Mechanism of action of Orthosiphon stamineus against non-alcoholic fatty liver disease: Insights from systems pharmacology and molecular docking approaches

Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of a metabolic syndrome caused by excessive accumulation of fat in the liver. Orthosiphon stamineus also known as Orthosiphon aristatus is a medicinal plant with possible potential beneficial effects on various metabolic disorders. This study aims to investigate the in vitro inhibitory effects of O. stamineus on hepatic fat accumulation and to further use the computational systems pharmacology approach to identify the pharmacokinetic properties of the bioactive compounds of O. stamineus and to predict their molecular mechanisms against NAFLD. Methods: The effects of an ethanolic extract of O. stamineus leaves on cytotoxicity, fat accumulation and antioxidant activity were assessed using HepG2 cells. The bioactive compounds of O. stamineus were identified using LC/MS and two bioinformatics databases, namely the Traditional Chinese Medicine Integrated Database (TCMID) and the Bioinformatics Analysis Tool for the Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). Pathway enrichment analysis was performed on the predicted targets of the bioactive compounds to provide a systematic overview of the molecular mechanism of action, while molecular docking was used to validate the predicted targets. Results: A total of 27 bioactive compounds corresponding to 50 potential NAFLD-related targets were identified. O. stamineus exerts its anti-NAFLD effects by modulating a variety of cellular processes, including oxidative stress, mitochondrial β-oxidation, inflammatory signalling pathways, insulin signalling, and fatty acid homeostasis pathways. O. stamineus is significantly targeting many oxidative stress regulators, including JNK, mammalian target of rapamycin (mTOR), NFKB1, PPAR, and AKT1. Molecular docking analysis confirmed the expected high affinity for the potential targets, while the in vitro assay indicates the ability of O. stamineus to inhibit hepatic fat accumulation. Conclusion: Using the computational systems pharmacology approach, the potentially beneficial effect of O. stamineus in NAFLD was indicated through the combination of multiple compounds, multiple targets, and multicellular components.     

Effect of gender on the reliability of COVID-19 rapid antigen test among elderly

Defining con-founders that affect the reliability of diagnostic tests for coronavirus disease 2019 is vital to breaking the chain of infection. The elderly population is a higher risk group for the emerging virus. However, gender seems to exert a critical role in modifying the infection risk among women owing to hormonal changes. The menopause transition is an exceptional period for older women where the protective and immunomodulatory effects of the estrogen hormone are lost. Accordingly, attention should be given to postmenopausal women since they will have an increased risk compared to their pre-menopausal peers.     

The impact of the updated EORTC/MSG criteria on the classification of hematological patients with suspected invasive pulmonary aspergillosis

ObjectivesOur aim was to evaluate the effect of the updated European Organization for Research and Treatment of Cancer (EORTC) and Mycoses Study Group 2019 definitions for invasive pulmonary aspergillosis (IPA) on patient classification and the related all-cause 12-week mortality.MethodsIn this retrospective cohort study from our tertiary care centre, we reclassified patients with haematological malignancy who underwent bronchoalveolar lavage between 2014 and 2019 for suspected IPA using the novel EORTC 2019 criteria. We performed receiver operating characteristic curve analysis to define the optimal cut-off for positive PCR and galactomannan and present survival analyses and their possible association with these diagnostic criteria through post hoc comparisons with log rank and Cox regression.ResultsFrom 323 episodes of suspected IPA in 282 patients, 73 were reclassified: 31 (42.5%) from possible to probable IPA, 5 (6.8%) from EORTC criteria not met to probable IPA, and 37 (50.7%) from EORTC criteria not met to possible IPA. Probable IPA increased therefore 11.1% (64/323, 19.8% to 100/323, 30.9%), mostly due to positive PCR (31/36, 86.1%). There was no difference in mortality between newly defined possible and probable IPA (log rank p = 0.950). Mortality was higher in probable cases with lower cycle thresholds (Ct values) versus higher Ct values (p = 0.004). Receiver operating characteristic curve analysis showed an optimal Ct value cut-off of 36.8 with a sensitivity of 75% (95% CI 64.9%–85.1%) and a specificity of 61.7% (95% CI 53.5–69.9) for 12-week mortality.DiscussionThe new EORTC criteria led to 11.1% more probable IPA diagnoses, mostly due to Aspergillus PCR. Restricting positive PCR to below a certain threshold might improve the discrimination of the new EORTC IPA categories for mortality.     

Double deficiency of cathepsin B and L in the mouse pancreas alters trypsin activity without affecting acute pancreatitis severity

BackgroundPremature intracellular trypsinogen activation has long been considered a key initiator of acute pancreatitis (AP). Cathepsin B (CTSB) activates trypsinogen, while cathepsin L (CTSL) inactivates trypsin(ogen), and both proteins play a role in the onset of AP.MethodsAP was induced by 7 hourly intraperitoneal injections of cerulein (50 μg/kg) in wild-type and pancreas-specific conditional Ctsb knockout (Ctsb^Δpan), Ctsl knockout (Ctsl^Δpan), and Ctsb;Ctsl double-knockout (Ctsb^Δpan;Ctsl^Δpan) mice. Pancreatic samples were collected and analyzed by histology, immunohistochemistry, real-time PCR, and immunoblots. Trypsin activity was measured in pancreatic homogenates. Peripheral blood was collected, and serum amylase activity was measured.ResultsDouble deletion of Ctsb and Cstl did not affect pancreatic development or mouse growth. After 7 times cerulein injections, double Ctsb and Ctsl deficiency in mouse pancreases increased trypsin activity to the same extent as that in Ctsl-deficient mice, while Ctsb deficiency decreased trypsin activity but did not affect the severity of AP. Ctsb^Δpan;Ctsl^Δpan mice had comparable serum amylase activity and histopathological changes and displayed similar levels of proinflammatory cytokines, apoptosis, and autophagy activity compared with wild-type, Ctsb^Δpan, and Ctsl^Δpan mice.ConclusionDouble deletion of Ctsb and Ctsl in the mouse pancreas altered intrapancreatic trypsin activity but did not affect disease severity and inflammatory response after cerulein-induced AP.     

Robust antibody response after a third BNT162b2 vaccine compared to the second among immunocompromised and healthy individuals,a prospective longitudinal cohort study

PurposeAs protection from COVID-19 following two doses of the BNT162b2 vaccine showed a time dependent waning, a third (booster) dose was administrated. This study aims to compare the antibody response following the third dose versus the second and to evaluate post-booster seroconversion.MethodsA prospective observational study conducted in Maccabi Healthcare Services. Serial SARS-CoV-2 Spike IgG tests, 1,2,3 and 6 months following the second vaccine dose and one month following the third were obtained. Neutralizing antibody levels were measured in a subset of participants. Per individual SARS-CoV-2 Spike IgG titer ratios were calculated one month after the booster administration compared to titers one month following the second dose and prior to booster.ResultsAmong 110 participants, 56 (51%) were women. Mean age was 61.7 ± 1.9 years and 66 (60%) were immunocompromised. One month after third dose, IgG titers were induced 7.83 (95 %CI 5.25–11.67) folds and 2.40 (95 %CI 1.90–3.03) folds compared to one month after the second, in the immunocompromised and immunocompetent groups, respectively. Of the 17 immunocompromised participants who were seronegative after the second dose, 4 (24%) became seropositive following the third. Comparing the titers prior to the third dose, an increase of 50.7 (95 %CI 32.5–79.1) fold in the immunocompromised group and 25.7 (95 %CI 19.1–34.7) fold in and immunocompetent group, was observed.ConclusionA third BNT162b2 vaccine elicited robust humoral response, superior to the response observed following the second, among immunocompetent and immunocompromised individuals.     

阿帕替尼单药在标准方案治疗失败晚期结直肠癌患者中的疗效及安全性

目的：探讨阿帕替尼单药在标准治疗方案失败晚期结直肠癌（colorectal cancer，CRC）患者中的疗效和安全性。方法：本研究为前瞻性研究设计，用PASS15 软件计算研究所需的样本量，从2017 年7 月到2018 年8 月入组标准方案治疗失败的晚期CRC患者52 例，给予阿帕替尼起始剂量750 mg或500 mg单药治疗；评估患者的客观缓解率（ORR）和疾病控制率（DCR），随访评价患者的无进展生存期（PFS）和总生存期（OS），并记录治疗过程中出现的不良反应。主要研究终点为PFS，次要研究终点为ORR、DCR、OS和安全性。结果：纳入研究的52 例CRC患者中45 例可以评价疗效及安全性，其均为既往接受过至少2 次系统性化疗的晚期CRC患者。疗效：完全缓解0 例、部分缓解5 例、疾病稳定30 例、疾病进展10 例，ORR为11.11%、DCR为77.78%；预后：45 例患者的中位PFS 为3.95 个月（95% CI=3.16~4.74），中位OS为10.3 个月（95% CI=5.70~14.90）；3 级以上不良反应：手足综合征6 例（13.33%），高血压5 例（11.11%），蛋白尿5 例（6.67%），转氨酶升高4 例（8.89%），腹泻3 例（6.67%），疲劳2 例（4.44%），出血1例（2.22%）。结论：阿帕替尼单药治疗标准方案失败的晚期CRC患者具有潜在的临床获益，安全性事件总体可控。     

妊娠早期阴道微环境变化及与阴道炎症的关系分析

目的分析妊娠早期阴道微环境变化及与阴道炎症的关系。方法回顾性分析2017年3月-2018年12月韶关市曲江区妇幼保健计划生育服务中心104例妊娠早期孕产妇临床资料。记录其非妊娠期及妊娠早期阴道微环境变化情况,包括酸碱度(pH)、菌群密集度、菌群多样性、阴道微生物功能正常率、乳杆菌阳性率、阴道微生态正常率,并比较妊娠早期阴道炎症发生情况及其阴道微环境。结果孕产妇非妊娠期pH、阴道微生物功能正常率、乳杆菌阳性率及阴道微生态正常率明显高于妊娠早期,菌群密集度、菌群多样性则低于妊娠早期,差异均有统计学意义(P<0.05)。孕产妇妊娠早期阴道炎症组pH、菌群密集度、菌群多样性明显高于无阴道炎症组,阴道微生物功能正常率及乳杆菌阳性率则低于无阴道炎症组,差异均有统计学意义(P<0.05)。结论妊娠早期阴道微环境出现一系列变化,造成阴道炎症发生率升高,对此临床应给予重视。