) found that the success rate of OG was higher than ED in the Old group (87.5%-25.0%) and in the Periodontitis group (83.3%-25.0%). Conclusion: Primary culturing of PDLSCs within 4 h and using the outgrowth method led to higher success rates regardless of patient demographics. It can achieve successful PDLSCs culture of older patients or patients with periodontal disease by appropriate culture technique.

Helicobacter pylori eradication with high-dose proton pump inhibitor-amoxicillin dual therapy: A systematic review and meta-analysis.

BACKGROUND: Resistance of Helicobacter pylori to many antibiotics, which lowers the efficacy of eradication therapy, is increasingly prevalent. High-dose proton pump inhibitor (PPI)-amoxicillin dual therapy (HDDT) has been used for H. pylori eradication for years, and resistance to amoxicillin is relatively rare. Although many studies have compared the eradication rate of HDDT with that of guideline therapies, the reported efficacy of HDDT varies greatly and is inconsistent. AIMS: This study investigated the eradication rate and adverse effects of HDDT compared with the guidelines at the time of the study. METHODS: Several open public databases, including Cochrane, EMBASE, PubMed, and MEDLINE, were searched. The results of the current literature on the eradication and adverse event rates of HDDT compared with the latest recommended first-line therapies were analysed. Notably, 14 out of the 16 included studies were conducted in Asian regions. RESULTS: The eradication rate of HDDT was lower but not significantly different from those of control therapies (odds ratio [OR] = 0.92, 95% confidence interval [CI] = 0.67-1.26) in the intent-to-treat (ITT) analysis. A similar trend was observed in the per-protocol (PP) analysis (OR = 0.88, 95% CI = 0.47-1.63). Notably, the adverse effect risk in HDDT was significantly lower than in other therapies (I2 = 67.75%, OR = 0.42, 95% CI = 0.33-0.54, P = 0.00004). When the eradication rate of the control group was lower than 81%, HDDT was significantly better than control therapies (OR = 2.44, 95% CI = 1.23-4.84). CONCLUSION: HDDT used four times a day for 14 days showed better efficacy and safety than the guideline treatments for H. pylori infection in areas with high antimicrobial resistance.

Probiotic Lactobacillus spp. improves Drosophila memory by increasing lactate dehydrogenase levels in the brain mushroom body neurons.

Probiotics are live microorganisms that offer potential benefits to their hosts and can occasionally influence behavioral responses. However, the detailed mechanisms by which probiotics affect the behavior of their hosts and the underlying biogenic effects remain unclear. Lactic acid bacteria, specifically Lactobacillus spp. are known probiotics. Drosophila melanogaster, commonly known as the fruit fly, is a well-established model organism for investigating the interaction between the host and gut microbiota in translational research. Herein, we showed that 5-day administration of Lactobacillus acidophilus (termed GMNL-185) or Lacticaseibacillus rhamnosus (termed GMNL-680) enhances olfactory-associative memory in Drosophila. Moreover, a combined diet of GMNL-185 and GMNL-680 demonstrated synergistic effects on memory functions. Live brain imaging revealed a significant increase in calcium responses to the training odor in the mushroom body ß and γ lobes of flies that underwent mixed feeding with GMNL-185 and GMNL-680. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and whole-mount brain immunohistochemistry revealed significant upregulation of lactate dehydrogenase (LDH) expression in the fly brain following the mixed feeding. Notably, the genetic knockdown of Ldh in neurons, specifically in mushroom body, ameliorated the beneficial effects of mixed feeding with GMNL-185 and GMNL-680 on memory improvement. Altogether, our results demonstrate that supplementation with L. acidophilus and L. rhamnosus enhances memory functions in flies by increasing brain LDH levels.

p35/CDK5 Regulates Bladder Cancer Proliferation and Migration and Promotes Higher Tumor Grade and Poor Survival Rate in Patients With Bladder Cancer.

BACKGROUND/AIM: Bladder cancer remains a significant global health concern, necessitating a deeper understanding of the molecular mechanisms underlying its progression. Cyclin-Dependent Kinase 5 (CDK5) has recently emerged as a potential player in bladder cancer pathogenesis. This study investigated the involvement of CDK5 in bladder cancer, emphasizing its potential as a therapeutic target. MATERIALS AND METHODS: The expression levels of CDK5 and p35 (CDK5 regulatory protein) and their roles in the tumor grade and malignancy of patient samples were evaluated using western blot analysis and immunohistochemistry. In addition, tumor cancer genome atlas (TCGA) was utilized to evaluate survival rate in patients with bladder cancer. We further confirmed the role of CDK5 with in vitro experiments using western blot analysis, immunocytochemistry, cell culture-based proliferation and migration assays. RESULTS: Higher CDK5 and p35 were associated with a higher tumor grade and poor survival rate in patients with bladder cancer. To confirm the role of CDK5 in vitro, we over-expressed CDK5 in bladder cancer cells. The results showed that the over-expression of CDK5 enhanced bladder cancer cell proliferation and migration. In addition, CDK5 inhibition by a pan-CDK inhibitor, Roscovitine (RV), significantly reduced proliferation of bladder cancer cells. Indeed, the migration and adhesion of bladder cancer cells were inhibited by RV treatment. CONCLUSION: CDK5 might play important roles in bladder cancer progression and be a potential diagnostic and therapeutic target in the near future.

Molecular characterization of rifabutin-resistance in refractory Helicobacter pylori infection in Taiwan.

OBJECTIVES: To explore the molecular characteristics of rpoB, encoding ß-subunit of DNA-directed RNA polymerase, and unravel the link to rifabutin-resistance in patients with refractory Helicobacter pylori infection. METHODS: From January 2018-March 2021, a total of 1590 patients were screened for eligibility to participate in the study. Patients with refractory H. pylori infection were confirmed by using the (13C)-urea breath assay. All enrolled patients underwent esophagogastroduodenoscopy, and biopsies were taken for H. pylori culture and antibacterial susceptibility testing. Sequence analysis of rpoB was conducted for all rifabutin-resistant isolates. RESULTS: In total, 70 patients were diagnosed with refractory H. pylori infection, and 39 isolates were successfully cultured. Amongst, 10 isolates were identified as rifabutin-resistance and nine isolates exhibited at least one amino acid substitution in RpoB. Isolates with a minimal inhibitory concentration >32 mg/l displayed a higher number of mutational changes in RpoB than the others. Additionally, more amino acid substitutions in RpoB correlated with developing a higher minimal inhibitory concentration for H. pylori rifabutin-resistance. CONCLUSION: Our findings highlight the relationship between rifabutin-resistance in refractory H. pylori infection and specific mutations in RpoB, which will aid the clinical selection of appropriate antibacterial agents with better therapeutic effects.

Nanoparticle-enhanced postbiotics: Revolutionizing cancer therapy through effective delivery.

AIM: Gastric cancer contributes to cancer-related fatalities. Conventional chemotherapy faces challenges due to severe adverse effects, prompting recent research to focus on postbiotics, which are safer biomolecules derived from nonviable probiotics. Despite promising in vitro results, efficient in vivo delivery systems remain a challenge. This study aimed to design a potential nanoparticle (NP) formulation encapsulating the Lacticaseibacillus paracasei GMNL-133 (SGMNL-133) isolate to enhance its therapeutic efficacy in treating gastric cancer. MAIN METHODS: We successfully isolated GMNL-133 (SGMNL-133) by optimizing the lysate extraction and column elution processes for L. paracasei GMNL-133, resulting in substantial enhancement of its capacity to inhibit the proliferation of gastric cancer cells. Additionally, we developed a potential NP utilizing arginine-chitosan and fucoidan encapsulating SGMNL-133. KEY FINDINGS: This innovative approach protected the SGMNL-133 from degradation by gastric acid, facilitated its penetration through the mucus layer, and enabled interaction with gastric cancer cells. Furthermore, in vivo experiments demonstrated that the encapsulation of SGMNL-133 in NPs significantly enhanced its efficacy in the treatment of orthotopic gastric tumors while simultaneously reducing tissue inflammation levels. SIGNIFICANCE: Recent research highlights postbiotics as a safe alternative, but in vivo delivery remains a challenge. Our study optimized the extraction of the lysate and column elution of GMNL-133, yielding SGMNL-133. We also developed NPs to protect SGMNL-133 from gastric acid, enhance mucus penetration, and improve the interaction with gastric cancer cells. This combination significantly enhanced drug delivery and anti-gastric tumor activity.

Clostridium innocuum, an emerging pathogen that induces lipid raft-mediated cytotoxicity.

Clostridium innocuum is an emerging spore-forming anaerobe that is often observed in Clostridioides difficile-associated inflammatory bowel disease (IBD) exacerbations. Unlike C. difficile, C. innocuum neither produces toxins nor possesses toxin-encoding genetic loci, but is commonly found in both intestinal and extra-intestinal infections. Membrane lipid rafts are composed of dynamic assemblies of cholesterol and sphingolipids, allowing bacteria to gain access to cells. However, the direct interaction between C. innocuum and lipid rafts that confers bacteria the ability to disrupt the intestinal barrier and induce pathogenesis remains unclear. In this study, we investigated the associations among nucleotide-binding oligomerization domain containing 2 (NOD2), lipid rafts, and cytotoxicity in C. innocuum-infected gut epithelial cells. Our results revealed that lipid rafts were involved in C. innocuum-induced NOD2 expression and nuclear factor (NF)-κB activation, triggering an inflammatory response. Reducing cholesterol by simvastatin significantly dampened C. innocuum-induced cell death, indicating that the C. innocuum-induced pathogenicity of cells was lipid raft-dependent. These results demonstrate that NOD2 mobilization into membrane rafts in response to C. innocuum-induced cytotoxicity results in aggravated pathogenicity.

Suppressive Effects of Lactobacillus on Depression through Regulating the Gut Microbiota and Metabolites in C57BL/6J Mice Induced by Ampicillin.

Depression is a medical and social problem. Multiple metabolites and neuroinflammation regulate it. Modifying the gut microbiota with probiotics to reduce depression through the gut-brain axis is a potential treatment strategy. In this study, three anti-depressive potentials of Lactobacillus spp. (LAB), including L. rhamnosus GMNL-74, L. acidophilus GMNL-185 and L. plantarum GMNL-141, which combined to produce low dosage LAB (1.6 × 108 CFU/mouse, LABL) and high dosage LAB (4.8 × 108 CFU/mouse, LABH), were administered to C57BL/6 mice induced depression by ampicillin (Amp). A behavioral test of depression, 16S ribosomal RNA gene amplicon sequencing, bioinformatic analysis, and short-chain fatty acid (SCFA) content measurement were executed to investigate the gut microbiota composition, activation of nutrient metabolism pathways, levels of inflammatory factors, gut-derived 5-HT biosynthesis genes, and SCFA levels in C57BL/6 mice. Results showed that after mice were induced by Amp, both LAB groups recovered from depressive behaviors, decreased the abundance of Firmicutes, and increased the abundance of Actinobacteria and Bacteroidetes in the mouse ileum. The prediction of metabolism pathways of microbes revealed the activation of arginine and proline metabolism, cyanoamino acid metabolism, and nicotinate and nicotinamide metabolism were increased, and fatty acid synthesis was decreased in both LAB groups. The LABH groups showed increased levels of acetic acid, propanoic acid, and iso-butyric acid and decreased butyric acid levels in the cecum. LABH treatment increased claudin-5 and reduced IL-6 mRNA expression. Both LAB groups also reduced monoamine oxidase, and the LABH group increased vascular endothelial growth factor mRNA expression. These results showed that the composite of three LAB exerts antidepressant effects by regulating the gut microbiota and modifying the levels of depression-related metabolites in C57BL/6J Amp-treated mice.

RopB represses the transcription of speB in the absence of SIP in group A Streptococcus.

RopB is a quorum-sensing regulator that binds to the SpeB-inducing peptide (SIP) under acidic conditions. SIP is known to be degraded by the endopeptidase PepO, whose transcription is repressed by the CovR/CovS two-component regulatory system. Both SIP-bound RopB (RopB-SIP) and SIP-free RopB (apo-RopB) can bind to the speB promoter; however, only RopB-SIP activates speB transcription. In this study, we found that the SpeB expression was higher in the ropB mutant than in the SIP-inactivated (SIP*) mutant. Furthermore, the deletion of ropB in the SIP* mutant derepressed speB expression, suggesting that apo-RopB is a transcriptional repressor of speB Up-regulation of PepO in the covS mutant degraded SIP, resulting in the down-regulation of speB We demonstrate that deleting ropB in the covS mutant derepressed the speB expression, suggesting that the speB repression in this mutant was mediated not only by PepO-dependent SIP degradation but also by apo-RopB. These findings reveal a crosstalk between the CovR/CovS and RopB-SIP systems and redefine the role of RopB in regulating speB expression in group A Streptococcus.

Clostridium scindens metabolites trigger prostate cancer progression through androgen receptor signaling.

Prostate cancer (PCa) is one of the most common malignancies in men; recently, PCa-related mortality has increased worldwide. Although androgen deprivation therapy (ADT) is the standard treatment for PCa, patients often develop aggressive castration-resistant PCa (CRPC), indicating the presence of an alternative source of androgen. Clostridium scindens is a member of the gut microbiota and can convert cortisol to 11ß-hydroxyandrostenedione (11ß-OHA), which is a potent androgen precursor. However, the effect of C. scindens on PCa progression has not been determined. In this study, androgen-dependent PCa cells (LNCaP) were employed to investigate whether C. scindens-derived metabolites activate androgen receptor (AR), which is a pivotal step in the development of PCa. Results showed that cortisol metabolites derived from C. scindens-conditioned medium promoted proliferation and enhanced migration of PCa cells. Furthermore, cells treated with these metabolites presented activated AR and stimulated AR-regulated genes. These findings reveal that C. scindens has the potential to promote PCa progression via the activation of AR signaling. Further studies on the gut-prostate axis may help unravel an alternative source of androgen that triggers CRPC exacerbation.

Multiple amino acid substitutions in penicillin-binding protein-1A confer amoxicillin resistance in refractory Helicobacter pylori infection.

BACKGROUND: Amoxicillin resistance in Helicobacter pylori is mainly associated with mutations in penicillin-binding protein-1A (PBP-1A). However, the specific amino acid substitutions in PBP-1A that confer amoxicillin resistance in H. pylori remain to be investigated. OBJECTIVE: This study aimed to investigate the molecular mechanism underlying amoxicillin resistance in patients with refractory H. pylori infection. METHODS: Esophagogastroduodenoscopy (EGD) was performed in patients with persistent H. pylori infection after at least two courses of H. pylori eradication therapy between January-2018 to March-2021. Refractory H. pylori was cultured from the gastric biopsy specimens. Antibiotic susceptibility testing was conducted to determine the minimum inhibitory concentrations (MICs). Sequence analysis of pbp-1A was performed for amoxicillin-resistant strains. RESULTS: Thirty-nine successfully cultured isolates were classified as refractory H. pylori isolates, and seventeen isolates were resistant to amoxicillin (MIC > 0.125 mg/L). Sequence analysis of resistant strains showed multiple mutations in the C-terminal region of PBP-1A that conferred amoxicillin resistance in H. pylori. However, the number of PBP-1A mutations did not correlate with the high MICs of amoxicillin-resistant isolates. Notably, some amino acid substitutions were identified in all Taiwanese isolates with history of eradication failure but not in published amoxicillin-susceptible strains, suggesting that the mutations may play a role in conferring antibiotic resistance to these strains. CONCLUSIONS: Our results show that amoxicillin resistance in refractory H. pylori is highly correlated with numerous PBP-1A mutations that are strain specific. Continuous improvements in diagnostic tools, particularly molecular analysis approaches, can help to optimize current antimicrobial regimens.

Gastroprotective Effect of Anisomeles indica on Aspirin-Induced Gastric Ulcer in Mice.

Gastric ulcers are commonly seen in the upper gastrointestinal tract and may be related to the Helicobacter pylori infection and the use of aspirin, a nonsteroidal anti-inflammatory drug (NSAID). Typically, proton-pump inhibitors (PPIs) are used to treat gastric ulcers; however, adverse effects have emerged following long-term treatment. Natural medicines are used as alternative therapeutic agents in the treatment of gastric ulcers, with few side effects. Despite various reports on the anti-H. pylori and anti-gastric cancer activities of Anisomeles indica, its gastroprotective effect on ulcers remains undetermined. This study investigated the protective effect of A. indica on aspirin-induced gastric ulcers in murine models. Our results show that three fractions of ethanol-extracted A. indica inhibited aspirin-induced gastric injury. Among these, A. indica Fraction 1 was observed to enrich ovatodiolide, which effectively diminished gastric acidity and alleviated aspirin-induced inflammation in the stomach. Our results provide evidence that A. indica could be developed as an effective therapeutic agent for gastroprotective purposes.

Antrodia salmonea Extracts Regulate p53-AR Signaling and Apoptosis in Human Prostate Cancer LNCaP Cells.

Antrodia salmonea (AS) is a genus of Antrodia, an epiphyte of Cunninghamia konishii in Taiwan. AS has been reported to have potential therapeutic effects on different diseases, including diarrhea, abdominal pain, and hypertension. AS has been reported to have anticancer effects on numerous cancer types, such as ovarian carcinoma and triple-negative breast cancer. Our previous studies demonstrated that antrocins and triterpenoids are possibly bioactive compositions. However, the effects of AS on prostate cancer remain unknown. Therefore, we investigated the role of AS in prostate cancer growth, apoptosis, and cell cycle regulation. The results showed that AS extracts significantly inhibited the proliferation of prostate cancer LNCaP cells in a dose-dependent manner and increased the levels of apoptotic markers (cleaved PARP and cleaved caspase 3/8/9). In addition, the cell cycle-related proteins CDK1, CDK2, CDK4, and their respective specific regulators Cyclin B1, Cyclin A, and Cyclin D were also affected. Besides, AS treatment increased p53 protein levels and slowed its degradation in LNCaP cells. Interestingly, we found that AS treatment reduced both total protein and Ser-81 phosphorylation levels of the androgen receptor (AR). Notably, the increase of nuclear p53 was accompanied by the down-regulation of AR, suggesting a reverse regulation between p53 and AR in LNCaP cells was triggered by AS treatment. These findings suggest that AS extracts trigger the apoptosis of prostate cancer cells through the reverse regulation of p53 and AR and elucidate that AS extracts might be a potential treatment for androgen-dependent prostate cancer in the near future.

Mechanism Underlying Metformin Action and Its Potential to Reduce Gastric Cancer Risk.

Diabetes mellitus is associated with a high risk of developing gastric cancer (GC). Metformin, which is conventionally used to treat type 2 diabetes, induces AMP-activated protein kinase signaling and suppresses gluconeogenesis. Recent studies have reported that metformin is associated with beneficial effects in cancer prevention and treatment owing to its anti-tumor effects. This makes metformin a potential medication for GC therapy. However, contradicting reports have emerged regarding the efficacy of metformin in reducing the risk of GC. This review summarizes the impact of metformin on mitigating GC risk by analyzing clinical databases. The mechanism underlying the anti-tumor effect of metformin on GC is also discussed.