Licochalcone a improves cardiac functions after ischemia-reperfusion via reduction of ferroptosis in rats.

Myocardial ischemia-reperfusion (I/R) injury triggers several cell death types, including apoptosis, autophagy, and ferroptosis. Licochalcone A (LCA), a natural flavonoid compound isolated from the root of Glycyrrhiza glabra, has been demonstrated to exert potential pharmacological benefits, such as antioxidant, antitumor, and anti-inflammatory activities. The present study aimed to investigate the involvement of ferroptosis in the pathogenesis of I/R and determine whether LCA can inhibit ferroptosis to prevent the myocardial I/R injury in rats. The effects of LCA on myocardial I/R injury were detected by examining the left ventricular-developed pressure and triphenyltetrazolium chloride staining. We conducted Western blotting analyses, ELISA assay, and quantitative real-time PCR to determine the levels of ferroptosis-related molecules. To demonstrate the cardioprotective effect of LCA in vitro, H9c2 and primary neonatal rat cardiomyocytes were co-treated with ferroptosis inducers (erastin, RSL3, or Fe-SP) and LCA for 16 and 24 h. Our ex vivo study showed that LCA increased the cardiac contractility, and reduced the infarct volume and ferroptosis-related biomarkers in rat hearts after I/R. Moreover, LCA reduced the levels of ferroptosis inducers-induced reactive oxygen species generation, lipid peroxidation, and ferroptosis-related biomarkers in cultured H9c2 cells and cardiomyocytes. LCA also reduced the Fe-SP-increased nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 protein levels in cultured cardiomyocytes. In the present study, we showed that the LCA-induced cardioprotective effects in attenuating the myocardial I/R injury were correlated with ferroptosis regulation, and provided a possible new therapeutic strategy for prevention or therapy of the myocardial I/R injury.

Addressing Unmet Needs in Vaccination for Older Adults in the Asia Pacific: Insights from the COVID-19 Pandemic.

The impact of vaccinating the older population against vaccine-preventable diseases in terms of health, social and economic benefits has been increasingly recognised. However, there is a gap in the utilisation of vaccines worldwide. The population is ageing at an unprecedented pace in the Asia-Pacific (APAC) region, with the number of persons older than 65 years set to double by 2050 to around 1.3 billion. More than 18% of the population in Japan, Hong Kong, and China is over the age of 65 years. This highlights the importance of prioritising resources to address societal obligations toward the needs of the ageing generation. This review provides an overview of the challenges to adult vaccination in APAC, drivers to increase vaccination coverage, vaccination insights gained through the COVID-19 pandemic, and potential measures to increase the uptake of adult vaccines in the region.

Palmitic acid methyl ester induces cardiac hypertrophy through activating the GPR receptor-mediated changes of intracellular calcium concentrations and mitochondrial functions.

Myocardial hypertrophy is associated with a significant increase in intracellular Ca2+ , which can be induced by long-chain fatty acid. Palmitic acid methyl ester (PAME), a fatty acid ester released from adipose tissue, superior cervical ganglion, and retina, has been found to have anti-inflammation, antifibrosis, and peripheral vasodilation effects. However, the effects of PAME on cardiomyocytes are still unclear. The aim of this study was to determine whether PAME could disrupt the intracellular Ca2+ balance, leading to cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were treated with various concentrations (10-100 µM) of PAME for 1-4 days. Cytosolic Ca2+ and mitochondrial Ca2+ concentrations were examined using Fura-2 AM and Rhod-2, respectively. After treatment with PAME for 4 days, mitochondrial Ca2+ , an indicator of the state of mitochondrial permeability transition pore (MPTP), and cell death were monitored by flow cytometric analysis. ATP levels were detected using the ATP assay kit. Cardiomyocyte hypertrophy was analyzed by measuring the cardiac hypertrophy biomarker and cell area using quantitative real time-polymerase chain reaction, Western Blot analysis and immunofluorescence analysis. Our results show that PAME concentration- and time-dependently increased cytosolic and mitochondria Ca2+ through the mitochondrial calcium uniporter. Moreover, treatment with PAME for 4 days caused MPTP opening, thereby reducing ATP production and enhancing reactive oxygen species (ROS) generation, and finally led to cardiomyocyte hypertrophy. These effects caused by PAME treatment were attenuated by the G-protein coupled receptor 40 (GPR40) inhibitor. In conclusion, PAME impaired mitochondrial function, which in turn led to cardiomyocyte hypertrophy through increasing the mitochondrial Ca2+ levels mediated by activating the GPR40 signaling pathway.

Activation of progesterone receptor is essential for folic acid-regulated cancer cell proliferation and migration.

We previously demonstrated that activation of progesterone receptor (PR) is essential for folic acid (FA)-inhibited proliferation in colorectal cancer cell lines. In the present study, we further investigated whether the requirement of PR activation for the FA-regulated cell proliferation and migration is a general phenomenon for all cancer cell lines or specific for colorectal cancer cell lines only. Initially, we examined the expression of PR in various cancer cell lines using Western blot analyses and RT-PCR technique, and then investigated the effects of FA on these cancer cell lines. Our data showed that the effects of FA on proliferation and migration only occurred in the PR positive (+) cancer cell lines, but not the PR negative (-) cancer cell lines, and these effects were abolished by pre-treatment with the PR specific inhibitor, Org 31710. On the other hand, FA significantly reduced the proliferation and migration in the PR (-) cancer cell lines transfected with PR pcDNA. However, FA did not significantly affect the proliferation and migration in the PR-transefected Hep-3B cell line, which does not express endogenous PR and FA receptor (FR). Since we previously showed that FA-regulated proliferation in colorectal and breast cancer cell lines through the cSrc-mediated pathway, we conducted immunoprecipitation assay to demonstrate that PR formed a complex with FR and cSrc, but FR did not directly associate with cSrc. Taken together, these findings suggest that the requirement of PR activation for the FA-regulated cell proliferation and migration is a general phenomenon for all cancer cell lines.

Baicalein and luteolin inhibit ischemia/reperfusion-induced ferroptosis in rat cardiomyocytes.

BACKGROUND: Ischemia/reperfusion (I/R) is associated with severe cellular damage and death. Ferroptosis, a new form of regulated cell death caused by the accumulation of iron-mediated lipid peroxidation, has been found in several diseases including I/R injury, which was reported to be suppressed by flavonoids. Baicalein (BAI) and luteolin (Lut) are flavonoids and were shown to reduce the myocardial I/R injury. BAI was found to suppress ferroptosis in cancer cells via reducing reactive oxygen species (ROS) generation. However, the anti-ferroptosis effect of Lut on ferroptosis has not been reported. This study aimed to investigate whether ferroptosis reduction contributes to the BAI- and Lut-protected cardiomyocytes. METHODS: This research used erastin, RSL3, and Fe-SP to induce ferroptosis. Cell viability was examined using MTT assay. Annexin V-FITC, CM-H2DCFDA, and Phen Green SK diacetate (PGSK) fluorescent intensity were detected to analyze apoptotsis, ROS levels, and Fe2+ concentrations, respectively. qPCR and Western blot analysis were conducted to detect the levels of mRNA and protein, respectively. RESULTS: Our data show that BAI and Lut protected cardiomyocytes against ferroptosis caused by ferroptosis inducers and I/R. Moreover, both BAI and Lut decreased ROS and malondialdehyde (MDA) generation and the protein levels of ferroptosis markers, and restored Glutathione peroxidase 4 (GPX4) protein levels in cardiomyocytes reduced by ferroptosis inducers. BAI and Lut reduced the I/R-induced myocardium infarction and decreased the levels of Acsl4 and Ptgs2 mRNA. CONCLUSIONS: BAI and Lut could protect the cardiomyocytes against the I/R-induced ferroptosis via suppressing accumulation of ROS and MDA.

Xanthohumol Protects the Rat Myocardium against Ischemia/Reperfusion Injury-Induced Ferroptosis.

Ferroptosis is an iron-dependent form of cell death caused by the inactivation of glutathione peroxidase 4 (GPX4) and accumulation of lipid peroxides. Ferroptosis has been found to participate in the ischemia-reperfusion (I/R) injury, leading to heart dysfunction and myocardial cell death. Xanthohumol (XN), a prenylated flavonoid isolated from Humulus lupulus, has multiple pharmacological activities, such as anti-inflammatory and antioxidant. This study is aimed at investigating whether XN could attenuate the I/R-induced ferroptosis in cardiomyocytes and the underlying mechanisms. Cardiomyocytes were treated with Fe-SP and RSL3, and the rat hearts were treated with I/R. The results from the present study show that XN was able to protect cardiomyocytes against Fe-SP- and RSL3-induced ferroptotic cell death by decreasing the production of lipid peroxidation and ROS, chelating iron, reducing the NRF2 protein level, and modulating the protein levels of GPX4. Moreover, XN significantly decreased the mRNA levels of ferroptosis markers, Ptgs2 and Acsl4, and the protein levels of ACSL4 and NRF2 and modulated the protein levels of GPX4 in I/R-treated hearts. The findings from the present study suggest that XN might have the therapeutic potential for the I/R-induced ferroptosis injury.

Analysis of Fungal and Bacterial Co-Infections in Mortality Cases among Hospitalized Patients with COVID-19 in Taipei, Taiwan.

Fungal or bacterial co-infections in patients with H1N1 influenza have already been reported in many studies. However, information on the risk factors, complications, and prognosis of mortality cases with coronavirus disease 2019 (COVID-19) are limited. We aimed to assess 36 mortality cases of 178 hospitalized patients among 339 patients confirmed to have had SARS-CoV-2 infections in a medical center in the Wenshan District of Taipei, Taiwan, between January 2020 and September 2021. Of these 36 mortality cases, 20 (60%) were men, 28 (77.7%) were aged >65 years, and the median age was 76 (54-99) years. Comorbidities such as hypertension, coronary artery disease, and chronic kidney disease were more likely to be found in the group with length of stay (LOS) > 7 d. In addition, the laboratory data indicating elevated creatinine-phosphate-kinase (CPK) (p < 0.001) and lactic acid dehydrogenase (LDH) (p = 0.05), and low albumin (p < 0.01) levels were significantly related to poor prognosis and mortality. The respiratory pathogens of early co-infections (LOS < 7 d) in the rapid progression to death group (n = 7 patients) were two bacteria (22.2%) and seven Candida species (77.8.7%). In contrast, pathogens of late co-infections (LOS > 7 d) (n = 27 patients) were 20 bacterial (54.1%), 16 Candida (43.2%), and only 1 Aspergillus (2.7%) species. In conclusion, the risk factors related to COVID-19 mortality in the Wenshan District of Taipei, Taiwan, were old age, comorbidities, and abnormal biomarkers such as low albumin level and elevated CPK and LDH levels. Bacterial co-infections are more common with Gram-negative pathogens. However, fungal co-infections are relatively more common with Candida spp. than Aspergillus in mortality cases of COVID-19.

A Retrospective Study of the Safety and Immunogenicity of MVC-COV1901 Vaccine for People Living with HIV.

BACKGROUND: This study aimed to assess the safety and immunogenicity of MVC-COV1901, a recombinant COVID-19 protein vaccine, containing S-2P protein adjuvanted with CpG 1018 and aluminum hydroxide, for people living with HIV (PWH). METHODS: A total of 57 PWH of ≥20 years of age who are on stable antiretroviral therapy were compared with 882 HIV-negative participants. Participants received two doses of MVC-COV1901 28 days apart. RESULTS: No vaccine-related serious adverse events (SAEs) were recorded. Seroconversion rates (SCRs) of 100% and 99.8% were achieved in PWH and comparators, respectively, 28 days after the second dose. After adjusting for sex, age, BMI category, and comorbidity, the adjusted GMT ratio of comparator/PWH was 3.2 (95% CI 2.5-4). A higher CD4/CD8 ratio was associated with a higher GMT (R = 0.27, p = 0.039). MVC-COV1901 has shown robust safety but elicited weaker immune responses in PWH. CONCLUSIONS: Further investigations may be needed to determine whether PWH require distinct immunization strategies with improved immunogenicity. The main study is registered at ClinicalTrials.gov (NCT04695652).

Multicenter surveillance of in vitro activities of cefepime-zidebactam, cefepime-enmetazobactam, omadacycline, eravacycline, and comparator antibiotics against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex causing bloodstream infection in Taiwan, 2020.

OBJECTIVES: To determine the in vitro activities of novel and comparator antibiotics against Gram-negative bacteria (GNB) in Taiwan. METHODS: Isolates of Escherichia coli (n = 335), Klebsiella pneumoniae (n = 316; 144 isolates with hyperviscosity characteristics), Pseudomonas aeruginosa (n = 271), Acinetobacter baumannii complex (n = 187), and non-typhoidal Salmonella species (n = 226), Shigella species (n = 13) from miscellaneous culture sources were collected in 2020 in Taiwan. The MICs of the isolates to test antibiotics were determined using the broth microdilution method. GeneXpert was used to detect genes encoding carbapenemases among the carbapenem-non-susceptible (NS) Enterobacterales isolates. RESULTS: The MIC values of the cefepime-enmetazobactam combination against extended-spectrum ß-lactamase-producing E. coli and K. pneumoniae isolates (MIC90 ≤ 0.5 mg/L), blaKPC-harboring E. coli isolates (0.25 mg/L; n = 2), and 80% of blaOXA-48-like gene-harboring K. pneumoniae isolates (≤2 mg/L) were low. The MIC ranges of the cefepime-zidebactam against carbapenemase-producing Enterobacterales isolates (irrespective of the carbapenemase type [MIC90 ≤ 4 mg/L]) and carbapenem-NS or ceftolozane-tazobactam-NS P. aeruginosa isolates (MIC90 value, 8 mg/L) were significantly lower than those of the cefepime-enmetazobactam. CONCLUSIONS: The efficacy of novel antibiotics against important drug-resistant GNB must be monitored and validated during the clinical treatment of patients.

Cytomegalovirus proctitis in non-human immunodeficiency virus infected patients: A case report and literature review.

Cytomegalovirus (CMV) infection is associated with significant morbidity and mortality in both immunocompetent and immunocompromised patients. CMV is a ubiquitous Herpesviridae virus with a wide spectrum of pathologies in humans. Immunocompetent patients generally develop a benign, self-limited mononucleosis-like syndrome, whereas gastrointestinal tissue-invasive disease is more frequently seen in immunocompromised. The clinical manifestations of CMV colitis or proctitis are demarcated by bloody diarrhea, ulcerations, ulcero-infiltrative changes, and pseudomembranous formation on colonoscopy. Gastrointestinal CMV infections complicated with deep rectal ulcer and fistula formation are rare in patients with systemic lupus erythematosus. Ganciclovir is also the gold standard therapy for CMV colitis or proctitis.

In vitro activity of cefiderocol, cefepime/enmetazobactam, cefepime/zidebactam, eravacycline, omadacycline, and other comparative agents against carbapenem-non-susceptible Pseudomonas aeruginosa and Acinetobacter baumannii isolates associated from bloodstream infection in Taiwan between 2018-2020.

BACKGROUND/PURPOSE: This study aimed to investigate the in vitro susceptibilities of carbapenem-non-susceptible Pseudomonas aeruginosa (CNSPA) and Acinetobacter baumannii (CNSAB) isolates to cefiderocol, novel ß-lactamase inhibitor (BLI) combinations, new tetracycline analogues, and other comparative antibiotics. METHODS: In total, 405 non-duplicate bacteremic CNSPA (n = 150) and CNSAB (n = 255) isolates were collected from 16 hospitals in Taiwan between 2018 and 2020. Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method, and susceptibilities were interpreted according to the relevant guidelines or in accordance with results of previous studies and non-species-related pharmacokinetic/pharmacodynamic data. RESULTS: Among the isolates tested, cefiderocol demonstrated potent in vitro activity against CNSPA (MIC50/90, 0.25/1 mg/L; 100% of isolates were inhibited at ≤4 mg/L) and CNSAB (MIC50/90, 0.5/2 mg/L; 94.9% of isolates were inhibited at ≤4 mg/L) isolates. More than 80% of CNSPA isolates were susceptible to cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, and amikacin, based on breakpoints established by the Clinical and Laboratory Standards Institute. Activities of new BLI combinations varied significantly. Tetracycline analogues, including tigecycline (MIC50/90, 1/2 mg/L; 92.5% of CNSAB isolates were inhibited at ≤2 mg/L) and eravacycline (MIC50/90, 0.5/1 mg/L; 99.6% of CNSAB isolates were inhibited at ≤2 mg/L) exhibited more potent in vitro activity against CNSAB than omadacycline (MIC50/90, 4/8 mg/L). CONCLUSIONS: The spread of CNSPA and CNSAB poses a major challenge to global health. Significant resistance be developed even before a novel agent becomes commercially available. The development of on-site antimicrobial susceptibility tests for these novel agents is of great clinical importance.

Nationwide surveillance of antimicrobial resistance in invasive isolates of Streptococcus pneumoniae in Taiwan from 2017 to 2019.

BACKGROUND/PURPOSE: Streptococcus pneumoniae causes pneumonia and other invasive diseases, and is a leading cause of mortality in the elderly population. The present study aimed to provide current antimicrobial resistance and epidemiological profiles of S. pneumoniae infections in Taiwan. METHODS: A total of 252 nonduplicate S. pneumoniae isolates were collected from patients admitted to 16 hospitals in Taiwan between January 2017 and December 2019, and were analyzed. The minimum inhibitory concentration of antibiotics was determined using the Vitek 2 automated system for antimicrobial susceptibility testing. Furthermore, epidemiological profiles of S. pneumoniae infections were analyzed. RESULTS: Among the strains analyzed, 88% were recognized as invasive pneumococcal strains. According to the Clinical and Laboratory Standards Institute criteria for non-meningitis, the prevalence of penicillin-non-susceptible S. pneumoniae demonstrated a declining trend from 43.6% in 2017 to 17.2% in 2019. However, the rate of penicillin-non-susceptible S. pneumoniae was 85.7% based on the criteria for meningitis. Furthermore, the prevalence of ceftriaxone-non-susceptible S. pneumoniae was 62.7% based on the criteria for meningitis. Isolates demonstrated higher susceptibility toward doripenem and ertapenem than toward meropenem and imipenem. An increased rate of non-susceptibility toward levofloxacin was observed in southern Taiwan (15.1%) and elderly patients (≥65 years; 11.4%). Most isolates were susceptible to vancomycin and linezolid. CONCLUSION: Empirical treatment with ceftriaxone monotherapy for pneumococcal meningitis should be carefully monitored owing to its high non-susceptibility rate. The susceptibility rates of most isolates to penicillin (used for treating non-meningitis pneumococcal diseases), carbapenems (ertapenem and doripenem), respiratory quinolones (moxifloxacin and levofloxacin), vancomycin, and linezolid suggested the potential of these antibiotics in treating pneumococcal diseases in Taiwan.

Cancer as an infectious disease: A different treatment alternative using a combination of tigecycline and pyrvinium pamoate - An example of breast cancer.

BACKGROUND: Tigecycline is an antibiotic that well tolerated for treating complicated infections. It has received attention as an anti-cancer agent and expected to solve two major obstacles, sides effects that accompany chemotherapy and drug resistance, in the breast cancer treatment. However, previous studies reported that the levels in the blood are typically low of tigecycline, so higher doses are needed to treat cancer, that may increase the risk of side effects. To achieve better anti-cancer effects for tigecycline, we need to find a novel adjunct agent. METHODS: In this study, we used different concentration of pyrvinium pamoate combined with tigecycline to treat cell. And assess the effect of two drugs in inhibit cell proliferation, induce cell autophagy, or increase cell apoptosis to evaluate the consequent of combined therapy. RESULTS: We observed that after the combined therapy, the cell cycle arrest at G1/s phase, the level of p21 increased, but decreased the levels of CDK2. Others, two drugs via different mechanisms to inhibit cancer cell proliferation and with selective cytotoxic to different cell lines. That could enhance the effect of breast cancer treatment. CONCLUSION: Combining low dose of tigecycline use with pyrvinium pamoate is a novel approach for breast cancer treatment. Appropriate combined therapy in breast cancer is recommended to improve outcomes. Other problems like drug resistance occur in patients or the microbes surrounding breast tissues would confer susceptibility to cancers then influence the effectiveness of treatment, which could be improved through combined therapy.