Isolation, Bioactivity, and Molecular Docking of a Rare Gastrodin Isocitrate and Diverse Parishin Derivatives from Gastrodia elata Blume.

Gastrodia elata Blume (G. elata) is a well-known medicine food homology plant widely used in treating neurological disorders such as Alzheimer's disease (AD). Here, undiscovered gastrodin derivatives were systematically studied. Seven novel gastrodin derivatives (1-7), including a unique gastrodin isocitrate (1) and six differently substituted parishin derivatives (2-7), were isolated. Structural identification was mainly based on 1D and 2D NMR data, high-resolution ESI-MS data, and HPLC analysis. Notably, the stereochemistry of 1 was further elucidated by ECD calculations. Compounds 1 and 6 showed neuroprotective effects on the H2O2-induced PC12 cell injury model. Molecular docking analysis exhibited that 1 and 6 had good affinities with three popular AD-related targets. These findings not only enriched the chemical diversity but also revealed potential active components in G. elata.

Sensory neuron transient receptor potential vanilloid-1 channel regulates angiogenesis through CGRP in vivo.

Angiogenesis plays a key role in bone regeneration. The role of neurons of peripheral nerves involved in angiogenesis of bone defects needs to be explored. The transient receptor potential vanilloid 1 (TRPV1), a nociceptor of noxious stimuli, is expressed on sensory neurons. Apart from nociception, little is known about the role of sensory innervation in angiogenesis. Calcitonin gene-related peptide (CGRP), a neuropeptide secreted by sensory nerve terminals, has been associated with vascular regeneration. We characterized the reinnervation of vessels in bone repair and assessed the impact of TRPV1-CGRP signaling on early vascularization. We investigated the pro-angiogenic effect of neuronal TRPV1 in the mouse model of femur defect. Micro-CT analysis with Microfil® reagent perfusion demonstrated neuronal TRPV1 activation enhanced angiogenesis by increasing vessel volume, number, and thickness. Meanwhile, TRPV1 activation upregulated the mRNA and protein expression of vascular endothelial growth factor A (VEGF-A), cell adhesion molecule-1 (CD31), and CGRP. Immunostaining revealed the co-localization of TRPV1 and CGRP in dorsal root ganglia (DRG) sensory neurons. By affecting neuronal TRPV1 channels, the release of neuronal and local CGRP was controlled. We demonstrated that TRPV1 influenced on blood vessel development by promoting CGRP release from sensory nerve terminals. Our results showed that neuronal TRPV1 played a crucial role in regulating angiogenesis during bone repair and provided important clinical implications for the development of novel therapeutic approaches for angiogenesis.

In situ electrochemical potential-induced synthesis of metal organic framework membrane on polymer support for H2/CO2 separation.

Metal-Organic Framework (MOF) membranes act as selective layers have offered unprecedented opportunities for energy-efficient and cost-effective gas separation. Searching for the green and sustainable synthesis method of dense MOF membrane has received huge attention in both academia and industry. In this work, we demonstrate an in situ electrochemical potential-induced synthesis strategy to aqueously fabricate Metal Azolate Framework-4 (MAF-4) membranes on polypropylene (PP) support. The constant potential can induce the heterogeneous nucleation and growth of MAF-4, resulting an ultrathin membrane with the thickness of only 390 nm. This high-quality membrane exhibits a high H2/CO2 separation performance with the H2 permeance as high as 1565.75 GPU and selectivity of 11.6. The deployment of this environment friendly one-step fabrication method under mild reaction conditions, such as low-cost polymer substrate, water instead of organic solvent, room temperature and ambient pressure shows great promise for the scale-up of MOF membranes.

Massive hemoptysis in pregnancy due to invasive pulmonary aspergillosis with pulmonary tuberculosis co-infection.

A 37-year-old woman, 25 weeks pregnant, experienced sudden massive hemoptysis. She had a background history of systemic lupus erythematosus (SLE) and past pulmonary tuberculosis (PTB). Emergency intubation was necessary, and bronchoscopy revealed blood pooling in both main bronchi, with active bleeding from the right upper lobe bronchus. Urgent computed tomography (CT) angiography of the bronchial artery identified a bleeding source and was successfully embolized. Antifungal and anti-tuberculous therapy was initiated based on bronchoalveolar lavage results. Despite initial improvement, hemoptysis recurred after the third week, leading to repeat embolization, followed by a caesarean section and right upper lobectomy. Both mother and baby survived, remaining well at a 6-week follow-up, emphasizing the complexities of managing recurrent hemoptysis during pregnancy and potential drug interactions.

The prevalence and predictors of poor sleep quality and excessive daytime sleepiness in epilepsy: A single tertiary centre experience in Malaysia.

BACKGROUND AND OBJECTIVE: People with epilepsy frequently encounter sleep disruptions that can stem from a variety of complex factors. Epilepsy-related sleep disturbance can lead to reduced quality of life and excessive daytime hypersomnolence. Identification of sleep disturbances may help in the overall management of epilepsy patients. This study was conducted to determine the prevalence and predictors of poor sleep quality and daytime sleepiness in epilepsy. METHODS: A cross-sectional study on 284 epilepsy patients was performed in a local tertiary centre. The demographic and clinical epilepsy data were collected. The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) questionnaires were utilised to determine the quality of life and daytime hypersomnolence of epilepsy patients, respectively. RESULTS: Poor sleep quality was reported in 78 (27.5%) patients while daytime hypersomnolence was present in 17 (6%) patients. The predictors of poor sleep quality include structural causes (OR = 2.749; 95% CI: 1.436, 5.264, p = 0.002), generalised seizures (OR = 1.959, 95% CI: 1.04, 3.689, p = 0.037), and antiseizure medications such as Carbamazepine (OR = 2.34; 95% CI: 1.095, 5.001, p = 0.028) and Topiramate (OR 2.487; 95% CI: 1.028, 6.014, p = 0.043). Females are 3.797 times more likely score higher in ESS assessment (OR 3.797; 95% CI: 1.064, 13.555 p = 0.04). DISCUSSION: Sleep disturbances frequently coexist with epilepsy. Patients should be actively evaluated using the PSQI and ESS questionnaires. It is imperative to identify the key factors that lead to reduced sleep quality and heightened daytime sleepiness in patients with epilepsy, as this is essential to properly manage their condition.

Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs.

The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC50: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC50: 3.79 vs 5.80 µM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.

Virtual screening of novel mTOR inhibitors for the potential treatment of human colorectal cancer.

The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 µM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 µM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 µM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.

The benefit of indwelling pleural catheter with ambulatory pneumothorax device and autologous blood patch pleurodesis in lymphangioleiomyomatosis with persistent air leak.

We report a 35-year-old woman who presented with dyspnoea and chest pain for 1 week. High-resolution computed tomography (HRCT) thorax revealed bilateral pneumothoraces with diffuse lung cysts. Bilateral intercostal chest tubes were inserted, and there was a persistent air leak (PAL) bilaterally. We performed an autologous blood patch pleurodesis (ABPP) for the left PAL. For the right PAL, she underwent a successful right video-assisted thoracic (VATS) surgery, wedge biopsy, and surgical pleurodesis. Histopathology examination confirmed the diagnosis of lymphangioleiomyomatosis (LAM). The left pneumothorax recurred. An indwelling pleural catheter (Rocket® IPC™; Rocket Medical plc; WASHINGTON) was inserted and the patient was discharged after 1 day with an atrium pneumostat (Pneumostat™; Atrium Medical Corporation, Hudson, NH, USA) chest drain valve. The patient was initiated on Sirolimus 2 mg daily. The left PAL resolved at 6 weeks. This case highlights the benefit of IPC with an ambulatory pneumothorax device in a patient with LAM with PAL.

Axl alleviates DSS-induced colitis by preventing dysbiosis of gut microbiota.

Axl is a tyrosine kinase receptor, a negative regulator for innate immune responses and inflammatory bowel disease (IBD). The gut microbiota regulates intestinal immune homeostasis, but the role of Axl in the pathogenesis of IBD through the regulation of gut microbiota composition remains unresolved. In this study, mice with DSS-induced colitis showed increased Axl expression, which was almost entirely suppressed by depleting the gut microbiota with antibiotics. Axl-/- mice without DSS administration exhibited increased bacterial loads, especially the Proteobacteria abundant in patients with IBD, significantly consistent with DSS-induced colitis mice. Axl-/- mice also had an inflammatory intestinal microenvironment with reduced antimicrobial peptides and overexpression of inflammatory cytokines. The onset of DSS-induced colitis occurred faster with an abnormal expansion of Proteobacteria in Axl-/- mice than in WT mice. These findings suggest that a lack of Axl signaling exacerbates colitis by inducing aberrant compositions of the gut microbiota in conjunction with an inflammatory gut microenvironment. In conclusion, the data demonstrated that Axl signaling could ameliorate the pathogenesis of colitis by preventing dysbiosis of gut microbiota. Therefore, Axl may act as a potential novel biomarker for IBD and can be a potential candidate for the prophylactic or therapeutic target of diverse microbiota dysbiosis-related diseases.

Design, synthesis and biological evaluation of cajanonic acid A analogues as potent PPAR γ antagonists.

Peroxisome proliferator-activated receptor γ (PPAR γ) antagonists are a key instrument of insulin sensitizers since they have the ability to sensitize insulin and can avoid adverse reactions caused by receptor agonist. In this paper, two series of 28 novel Cajanonic acid A (CAA) derivatives were designed and synthesized. The biological activity showed that a novel CAA derivative 9f was identified as a potential PPAR γ antagonist by medicinal chemistry efforts. The results in vitro displayed that compound 9f could improve the PPAR γ antagonist activity (96.2 % / 50.2 % decrease in PPAR γ transactivation at 10 µM / 1 µM, respectively). It also could improve the glucose consumption activity of insulin-resistant HepG2/3T3-L1 cell line (33.27 % / 72.61 % increase in glucose consumption). And in 3 T3-L1 adipocytes, it showed anti-adipogenesis activity (7.04 % increase in oil red staining). Further, in vivo study suggested that compound 9f could improve the oral glucose tolerance in db/db mice. Taken together, derivative 9f served as a promising candidate for anti-diabetic drug discovery and deserve further study.

Rapid and visual detection of Mycoplasma synoviae by recombinase-aided amplification assay combined with a lateral flow dipstick.

Mycoplasma synoviae (MS) is an important avian pathogen that has brought substantial economic losses to the global poultry industry. Fast and accurate diagnosis is one of the critical factors for the control of MS infection. This study established a simple, rapid and visual detection method for MS using a recombinase-aided amplification (RAA) combined with a lateral flow dipstick (LFD). The reaction temperature and time of the RAA-LFD assay were optimized after selecting the primers and probe, and the specificity and sensitivity rates were analyzed. The results showed that RAA could amplify the target gene in 20 min at a constant temperature of 38°C, and the amplification products could be visualized by LFD within 5 min. There was no cross-reaction with Mycoplasma gallisepticum (MG), Pasteurella multocida (P. multocida), Escherichia coli (E. coli), Newcastle disease virus (NDV), infectious bursal disease virus (IBDV), infectious bronchitis virus (IBV), and avian reovirus (ARV). Furthermore, the RAA-LFD assay exhibited high sensitivity with a detection limit of 10 copies/µL. A total of 128 clinical samples with suspected infection of MS were tested by RAA-LFD, PCR, and real-time fluorescence quantitative PCR (RFQ-PCR). The coincidence rate of the detection results was 95.3% between RAA-LFD and PCR, and 98.4% between RAA-LFD and RFQ-PCR. These results suggested that the RAA-LFD method established in the present study was easy to use and was associated with strong specificity and high sensitivity. This method was very suitable for the rapid detection of MS in clinical practice.

Cerebral Tuberculoma with Mild Posterior Cervical Pain as the Main Symptom Despite Extensive Brain Lesions.

A 59-year-old woman with a diabetes history experienced mild neck pain. A neurological examination revealed only mild neck stiffness. Magnetic resonance imaging showed extensive T2-weighted high-intensity lesions with patchy gadolinium enhancement mainly involving the white matter in the right parietal lobe. A cerebrospinal fluid analysis revealed increased protein levels and pleocytosis. While QuantiFERON-TB Gold was positive, computed tomography (CT) and fluorodeoxyglucose on positron emission tomography-CT of the whole body showed no abnormal accumulation, suggesting tuberculosis. A brain biopsy revealed cerebral tuberculoma. As cerebral tuberculoma can show minimal neurological symptoms despite extensive lesions, a cautious examination and early treatment are required to prevent a devastating prognosis.

Early postnatal allergic airway inflammation induces dystrophic microglia leading to excitatory postsynaptic surplus and autism-like behavior.

Microglia play key roles in synaptic pruning, which primarily occurs from the postnatal period to adolescence. Synaptic pruning is essential for normal brain development and its impairment is implicated in neuropsychiatric developmental diseases such as autism spectrum disorders (ASD). Recent epidemiological surveys reported a strong link between ASD and atopic/allergic diseases. However, few studies have experimentally investigated the relationship between allergy and ASD-like manifestations, particularly in the early postnatal period, when allergic disorders occur frequently. Therefore, we aimed to characterize how allergic inflammation in the early postnatal period influences microglia and behavior using mouse models of short- and long-term airway allergy. Male mice were immunized by an intraperitoneal injection of aluminum hydroxide and ovalbumin (OVA) or phosphate-buffered saline (control) on postnatal days (P) 3, 7, and 11, followed by intranasal challenge with OVA or phosphate-buffered saline solution twice a week until P30 or P70. In the hippocampus, Iba-1-positive areas, the size of Iba-1-positive microglial cell bodies, and the ramification index of microglia by Sholl analysis were significantly smaller in the OVA group than in the control group on P30 and P70, although Iba-1-positive microglia numbers did not differ significantly between the two groups. In Iba-1-positive cells, postsynaptic density protein 95 (PSD95)-occupied areas and CD68-occupied areas were significantly decreased on P30 and P70, respectively, in the OVA group compared with the control group. Immunoblotting using hippocampal tissues demonstrated that amounts of PSD95, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 2, and N-methyl-D-aspartate (NMDA) receptor 2B were significantly increased in the OVA group compared with the control group on P70, and a similar increasing trend for PSD95 was observed on P30. Neurogenesis was not significantly different between the two groups on P30 or P70 by doublecortin immunohistochemistry. The social preference index was significantly lower in the three chamber test and the number of buried marbles was significantly higher in the OVA group than in the control group on P70 but not on P30, whereas locomotion and anxiety were not different between the two groups. Compared with the control group, serum basal corticosterone levels were significantly elevated and hippocampal glucocorticoid receptor (GR) amounts and nuclear GR translocation in microglia, but not in neurons or astrocytes, were significantly decreased in the OVA group on P70 but not on P30. Gene set enrichment analysis of isolated microglia revealed that genes related to immune responses including Toll-like receptor signaling and chemokine signaling pathways, senescence, and glucocorticoid signaling were significantly upregulated in the OVA group compared with the control group on P30 and P70. These findings suggest that early postnatal allergic airway inflammation induces dystrophic microglia that exhibit defective synaptic pruning upon short- and long-term allergen exposure. Furthermore, long-term allergen exposure induced excitatory postsynaptic surplus and ASD-like behavior. Hypothalamo-pituitary-adrenal axis activation and the compensatory downregulation of microglial GR during long-term allergic airway inflammation may also facilitate these changes.

Cyclophilin A is an endogenous ligand for the triggering receptor expressed on myeloid cells-2 (TREM2).

Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface receptor expressed on macrophages, microglial cells, and pre-osteoclasts, and that participates in diverse cellular function, including inflammation, bone homeostasis, neurological development, and coagulation. In spite of the indispensable role of the TREM2 protein in the maintenance of immune homeostasis and osteoclast differentiation, the exact ligand for TREM2 has not yet been identified. Here, we report a putative TREM2 ligand which is secreted from MC38 cells and identified as a cyclophilin A (CypA). A specific interaction between CypA and TREM2 was shown at both protein and cellular levels. Exogenous CypA specifically interacted and co-localized with TREM2 in RAW264.7 cells, and the physical interactions were shown to regulate TREM2 signaling transduction. The Pro144 residue in the extracellular domain of TREM2 was found to be the specific binding site of CypA. When considered together, this provides evidence that CypA interacts specifically with TREM2 as a potent ligand.

Successful treatment of a complex malignant pleural effusion with 1 mg alteplase instilled through a non-draining indwelling pleural catheter.

Indwelling pleural catheter (IPC) is the treatment of choice in managing symptomatic recurrent malignant pleural effusion (MPE). Loculated effusions following insertion may occur due to infection, catheter malfunction or the inflammatory nature of MPE. Loculations may lead to ineffective drainage and make the IPC non-functional. We report a 56-year-old man with symptomatic loculated malignant pleural effusion with an IPC, successfully drained with a single dose of 1 mg recombinant tissue plasminogen activator alteplase. This is the lowest dose currently applied in our centre for efficient drainage and improvement of dyspnoea.

Disease-modifying antirheumatic drugs and organising pneumonia.

Organising pneumonia (OP) in rheumatoid arthritis (RA) may be part of pulmonary manifestation (disease related) or disease-modifying antirheumatic drugs (DMARDs) related. We report a case series of RA patients with DMARDs related OP. A 65-year-old woman developed OP 3 weeks after initiation of methotrexate (MTX). High-resolution CT (HRCT) scan of the thorax revealed bilateral consolidations in the lung bases. She had complete radiological resolution 6 months after corticosteroid therapy with cessation of MTX. The second case was of a 60-year-old woman on MTX with recent addition of leflunomide due to flare of RA. She developed worsening cough 4 months later and HRCT scan revealed consolidation in the left upper lobe with biopsy proven OP. She responded within 6 months of corticosteroid therapy with clinical and radiological resolution. This case series highlights that OP may developed with low-dose MTX (as early as 3 weeks) and leflunomide and the diagnosis requires a high index of suspicion.

Cryodebulking of endobronchial hamartoma via fibreoptic bronchoscopy and literature review.

Endobronchial hamartoma is a rare tumour. We report a 65-year-old woman with a history of recurrent pneumonia. Bronchoscopy revealed a 1 cm endobronchial mass obstructing the left upper lobe bronchus. Histopathological examination was consistent with a pulmonary hamartoma. This lesion was successfully debulked endoscopically with the use of a flexible cryoprobe without any complications. This case highlights both the importance of investigating recurrent pneumonia and the usefulness of endoscopic recanalisation in an obstructed segmental bronchus.

What happens when we treat the "Typhoid Mary" of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was declared a pandemic on 11 March 2020. We have since seen its fast spread worldwide. A likely contributing factor was the lack of symptoms of some of the carriers, making them unaware of their risk of spreading to other more vulnerable individuals. The other important finding has been the reported cases of infectivity despite lack of symptoms. We describe the SARS-CoV-2 pneumonia patterns in asymptomatic individuals. The common computed tomography (CT) thorax patterns found are peripheral ground-glass opacification (GGO) with upper or lower lobe predominance. We believe screening for 2019-novel coronavirus (COVID-19) in high-risk individuals may help identify the patients needing longer follow-up.

COVID-19 detected from targeted contact tracing, attempting to see the pattern in random happenings: early lessons in Malaysia

@#The world feels strange as we face what is for most of us ourfirst ever pandemic. The number of newly diagnosed casesrises daily in many parts of the world, and we are faced withthe reality that there are still many things to learn about thisnew disease. We share here our experience of treating ourfirst 199 COVID-19 patients in the Hospital Canselor TuankuMuhriz, Pusat Perubatan Universiti Kebangsaan Malaysia(PPUKM).

A descriptive study of the psychological experience of health care workers in close contact with a person with COVID-19

@#Background: COVID-19 has the potential to affect the mental health of health care workers (HCWs). It is known that HCWs who serve as front-liners during the COVID-19 pandemic experience stress and have the fear of contracting the infection. Little is known of how being a positive contact affects HCWs. Objective: We examined the experience of HCWs who were quarantined following a close unprotected contact with a COVID-19 positive colleague and explore the psychological impact especially as the timing of the quarantine coincided with the Eid (annual Muslim festival) celebration in Malaysia. Methods: This was a cross-sectional on-line questionnaire study, involving HCWs exposed to a COVID-19 positive colleague in Universiti Kebangsaan Malaysia Medical Centre, a teaching hospital. Data on demographics, levels of depression, anxiety and stress using a validated depression, anxiety, and stress scale (DASS-21) questionnaire, aspects of quarantine, wearing of masks, hand hygiene practice and swab experience were collected. Results: Twenty-two HCWs participated. Eighteen (81.8%) were between 30-39 years and 17 (77.3%) were women. Majority 19 (86.3%) were Malays. There were twelve (54.5%) medical officers, 5 (22.7%) specialists and 5(22.7%) allied health staff. Eighteen out of 22 (81.8%) felt they were able to do home quarantine adequately. All tested negative with a mean (Standard Deviation) hour of contact of 2.56±2.38 hours. Eighteen reported their biggest concern was infecting their families. Conclusion: HCWs undergoing contact swabbing and quarantine are vulnerable to depression, anxiety and stress. The ability of the HCW to adequately home quarantine should not be taken for granted. Psychological support should be offered to HCWs who are positive contacts.