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  1. Tan KS, Zhang Y, Liu L, Li S, Zou X, Zeng W, et al.
    PMID: 33662568 DOI: 10.1016/j.cbpb.2021.110590
    Cholinesterases act as bio scavengers to clear organophosphorus (OP) compounds and prodrugs. The butyrylcholinesterase (BChE) gene has been found in several types of teleost fish but this gene has yet to be identified in cyprinid fish. Indeed, BChE homologs have not been found in the zebrafish (Danio rerio) genomic database. Here, we demonstrate that BChE activity is present in zebrafish, in line with other groups' findings. Using in-gel native-PAGE enzymatic activity staining and LC-MS/MS technique, an atypical BChE-like protein was identified in zebrafish. The si:ch211-93f2.1 gene was cloned, and His-tagged recombinant protein was expressed using the Pichia yeast system. The purified protein (molecular weight ~ 180 kDa) showed BChE activity, and degraded acetylcholinesterase (ACh) at a higher rate than BCh. However, phylogram analysis shows that this novel cholinesterase shared an evolutionary origin with carboxylic esterase rather than BChE. The zebrafish BChE-like protein shares structural characteristics with cholinesterase and carboxylesterase. The 2-arachidonoylglycerol (2-AG), nicosulfuron, and triacetin exhibited a higher binding affinity to the zebrafish BChE-like protein than BCh and ACh. With the identification of BChE-like protein in zebrafish, this study could shed light on the origin of BChE and may contribute towards the development of a BChE knockout zebrafish model for sensitive drug or toxin screening.
  2. Tan TW, Tan HL, Chang MN, Lin WS, Chang CM
    PMID: 33810438 DOI: 10.3390/ijerph18073456
    (1) Background: The implementation of effective control measures in a timely fashion is crucial to control the epidemic outbreak of COVID-19. In this study, we aimed to analyze the control measures implemented during the COVID-19 outbreak, as well as evaluating the responses and outcomes at different phases for epidemic control in Taiwan. (2) Methods: This case study reviewed responses to COVID-19 and the effectiveness of a range of control measures implemented for epidemic control in Taiwan and assessed all laboratory-confirmed cases between 11 January until 20 December 2020, inclusive of these dates. The confirmation of COVID-19 infection was defined as the positive result of a reverse-transcriptase-polymerase-chain-reaction test taken from a nasopharyngeal swab. Test results were reported by the Taiwan Centers for Disease Control. The incidence rate, mortality rate, and testing rate were compiled, and the risk ratio was provided to gain insights into the effectiveness of prevention measures. (3) Results and Discussion: This study presents retrospective data on the COVID-19 incidence rate in Taiwan, combined with the vital preventive control measures, in a timeline of the early stage of the epidemic that occurred in Taiwan. The implementation of multiple strategy control measures and the assistance of technologies to control the COVID-19 epidemic in Taiwan led to a relatively slower trend in the outbreak compared to the neighboring countries. In Taiwan, 766 confirmed patients were included, comprised of 88.1% imported cases and 7.2% local transmission cases, within the studied period. The incidence rate of COVID-19 in Taiwan during the studied period was 32 per million people, with a mortality rate of 0.3 per million people. Our analysis showed a significantly raised incidence risk ratio in the countries of interest in comparison to Taiwan during the study period; in the range of 1.9 to 947.5. The outbreak was brought under control through epidemic policies and hospital strategies implemented by the Taiwan Government. (4) Conclusion: Taiwan's preventive strategies resulted in a drastically lower risk for Taiwan nationals of contracting COVID-19 when new pharmaceutical drug or vaccines were not yet available. The preventive strategies employed by Taiwan could serve as a guide and reference for future epidemic control strategies.
  3. Hamdan M, Shuhaina S, Hong JGS, Vallikkannu N, Zaidi SN, Tan YP, et al.
    Acta Obstet Gynecol Scand, 2021 Nov;100(11):1977-1985.
    PMID: 34462906 DOI: 10.1111/aogs.14247
    INTRODUCTION: Multiparous labor inductions are typically successful, and the process can be rapid, starting from a ripened cervix with a predictable response to amniotomy and oxytocin infusion. Outpatient Foley catheter labor induction in multiparas with unripe cervixes is a feasible option as the mechanical process of ripening is usually without significant uterine contractions and well tolerated. Labor contractions can be initiated by amniotomy and titrated oxytocin infusion in the hospital for well-timed births during working hours as night birth are associated with adverse events. We sought to evaluate outpatient compared with inpatient Foley catheter induction of labor in multiparas for births during working hours and maternal satisfaction.

    MATERIAL AND METHODS: A randomized trial was conducted in the University of Malaya Medical Center. A total of 163 term multiparas (no dropouts) with unripe cervixes (Bishop score ≤5) scheduled for labor induction were randomized to outpatient or inpatient Foley catheter. Primary outcomes were delivery during "working hours" 08:00-18:00 h and maternal satisfaction on allocated care (assessed by 11-point visual numerical rating score 0-10, with higher score indicating more satisfied).

    CLINICAL TRIAL REGISTRATION: ISRCTN13534944.

    RESULTS: Comparing outpatient and inpatient arms, delivery during working hours were 54/82 (65.9%) vs. 48/81 (59.3%) (relative risk 1.1, 95% CI 0.9-1.4, p = 0.421) and median maternal satisfaction visual numerical rating score was 9 (interquartile range 9-9) vs. 9 (interquartile range 8-9, p = 0.134), repectively. Duration of hospital stay and membrane rupture to delivery interval were significantly shorter in the outpatient arm: 35.8 ± 20.2 vs. 45.2 ± 16.2 h (p = 0.001) and 4.1 ± 2.9 vs. 5.3 ± 3.6 h (p = 0.020), respectively. Other maternal and neonatal secondary outcomes were not significantly different.

    CONCLUSIONS: The trial failed to demonstrate the anticipated increase in births during working hours with outpatient compared with inpatient induction of labor with Foley catheter in parous women with an unripe cervix. Hospital stay and membrane rupture to delivery interval were significantly shortened in the outpatient group. The rate of maternal satisfaction was high in both groups and no significant differences were found.

  4. Tan B, Li Y, Liu T, Tan X, He Y, You X, et al.
    Front Plant Sci, 2021;12:691651.
    PMID: 34456936 DOI: 10.3389/fpls.2021.691651
    As natural agroecology deteriorates, controlled environment agriculture (CEA) systems become the backup support for coping with future resource consumption and potential food crises. Compared with natural agroecology, most of the environmental parameters of the CEA system rely on manual management. Such a system is dependent and fragile and prone to degradation, which includes harmful bacteria proliferation and productivity decline. Proper water management is significant for constructing a stabilized rhizosphere microenvironment. It has been proved that water is an efficient tool for changing the availability of nutrients, plant physiological processes, and microbial communities within. However, for CEA issues, relevant research is lacking at present. The article reviews the interactive mechanism between water management and rhizosphere microenvironments from the perspectives of physicochemical properties, physiological processes, and microbiology in CEA systems. We presented a synthesis of relevant research on water-root-microbes interplay, which aimed to provide detailed references to the conceptualization, research, diagnosis, and troubleshooting for CEA systems, and attempted to give suggestions for the construction of a high-tech artificial agricultural ecology.
  5. Cao Y, Lu Z, Wang D, Tan KS, Liu W, Wu Q, et al.
    Eur J Pharmacol, 2021 Nov 15;911:174539.
    PMID: 34599913 DOI: 10.1016/j.ejphar.2021.174539
    Ischemia heart disease, one of the lethal cardiovascular diseases, irreversibly impairs cardiac function and is recognized as the primary risk factor for mortality in industrialized countries. The myocardial ischemia treatment still faces a considerable degree of increasing unmet needs. Isosteviol sodium (STVNa) and its derivatives have been proven to effectively alleviate metabolic diseases, hypertension, and heart hypertrophy. Little is known about how STVNa confers the cardioprotective effect during acute myocardial ischemia (AMI). In the present study, a rat model of acute ST-segment-elevation myocardial ischemia by left anterior descending (LAD) ligation was established. Compared to the AMI model group, STVNa administration (4 mg/kg, twice a day) well preserved left ventricle function by ejection fraction (45.10 ± 10.39 vs. 73.64 ± 13.15, p = 0.0013) and fractional shortening (22.94 ± 6.28 vs. 44.00 ± 11.05, p = 0.0017). Further analysis shows that high-dose STVNa (4 mg/kg) significantly improved the hemodynamics in AMI rats, with LVSP (88.25 ± 12.78 vs 99.75 ± 5.10, p = 0.018), max dP/dt (2978.45 ± 832.46 vs 4048.56 ± 827.23, p = 0.096), LVEDP (19.88 ± 2.00 vs 22.26 ± 3.21, p = 0.04) and left ventricular relaxation time constant (Tau) (0.030 ± 0.006 vs 0.021 ± 0.004, p = 0.021). Mechanically, STVNa administration retained the myocardial levels of phosphorylated AMPK, and CPT1b. Moreover, STVNa significantly increased the total energy expenditure, and reduced fatty acid accumulation through mitochondrial oxidative phosphorylation, which was supported by the indirect calorimetry and cellular energy analysis. Taken together, these findings suggest that STVNa is a potential cardioprotection agent for ischemic cardiomyopathy, likely through improving energy homeostasis, left ventricular hemodynamics, and heart function.
  6. Tan LJ, Tan GC, Hussin H, Othman MS, Lai SK
    PMID: 34687904 DOI: 10.1016/j.jpag.2021.10.002
    BACKGROUND: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital disorder characterized by underdevelopment of the uterus and vagina.

    CASE: A 4-year-old girl was declared dead on arrival to the hospital with a history of chronic constipation since birth. Postmortem examination showed Müllerian remnants attached to abnormal fibrous tissue. The fibrous tissue extended from the descending colon to the rectum and connected to a urinary bladder duplication cyst. The fibrous tissue formed into a constricted band around the rectum. The cause of death was Streptococcus pyogenes sepsis with intestinal obstruction secondary to the rectal fibrotic band and urinary bladder duplication cyst.

    SUMMARY AND CONCLUSION: MRKH syndrome is a rare congenital disorder, and the malformations rarely cause death. We describe the features of abnormal fibrous tissue and urinary bladder duplication cyst in a patient with MRKH syndrome.

  7. Tan KS, Wang D, Lu Z, Zhang Y, Li S, Lin Y, et al.
    Int J Mol Sci, 2021 Oct 06;22(19).
    PMID: 34639145 DOI: 10.3390/ijms221910806
    Heart failure is the end-stage of all cardiovascular diseases with a ~25% 5-year survival rate, and insufficient mitochondrial energy production to meet myocardial demand is the hallmark of heart failure. Mitochondrial components involved in the regulation of ATP production remain to be fully elucidated. Recently, roles of 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) in the pathophysiological processes of heart diseases have emerged, implicated by evidence that mitochondrial CNPase proteins are associated with mitochondrial integrity under metabolic stress. In this study, a zebrafish heart failure model was established, by employing antisense morpholino oligonucleotides and the CRISPR-Cas9 gene-editing system, which recapitulates heart failure phenotypes including heart dysfunction, pericardial edema, ventricular enlargement, bradycardia, and premature death. The translational implications of CNPase in the pathophysiological process of heart failure were tested in a pressure overload-induced heart hypertrophy model, which was carried out in rats through transverse abdominal aorta constriction (TAAC). AAV9-mediated myocardial delivery of CNPase mitigated the hypertrophic response through the specific hydrolysis of 2'-3'-cyclic nucleotides, supported by the decrease of cardiac hypertrophy and fibrosis, the integrity of mitochondrial ultrastructure, and indicators of heart contractility in the AAV9-TAAC group. Finally, the biometrics of a mitochondrial respiration assay carried out on a Seahorse cellular energy analyzer demonstrated that CNPase protects mitochondrial respiration and ATP production from AngII-induced metabolic stress. In summary, this study provides mechanistic insights into CNPase-2',3'-cyclic nucleotide metabolism that protects the heart from energy starvation and suggests novel therapeutic approaches to treat heart failure by targeting CNPase activity.
  8. Chee KH, Tan KL, Luqman I, Saiful SS, Chew YY, Chinna K, et al.
    Front Cardiovasc Med, 2021;8:676862.
    PMID: 34646868 DOI: 10.3389/fcvm.2021.676862
    Objective: Existing data showed that left ventricular diastolic dysfunction is common in individuals with type 2 diabetes mellitus (T2DM). However, most of the studies included diabetic patients who have prior cardiovascular disease, which might be the compounding factor for ventricular dysfunction. This study aimed to determine the prevalence and predictors of left ventricular diastolic dysfunction in an Asian population with T2DM without prior cardiovascular disease using the latest recommended echocardiographic assessment for left ventricular diastolic dysfunction. Design and Participants: This is a cross-sectional study in which eligible patients with T2DM without history of coronary artery disease, heart failure, or valvular heart disease were recruited. Demographic data, diabetic control, comorbidities, microvascular/macrovascular complications, and medications prescribed were recorded. Venous blood was sent to test for B-type natriuretic peptide, and transthoracic echocardiography was performed to assess left ventricular dysfunction. Setting: This study was performed in a tertiary healthcare center located in Kuala Lumpur, Malaysia. Results: Of the 301 patients, 83.1% have had T2DM for >10 years, with 45.8% being poorly controlled. Comorbidities include hypertension (77.1%), hyperlipidemia (91.0%), and pre-obesity/obesity (72.9%). Majority had absence of microvascular (albuminuria, retinopathy, and neuropathy) and macrovascular (peripheral vascular disease and stroke) complications. None had raised B-type natriuretic peptide levels, and 93.7% had no symptoms of heart failure. On echocardiographic assessment, 70.1% had left ventricular diastolic dysfunction, and 90.5% had Grade 1/mild severity. Age, ethnicity, insulin therapy, presence of hypertension, and hyperlipidemia were significantly associated with left ventricular diastolic dysfunction. Older T2DM patients of Chinese ethnicity and on insulin are about two times more likely to develop left ventricular diastolic dysfunction. Conclusion: There was a high prevalence of asymptomatic left ventricular diastolic dysfunction among patients with T2DM without prior known cardiovascular disease. Older age, insulin therapy, and Chinese ethnicity were risk factors for left ventricular diastolic dysfunction in T2DM.
  9. Arshad M, Abdul Hamid N, Chan MC, Ismail F, Tan GC, Pezzella F, et al.
    Cells, 2021 08 24;10(9).
    PMID: 34571823 DOI: 10.3390/cells10092176
    Cancer increases the global disease burden substantially, but it remains a challenge to manage it. The search for novel biomarkers is essential for risk assessment, diagnosis, prognosis, prediction of treatment response, and cancer monitoring. This paper examined NEDD8 ultimate buster-1 (NUB1) and F-adjacent transcript 10 (FAT10) proteins as novel biomarkers in cancer. This literature review is based on the search of the electronic database, PubMed. NUB1 is an interferon-inducible protein that mediates apoptotic and anti-proliferative actions in cancer, while FAT10 is a ubiquitin-like modifier that promotes cancer. The upregulated expression of both NUB1 and FAT10 has been observed in various cancers. NUB1 protein binds to FAT10 non-covalently to promote FAT10 degradation. An overexpressed FAT10 stimulates nuclear factor-kappa β, activates the inflammatory pathways, and induces the proliferation of cancer. The FAT10 protein interacts with the mitotic arrest deficient 2 protein, causing chromosomal instability and breast tumourigenesis. FAT10 binds to the proliferating cell nuclear antigen protein and inhibits the DNA damage repair response. In addition, FAT10 involves epithelial-mesenchymal transition, invasion, apoptosis, and multiplication in hepatocellular carcinoma. Our knowledge about them is still limited. There is a need to further develop NUB1 and FAT10 as novel biomarkers.
  10. Amran A, Tan CY, Tan KL, Ho RM, Anand AK, Leong CW
    Clin Pharmacol Drug Dev, 2021 12;10(12):1514-1518.
    PMID: 34107173 DOI: 10.1002/cpdd.964
    A newly developed branded generic of a moxifloxacin (MOX) 400-mg tablet formulation was manufactured prior to this study. A bioequivalence (BE) study was done to assess the pharmacokinetics of the formulation using a randomized, open-label, 2-period crossover, 2-sequence, and single-dose experiment. Thirty healthy male volunteers were recruited. The test formulation, Flonoxin 400 mg, was compared with the reference formulation, Avelox 400 mg. The pharmacokinetic parameters of MOX were calculated based on the plasma drug concentration-time profile. Noncompartmental analysis was performed to determine its safety and tolerability. The 90% confidence intervals (CIs) were 88.5%-104.6%, 96.1%-101.1%, and 96.8%-100.7% for Cmax , AUC0-t , and AUC0-inf , respectively. All CIs were within the 80.0%-125.0% boundary, thus fulfilling the acceptable BE criteria according to the ASEAN guidelines.
  11. Jawahir S, Tan EH, Tan YR, Mohd Noh SN, Ab Rahim I
    BMC Health Serv Res, 2021 Apr 27;21(1):391.
    PMID: 33906646 DOI: 10.1186/s12913-021-06412-5
    BACKGROUND: Provision of informal care may adversely affect health, daily and social activities of the informal caregivers, but few studies have examined these effects in relation to caregiving intensity. This study examined the predictive factors associated with the effects of caregiving roles on health, daily and social activities of informal caregivers, accounting for caregiving intensity.

    METHODS: Data of adults aged 18 years and over from the National Health and Morbidity Survey 2019 were used. Respondent's demographic, socioeconomic, health, and caregiving-related characteristics were described using complex samples analysis. Logistic regression analysis was performed to examine the factors affecting health, daily and social activities of caregivers, accounting for caregiving intensity.

    RESULTS: Five point one percent of adults in Malaysia provided informal care. High intensity caregivers were more likely to be actively employed and provided longer duration of care compared with low intensity caregivers. For low intensity caregiving, females, those aged 35-59 years, and those with long-term condition were more likely to have negative effects on health. Daily activities of non-Malays were more likely to be affected, while no factor was found significantly associated with effect on social activities. For high intensity caregiving, caregivers aged 60 and over, those received training and those without assistance were more likely to have negative effects on health. Daily activities of those without assistance were more likely to be affected. Social activities of non-Malays, those received training and those providing care for 2 years or more were more likely to be affected.

    CONCLUSIONS: Our study indicates that both low- and high-intensity caregivers have common features, with the exception of employment status and care duration. Caregiving, regardless of intensity, has a significant impact on caregivers. In order to reduce the negative consequences of caregiving responsibilities, all caregivers need assistance from the community and government, that is customised to their needs. By addressing the factors contributing to the negative effects of caregiving, a continuation of informal caregiving can be sustained through policies supporting the growing demand for informal care necessitated by an ageing population and higher life expectancy in Malaysia.

  12. Tan GN, Tan PC, Hong JGS, Kartik B, Omar SZ
    BMJ Open, 2021 05 13;11(5):e046528.
    PMID: 33986063 DOI: 10.1136/bmjopen-2020-046528
    OBJECTIVE: To evaluate four foods in women with hyperemesis gravidarum (HG) on their agreeability and tolerability.

    DESIGN: Prospective, randomised, within-subject cross-over trial.

    SETTING: Single-centre, tertiary, university hospital in Malaysia.

    PARTICIPANTS: 72 women within 24-hour of first admission for HG who were 18 years or above, with confirmed clinical pregnancy of less than 16 weeks' gestation were recruited and analysed. Women unable to consume food due to extreme symptoms, known taste or swallowing disorder were excluded.

    INTERVENTIONS: Each participant chewed and swallowed a small piece of apple, watermelon, cream cracker and white bread in random order and was observed for 10 min after each tasting followed by a 2 min washout for mouth rinsing and data collection.

    OUTCOME MEASURES: Primary outcome was food agreeability scored after 10 min using an 11-point 0-10 Visual Numerical Rating Scale (VNRS). Nausea was scored at baseline (prior to tasting) and 2 and 10 min using an 11-point VNRS. Intolerant responses of gagging, heaving and vomiting were recorded.

    RESULTS: On agreeability scoring, apple (mean±SD 7.2±2.4) ranked highest followed by watermelon (7.0±2.7) and crackers (6.5±2.6), with white bread ranked lowest (6.0±2.7); Kruskal-Wallis H test, p=0.019. Apple had the lowest mean nausea score and mean rank score, while white bread had the highest at both 2 and 10 min; the Kruskal-Wallis H test showed a significant difference only at 10 min (p=0.019) but not at 2 min (p=0.29) in the ranking analyses. The intolerant (gagged, heaved or vomited) response rates within the 10 min study period were apple 3/72 (4%), watermelon 7/72 (10%), crackers 8/72 (11%) and white bread 12/72 (17%): χ2 test for trend p=0.02.

    CONCLUSION: Sweet apple had the highest agreeability score, the lowest nausea severity and intolerance-emesis response rate when tasted by women with HG. White bread consistently performed worst.

  13. Tan GJ, Tan MP, Luben RN, Wareham NJ, Khaw KT, Myint PK
    Geriatr Gerontol Int, 2021 Aug;21(8):657-663.
    PMID: 34156750 DOI: 10.1111/ggi.14219
    AIM: To evaluate the relationship between habitual alcohol consumption and the risk of falls hospitalization.

    METHODS: The EPIC-Norfolk is a prospective population-based cohort study in Norfolk, UK. In total, 25 637 community dwelling adults aged 40-79 years were recruited. Units of alcohol consumed per week were measured using a validated Food Frequency Questionnaire. The main outcome was the first hospital admission following a fall.

    RESULTS: Over a median follow-up period of 11.5 years (299 211 total person years), the cumulative incidence function (95% confidence interval) of hospitalized falls at 121-180 months for non-users, light (>0 to ≤7 units/week), moderate (>7 to ≤28 units/week) and heavy (>28 units/week) were 11.08 (9.94-12.35), 7.53 (7.02-8.08), 5.91 (5.29-6.59) and 8.20 (6.35-10.56), respectively. Moderate alcohol consumption was independently associated with a reduced risk of falls hospitalization after adjustment for most major confounders (hazard ratio = 0.88; 95% confidence interval 0.79-0.99). The relationship between light alcohol consumption and falls hospitalization was attenuated by gender differences. Alcohol intake higher than the recommended threshold of 28 units/week was associated with an increased risk of falls hospitalization (hazard ratio 1.40 [1.14-1.73]).

    CONCLUSIONS: Moderate alcohol consumption appears to be associated with a reduced risk of falls hospitalization, and intake above the recommended limit is associated with an increased risk. This provides incentive to limit alcohol consumption within the recommended range and has important implications for public health policies for aging populations. Geriatr Gerontol Int 2021; 21: 657-663.

  14. Lalani S, Tan SH, Tan KO, Lim HX, Ong KC, Wong KT, et al.
    Life Sci, 2021 Dec 15;287:120097.
    PMID: 34715144 DOI: 10.1016/j.lfs.2021.120097
    AIMS: Enterovirus A71 (EV-A71) is an etiological agent of hand foot and mouth disease (HFMD) and has the potential to cause severe neurological infections in children. L-SP40 peptide was previously known to inhibit EV-A71 by prophylactic action. This study aimed to identify the mechanism of inhibition in Rhabdomyosarcoma (RD) cells and in vivo therapeutic potential of L-SP40 peptide in a murine model.

    MAIN METHODS: A pull-down assay was performed to identify the binding partner of the L-SP40 peptide. Co-immunoprecipitation and co-localization assays with the L-SP40 peptide were employed to confirm the receptor partner in RD cells. The outcomes were validated using receptor knockdown and antibody blocking assays. The L-SP40 peptide was further evaluated for the protection of neonatal mice against lethal challenge by mouse-adapted EV-A71.

    KEY FINDINGS: The L-SP40 peptide was found to interact and co-localize with nucleolin, the key attachment receptor of Enteroviruses A species, as demonstrated in the pull-down, co-immunoprecipitation and co-localization assays. Knockdown of nucleolin from RD cells led to a significant reduction of 3.5 logs of viral titer of EV-A71. The L-SP40 peptide demonstrated 80% protection of neonatal mice against lethal challenge by the mouse-adapted virus with a drastic reduction in the viral loads in the blood (~4.5 logs), skeletal muscles (1.5 logs) and brain stem (1.5 logs).

    SIGNIFICANCE: L-SP40 peptide prevented severe hind limb paralysis and death in suckling mice and could serve as a potential broad-spectrum antiviral candidate to be further evaluated for safety and potency in future clinical trials against EV-A71.

  15. Wang S, Huang J, Liu F, Tan KS, Deng L, Lin Y, et al.
    J Inflamm Res, 2021;14:7107-7130.
    PMID: 34992409 DOI: 10.2147/JIR.S344990
    PURPOSE: Inflammatory bowel diseases (IBDs) are global health problems that are associated with immune regulation, but clinical IBDs treatment is currently inadequate. Effective preventive or therapeutic methods for immune disorders rely on controlling the function of immune cells. Isosteviol sodium (STV-Na) has antioxidant activity, but the therapeutic effect of STV-Na against IBD remain undocumented. Herein, we investigated the therapeutic effect of STV-Na in mice models with IBDs.

    METHODS: Mice received 3.5% DSS for 7 days to establish IBD models. Intraperitoneal STV-Na was given 2 days before DSS and lasted for 9 days. Commercially available drugs used in treating IBDs (5-aminosalicylic acid, dexamethasone, and infliximab) were used as positive controls. Samples were collected 7 days after colitis induction. Histopathological score, biochemical parameters, molecular biology methods, and metabolomics were used for evaluating the therapeutic effect of STV-Na.

    RESULTS: Our data revealed that STV-Na could significantly alleviate colon inflammation in mice with colitis. Specifically, STV-Na treatment improved body weight loss, increased colon length, decreased histology scores, and restored the hematological parameters of mice with colitis. The untargeted metabolomics analysis revealed that metabolic profiles were restored by STV-Na treatment. Furthermore, STV-Na therapy suppressed the number of CD68 macrophages and F4/80 cell infiltration. And STV-Na suppressed M1 and M2 macrophage numbers along with the mRNA expressions of proinflammatory cytokines. Moreover, STV-Na administration increased the number of regulatory T (Treg) cells while decreasing Th1/Th2/Th17 cell counts in the spleen. Additionally, STV-Na treatment restored intestinal barrier disruption in DSS-triggered colitis tissues by ameliorating the TJ proteins, increasing goblet cell proportions, and mucin protein production, and decreasing the permeability to FITC-dextran, which was accompanied by decreased plasma LPS and DAO contents.

    CONCLUSION: These results indicate that STV-Na can ameliorate colitis by modulating immune responses along with metabolic reprogramming, and could therefore be a promising therapeutic strategy for IBDs.

  16. Sivanandy P, Leey TC, Xiang TC, Ling TC, Wey Han SA, Semilan SLA, et al.
    PMID: 35010624 DOI: 10.3390/ijerph19010364
    Parkinson's Disease (PD) is a disease that involves neurodegeneration and is characterised by the motor symptoms which include muscle rigidity, tremor, and bradykinesia. Other non-motor symptoms include pain, depression, anxiety, and psychosis. This disease affects up to ten million people worldwide. The pathophysiology behind PD is due to the neurodegeneration of the nigrostriatal pathway. There are many conventional drugs used in the treatment of PD. However, there are limitations associated with conventional drugs. For instance, levodopa is associated with the on-off phenomenon, and it may induce wearing off as time progresses. Therefore, this review aimed to analyze the newly approved drugs by the United States-Food and Drug Administration (US-FDA) from 2016-2019 as the adjuvant therapy for the treatment of PD symptoms in terms of efficacy and safety. The new drugs include safinamide, istradefylline and pimavanserin. From this review, safinamide is considered to be more efficacious and safer as the adjunct therapy to levodopa as compared to istradefylline in controlling the motor symptoms. In Study 016, both safinamide 50 mg (p = 0.0138) and 100 mg (p = 0.0006) have improved the Unified Parkinson's Disease Rating Scale (UPDRS) part III score as compared to placebo. Improvement in Clinical Global Impression-Change (CGI-C), Clinical Global Impression-Severity of Illness (CGI-S) and off time were also seen in both groups of patients following the morning levodopa dose. Pimavanserin also showed favorable effects in ameliorating the symptoms of Parkinson's Disease Psychosis (PDP). A combination of conventional therapy and non-pharmacological treatment is warranted to enhance the well-being of PD patients.
  17. Tan JK, Khoo CS, Beh HC, Hod R, Baharudin A, Yahya WNNW, et al.
    Epilepsy Res, 2021 Dec;178:106772.
    PMID: 34763265 DOI: 10.1016/j.eplepsyres.2021.106772
    BACKGROUND: Depression is the most frequent psychiatric comorbidity of epilepsy. However, clinicians often neglect to screen for depressive symptoms among patients with epilepsy and, therefore, fail to detect depression. Many studies have described the risks associated with depression in patients with epilepsy, but few studies have elaborated whether these risks are similar in those with undiagnosed depression, especially in a multiethnic community.

    METHODS: In the present cross-sectional study conducted at a tertiary teaching hospital, we aimed to investigate the prevalence and associated risk factors of undiagnosed depression in patients with epilepsy. We recruited patients with epilepsy aged 18-65 years after excluding those with background illnesses that may have contributed to the depressive symptoms. In total, 129 participants were recruited. We collected their demographic and clinical details before interviewing them using two questionnaires-the Neurological Disorders Depression Inventory for Epilepsy and Beck's Depression Inventory-II. Subsequently, if a participant screened positive for depression, the diagnosis was confirmed using the Diagnostic and Statistical Manual of Mental Disorders questionnaire, and a psychiatric clinic referral was offered.

    RESULTS: Among the 129 participants, 9.3 % had undiagnosed major depressive disorder, and there was a female preponderance (66.7 %). The risk factors for undiagnosed depression among patients with epilepsy included low socioeconomic background (p = 0.026), generalized epilepsy (p = 0.036), and temporal lobe epilepsy (p = 0.010). Other variables such as being underweight and unmarried were more common among patients diagnosed with depression than without but no statistically significant relationship was found.

    CONCLUSION: The prevalence of undiagnosed depression among patients with epilepsy was higher than that in population-based studies conducted in Western countries. Although questionnaires to screen for depression are widely available, some clinicians rarely use them and, therefore, fail to identify patients who may benefit from psychosocial support and treatment that would improve their disease outcomes and quality of life. The present study indicated that clinicians should use screening questionnaires to identify undiagnosed depression in people with epilepsy.

  18. Tan TL, Tan-Loh J, Chiew SC, Lim KH, Ng WW, Akmal M, et al.
    Med J Malaysia, 2021 Nov;76(6):820-827.
    PMID: 34806667
    INTRODUCTION: Despite the ever-growing number of community onset (CO) Pseudomonas aeruginosa (P. aeruginosa) bacteraemia, there is a dearth of district hospital-based research examining this significant infection, which is associated with high mortality. The objectives of this study were as following: (1) to determine the risk factors of CO P. aeruginosa bacteraemia, (2) to compare the 30-day mortality rate between P. aeruginosa and Escherichia coli bacteraemia and (3) to identify the predictors of 30-day mortality for CO gram negative bacteraemia.

    METHODS: This is a retrospective case control study in Hospital Seri Manjung and Hospital Teluk Intan, Perak, Malaysia. P. aeruginosa bacteraemia cases that occurred between 1st January 2015 to 31st December 2019 were included, whilst E. coli bacteraemia cases that occurred within the same period were recruited successively until 1:2 case control ratio was achieved. Subjects below 12-year-old and those with polymicrobial bacteraemia were excluded. Demographic, clinical and treatment data were collected using pre-tested data collection forms by trained investigators.

    RESULTS: A total of 61 patients with P. aeruginosa bacteraemia and 122 patients with E. coli bacteraemia were included. Recent admission in the earlier three months, regular haemodialysis, immunosuppressive therapy in the past 30 days, chronic wound/pressure sore at presentation and indwelling urinary catheter at presentation were identified as independent predictors of CO pseudomonal bacteraemia. Whilst older age was identified as a negative predictor of CO Pseudomonal bacteraemia (all p<0.05). The 30-day mortality rate was 34.4% in subjects with P. aeruginosa bacteraemia and 27.0% in those with E. coli bacteraemia (p=0.302). Predictors of 30-day mortality for community onset gram negative bacteraemia were as follow: older age, underlying solid tumours, neutropaenia at presentation, in-patient mechanical ventilation, and inpatient nasogastric tube insertion. Unexpectedly, receipt of inappropriate empirical antibiotics which was switched later (delayed and non-delayed switching) was identified as the negative predictors of mortality (all p<0.05).

    CONCLUSION: It is prudent to restrict the usage of empirical anti-pseudomonal antibiotics among individuals at risk as liberal usage of broad-spectrum antibiotics engenders emergence of drug resistant organism, particularly in district setting where community onset pseudomonal bacteraemia remains scarce. Subjects with elevated risk of mortality should receive early escalation of care as per sepsis management guidelines.

  19. Simon SE, Lim HS, Jayakumar FA, Tan EW, Tan KO
    PMID: 35082905 DOI: 10.1155/2022/7548191
    α-Mangostin, one of the major constituents of Garcinia mangostana, has been reported to possess several biological activities, including antioxidant, anti-inflammatory, antibacterial, and cytotoxic activities associated with the inhibition of cell proliferation and activation of apoptosis. However, the cellular signaling pathway mediated by α-mangostin has not been firmly established. To investigate the cellular activities of α-mangostin, human cancer cells, MCF-7 and MCF-7-CR cells, were treated with α-mangostin to measure the cellular responses, including cytotoxicity, protein-protein interaction, and protein expression. Cancer cells stably expressed Myc-BCL-XL and HA-MOAP-1 were also included in the studies to delineate the cell signaling events mediated by α-mangostin. Our results showed that the apoptosis signaling mediated by α-mangostin involves the upregulation of endogenous MOAP-1, which interacts with α-mangostin activated BAX (act-BAX) while downregulating the expression of BCL-XL. Moreover, α-mangostin was found to induce BAX oligomerization, the release of mitochondrial cytochrome C, and activation of caspase in MCF-7 cells. In overexpression studies, MCF-7 cells and spheroids stably expressed HA-MOAP-1 and Myc-BCL-XL exhibited differential chemosensitivity toward α-mangostin in which the stable clones expressing HA-MOAP-1 and MYC-BCL-XL were chemosensitive and chemoresistant to the apoptosis signaling events mediated by α-mangostin, respectively, when compared to untreated cells. Together, the data suggest that the cytotoxicity of α-mangostin involves the activation of MOAP-1 tumor suppressor and its interaction with act-BAX, leading to mitochondria dysfunction and cell death.
  20. Wang D, Tan KS, Zeng W, Li S, Wang Y, Xu F, et al.
    Life Sci, 2022 Mar 15;293:120336.
    PMID: 35065166 DOI: 10.1016/j.lfs.2022.120336
    AIMS: Individuals with nonalcoholic hepatosteatosis (NAFLD) have a worse atherogenic lipoprotein profile and are susceptible to cardiovascular diseases. The MEK-ERK signaling cascades are central regulators of the levels of LDL receptor (LDLR), a major determinant of circulating cholesterol. It is elusive how hepatic steatosis contributes to dyslipidemia, especially hypercholesterolemia.

    MAIN METHODS: The effects of BChE on signaling pathways were determined by immunoblotting in a BChE knockout hepatocyte cell line. DiI-LDL probe was used to explore the effect of BChE expression on LDL internalization. Co-immunoprecipitation and LC-MS were used to explore the interacting proteins with BChE. Finally, a hepatocyte-restricted BChE silencing mouse model was established by AAV8-Tbg-shRNA, and the hypercholesterolemia was induced by 65% kcal% high-fat, high-sucrose diet feeding.

    MAIN FINDINGS: Here we demonstrate that butyrylcholinesterase (BChE) governs the LDL receptor levels and LDL uptake capacity through the MEK-ERK signaling cascades to promote Ldlr transcription. BChE interacts and co-localizes with PRMT5, a protein methylation modifier controlling the ERK signaling. PRMT5 regulates LDLR-dependent LDL uptake and is a substrate of chaperone-mediated autophagy (CMA). BChE deficiency induces the PRTM5 degradation dependent on CMA activity, possibly through facilitating the HSC70 (Heat shock cognate 71 kDa) recognition of PRMT5. Remarkably, in vivo hepatocyte-restricted BChE silencing reduces plasma cholesterol levels substantially. In contrast, the BChE knockout mice are predisposed to hypercholesterolemia.

    SIGNIFICANCE: Taken together, these findings outline a regulatory role for the BChE-PRMT5-ERK-LDLR axis in hepatocyte cholesterol metabolism, and suggest that targeting liver BChE is an effective therapeutic strategy to treat hypercholesterolemia.

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