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Fulltext Small-molecule inhibitors of bacterial-producing metallo-β-lactamases: insights into their resistance mechanisms and biochemical analyses of their activities

Ayipo YO, Chong CF, Mordi MN

RSC Med Chem, 2023 Jun 22;14(6):1012-1048.
PMID: 37360393 DOI: 10.1039/d3md00036b

Antibiotic resistance (AR) remains one of the major threats to the global healthcare system, which is associated with alarming morbidity and mortality rates. The defence mechanisms of Enterobacteriaceae to antibiotics occur through several pathways including the production of metallo-β-lactamases (MBLs). The carbapenemases, notably, New Delhi MBL (NDM), imipenemase (IMP), and Verona integron-encoded MBL (VIM), represent the critical MBLs implicated in AR pathogenesis and are responsible for the worst AR-related clinical conditions, but there are no approved inhibitors to date, which needs to be urgently addressed. Presently, the available antibiotics including the most active β-lactam-types are subjected to deactivation and degradation by the notorious superbug-produced enzymes. Progressively, scientists have devoted their efforts to curbing this global menace, and consequently a systematic overview on this topic can aid the timely development of effective therapeutics. In this review, diagnostic strategies for MBL strains and biochemical analyses of potent small-molecule inhibitors from experimental reports (2020-date) are overviewed. Notably, N1 and N2 from natural sources, S3-S7, S9 and S10 and S13-S16 from synthetic routes displayed the most potent broad-spectrum inhibition with ideal safety profiles. Their mechanisms of action include metal sequestration from and multi-dimensional binding to the MBL active pockets. Presently, some β-lactamase (BL)/MBL inhibitors have reached the clinical trial stage. This synopsis represents a model for future translational studies towards the discovery of effective therapeutics to overcome the challenges of AR.
Fulltext A rare case of Dysphagia secondary to a large oesophageal lipoma

Koh KS, Chong VH, Yapp SK, Chong CF

Med J Malaysia, 2012 Oct;67(5):522-3.
PMID: 23770871

Dysphagia is considered a warning symptom that requires exclusion of significant pathology such as oesophageal cancer, especially in elderly patients. Benign neoplasms of the oesophagus are rare. We report the case of a 69-year-old lady who presented with a five years history of infrequent intermittent dysphagia that had rapidly progressed over one month. This was associated with globus sensation, weight loss, intermittent episodes of stridor and aspiration pneumonia. Investigations revealed a large oesophageal lipoma in the proximal oesophagus extending down to the lower oesophagus. This was successfully resected via a left cervical approach. She remained well two years after the surgery.
Cancers among South-East Asian Nationals in Brunei Darussalam

Chong VH, Telisinghe PU, Lim E, Tan J, Chong CF

Asian Pac J Cancer Prev, 2016;17(2):845-9.
PMID: 26925690

BACKGROUND: Worldwide, the incidence of cancers is increasing and is becoming a major public health issue, including those in the Asia Pacific region. South-East Asia is a region with diverse populations with different disease spectra. This study looked at the spectrum of cancers among South-East Asians working in Brunei Darussalam.
MATERIALS AND METHODS: The cancer registry from 1994 to 2012 maintained by the State Laboratory was retrospectively reviewed. Crude incidence rates were calculated based on the population census of 2010.
RESULTS: Altogether, there was a total of 418 cancer cases diagnosed among South-East Asians, giving an incidence of 5.1% (n=418/8,253). The affected nationals in decreasing frequency were Malaysians (53.1%), followed by Filipinos (25.8%), Indonesians (15.3%), Thais (3.8%), Myanmese (1.7%) and Vietnamese (0.2%) with no recorded cases for Singapore and the People's Republic of Laos. The overall mean age of diagnosis was 46.1±4.2 years old, with an increasing trend over the years (p<0.05 ANOVA). The overall gender ratio was 42.3:57.7 (male:female), more females among the Filipinos and Indonesians, more males among the Thais, and equal representation among the Malaysians and the Myanmese. The most common were cancers of the digestive system (19.9%), followed by female reproductive/gynecologic system (16.0%), breast (15.6%), hematological/lymphatic (12.0%) and head/neck (8.1%). There were differences in the prevalence of cancers among the various nationalities with highest crude incidence rate among the Myanmese (141.2/100,000), followed by the Malaysian (88.5/100,000), and the Filipinos (40.6/100,000) and the lowest among the Thais (18.4/100,000), Indonesians (10.5/100,000) and the Vietnamese (6.3/100,000).
CONCLUSIONS: Cancers among South-East Asian residing in Brunei Darussalam accounted for 5.1% of all cancers. The most common cancers were cancers of the digestive, gynecologic/female reproductive system and breast with certain types slowly increasing in proportions. There mean age of diagnoses was increasing.
Navigating the landscape of Rho GTPase signalling system in autoimmunity: A bibliometric analysis spanning over three decades (1990 to 2023)

Chong CF, Hasnizan NYU, Ahmad Mokhtar AM

Cell Signal, 2023 Nov;111:110855.
PMID: 37598919 DOI: 10.1016/j.cellsig.2023.110855

Ras-homologous (Rho) guanosine triphosphatases (GTPases) are considered a central player in regulating various biological processes, extending to immune regulation. Perturbations in Rho GTPase signalling have been implicated in immune-related dysregulation, contributing to the development of autoimmunity. This study presents a scientometric analysis exploring the interlink between the Rho GTPase signalling system and autoimmunity, while also delving into the trends of past studies. A total of 967 relevant publications from 1990 to 2023 were retrieved from the Web of Science Core Collection database after throrough manual filtering of irrelevant articles. The findings show an upward trajectory in publications related to this field since 2006. Over the past three decades, the United States of America (41.68%) emerged as the primary contributor in advancing our understanding of the association between the Rho GTPase signalling system and autoimmunity. Research in autoimmunity has mainly centered around therapeutic interventions, with an emphasis on studying leukocyte (macrophage) and endothelial remodelling. Interestingly, within the domains of multiple sclerosis and rheumatoid arthritis, the current focus has been directed towards comprehending the role of RhoA, Rac1, and Cdc42. Notably, certain subfamilies of Rho (such as RhoB and RhoC), Rac (including Rac2 and RhoG), Cdc42 (specifically RhoJ), and other atypical Rho GTPases (like RhoE and RhoH) consistently demonstrating compelling link with autoimmunity, but still warrants emphasis in the future study. Hence, strategic manipulation of the Rho signalling system holds immense promise as a pivotal approach to addressing the global challenge of autoimmunity.
Bioactive alkaloidal and phenolic phytochemicals as promising epidrugs for diabetes mellitus 2: A review of recent development

Ayipo YO, Chong CF, Abdulameed HT, Mordi MN

Fitoterapia, 2024 Mar 27;175:105922.
PMID: 38552806 DOI: 10.1016/j.fitote.2024.105922

Type 2 diabetes (T2D) remains a major chronic metabolic disorder affecting hundreds of millions of the global population, mostly among adults, engendering high rates of morbidity and mortality. It is characterized by complex aetiologies including insulin deficiency and resistance, and hyperglycemia, and these significantly constitute therapeutic challenges. Several pathways have been implicated in its pathophysiology and treatment including the epigenetic regulatory mechanism, notably, deoxyribonucleic acid (DNA) methylation/demethylation, histone modification, non-coding ribonucleic acid (ncRNA) modulation and other relevant pathways. Many studies have recently documented the implications of phytochemicals on the aforementioned biomarkers in the pathogenesis and treatment of T2D. In this review, the cellular and molecular mechanisms of the epigenetic effects of some bioactive alkaloidal and phenolic phytochemicals as potential therapeutic alternatives for T2D have been overviewed from the recent literature (2019-2024). From the survey, the natural product-based compounds, C1-C32 were curated as potent epigenetic modulators for T2D. Their cellular and molecular mechanisms of anti-T2D activities with relevant epigenetic biomarkers were revealed. Although, more comprehensive experimental analyses are observably required for validating their activity and toxicological indices. Thus, perspectives and challenges were enumerated for such demanding future translational studies. The review reveals advances in scientific efforts towards reversing the global trend of T2D through epigenetic phytotherapeutics.
Declining Incidence of Nasopharyngeal Carcinoma in Brunei Darussalam: a Three Decade Study (1986-2014)

Chong VH, Telisinghe PU, Lim E, Abdullah MS, Idris F, Chong CF

Asian Pac J Cancer Prev, 2015;16(16):7097-101.
PMID: 26514496

BACKGROUND: Nasopharyngeal carcinoma (NPC) is linked to Epstein Barr virus infection and is particularly common in the Far East, particularly among some Chinese groups. Certain ethnicities have been reported to have low incidence of NPC. This study looked at NPC in Brunei Darussalam over a three decade period.
MATERIALS AND METHODS: The cancer registry from 1986 to 2014 maintained by the State Laboratory was retrospectively reviewed. The age standardized rates (ASR) and the age specific incidence rates (ASIR) were calculated. Non NPC tumors were excluded from the study.
RESULTS: Altogether, there were a total of 450 NPC cases diagnosed accounting for 4.4% of all total cancer cases over the study period, declining from 10.3% in 1986-1990 to 2.3% in 2011-2014. The most common tumor type was the undifferentiated carcinoma (96.4%). The case characteristics were mean age 50.4 ± 14.4 years old, male 69%, and predominately Malays 74.4%, followed by Chinese 16.7%. The mean age of diagnosis increased over the study period from 45.6 ± 17.1 years (1986-1989) to 54.1 ± 12.5 years (ANOVA, p<0.01 for trend). There were no differences in the mean age of diagnosis between the ethnic groups or genders. The ASR showed a declining trend from 11.1 per 100,000 in 1986-1990 to 5.95 per 100,000 in 2011-2014, similar trends been observedfor both genders. Among the age groups, declining trends were seen in all the other age groups apart from the >70 years group. The overall ASRs for the Malays and Chinese were 7.92/100,000 and 8.83/100,000 respectively, both showing declining trends.
CONCLUSIONS: The incidence of NPC in Brunei Darussalam is comparable to rates reported from Singapore and Malaysia, but higher than rates reported from the other Southeast Asian nations. Unlike higher rates reported for Chinese compared to the Malays in other countries, the rates between the Malays and Chinese in our study was comparable. Importantly, the ASR is declining overall and for both genders and ethnic groups.
Fulltext Characteristics of young colorectal cancer in Brunei Darussalam: an epidemiologic study of 29 years (1986-2014)

Koh KS, Telisinghe PU, Bickle I, Abdullah MS, Chong CF, Chong VH

Asian Pac J Cancer Prev, 2015;16(8):3279-83.
PMID: 25921132

BACKGROUND: Colorectal cancer (CRC) is the most common gastrointestinal cancer and the incidence is increasing. CRC is more common with increasing age, but a proportion occurs in young adults, termed young CRC. This study assessed the incidence and the demographic of young CRC in Brunei Darussalam.

MATERIALS AND METHODS: All histologically proven CRC between 1986 and 2014 registered with the Department of Pathology cancer registry were reviewed and data extracted for analyses. Young CRC was defined as cancer in patients aged less than 45 years. The various population groups were categorized into locals (Malays, Chinese and Indigenous) and expatriates.

RESULTS: Over the study period, there were 1,126 histologically proven CRC (mean age 59.1 ± 14.7 years, Male 58.0%, Locals 91.8% and 8.2% expatriates). Young CRC accounted for 15.1% with the proportion declining over the years, from 29% (1986-1990) to 13.2% (2011-2014). The proportion of young CRC was highest among the indigenous (30.8%), followed by the expatriates (29.3%), Malays (14.3%) and lowest among the Chinese (10.8%). The mean age of young CRC was 35.9 ± 6.2; lowest among the indigenous (33.5 ± 6.7), expatriate (34.9 ± 6.0) groupd and the Malays (35.6 ± 6.5) compared to the Chinese (38.6 ± 4.6), a similar trend being observed in the non-young CRC groups. There were no difference between the genders and tumor locations (rectum or colon) between the young and the non-young CRC cases. Female young CRC was significantly younger than male (p<0.05) without any significant variation between the various population groups (p>0.05).

CONCLUSIONS: Our study showed that the young CRC accounted for 15.1% of all CRC with declining trend observed over recent years. Young CRC was more common among indigenous, expatriates and Malays and least common among the Chinese. There were no differences in the gender and tumor locations.
Fulltext Xanthogranulomatous pyelonephritis with reno-colic fistula: A rare complication of urinary tract infection

Onn LV, Bickle I, Chua HB, Telisinghe PU, Chong CF, Chong VH

Malays Fam Physician, 2017;12(3):33-36.
PMID: 29527279

Urinary tract infection (UTI) is one of the most common presentations in general practice and, in most instances, occurs in a single episode and is easily treated with a course of anti-microbial therapy. In the case of recurrent urinary tract infections, it is important to consider evaluation for any underlying causes. We report the case of a 32 year old female who had recurrent UTIs; this was a case of recurrent UTI secondary to xanthogranulomatous pyelonephritis from renal stones with resultant reno-colic fistula formation.
Carbazole derivatives as promising competitive and allosteric inhibitors of human serotonin transporter: computational pharmacology

Ayipo YO, Ahmad I, Chong CF, Zainurin NA, Najib SY, Patel H, et al.

J Biomol Struct Dyn, 2024;42(2):993-1014.
PMID: 37021485 DOI: 10.1080/07391102.2023.2198016

The human serotonin transporters (hSERTs) are neurotransmitter sodium symporters of the aminergic G protein-coupled receptors, regulating the synaptic serotonin and neuropharmacological processes related to neuropsychiatric disorders, notably, depression. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and (S)-citalopram are competitive inhibitors of hSERTs and are commonly the first-line medications for major depressive disorder (MDD). However, treatment-resistance and unpleasant aftereffects constitute their clinical drawbacks. Interestingly, vilazodone emerged with polypharmacological (competitive and allosteric) inhibitions on hSERTs, amenable to improved efficacy. However, its application usually warrants adjuvant/combination therapy, another subject of critical adverse events. Thus, the discovery of alternatives with polypharmacological potentials (one-drug-multiple-target) and improved safety remains essential. In this study, carbazole analogues from chemical libraries were explored using docking and molecular dynamics (MD) simulation. Selectively, two IBScreen ligands, STOCK3S-30866 and STOCK1N-37454 predictively bound to the active pockets and expanded boundaries (extracellular vestibules) of the hSERTs more potently than vilazodone and (S)-citalopram. For instance, the two ligands showed docking scores of -9.52 and -9.59 kcal/mol and MM-GBSA scores of -92.96 and -65.66 kcal/mol respectively compared to vilazodone's respective scores of -7.828 and -59.27 against the central active site of the hSERT (PDB 7LWD). Similarly, the two ligands also docked to the allosteric pocket (PDB 5I73) with scores of -8.15 and -8.40 kcal/mol and MM-GBSA of -96.14 and -68.46 kcal/mol whereas (S)-citalopram has -6.90 and -69.39 kcal/mol respectively. The ligands also conferred conformational stability on the receptors during 100 ns MD simulations and displayed interesting ADMET profiles, representing promising hSERT modulators for MDD upon experimental validation.Communicated by Ramaswamy H. Sarma.
Fulltext Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis

Xiao Y, Zhang S, Dai N, Fei G, Goh KL, Chun HJ, et al.

Gut, 2020 02;69(2):224-230.
PMID: 31409606 DOI: 10.1136/gutjnl-2019-318365

OBJECTIVE: To establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO).
DESIGN: In this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs).
RESULTS: In the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI -3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI -1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI -4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI -5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI -8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI -9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively.
CONCLUSION: Our findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms.
TRIAL REGISTRATION NUMBER: NCT02388724.
Vonoprazan 10 mg or 20 mg vs. lansoprazole 15 mg as maintenance therapy in Asian patients with healed erosive esophagitis: A randomized controlled trial

Xiao Y, Qian J, Zhang S, Dai N, Chun HJ, Chiu C, et al.

Chin Med J (Engl), 2024 Apr 20;137(8):962-971.
PMID: 38654422 DOI: 10.1097/CM9.0000000000003068

BACKGROUND: Erosive esophagitis (EE) is a gastroesophageal reflux disease characterized by mucosal breaks in the esophagus. Proton pump inhibitors are widely used as maintenance therapy for EE, but many patients still relapse. In this trial, we evaluated the noninferiority of vonoprazan vs. lansoprazole as maintenance therapy in patients with healed EE.
METHODS: We performed a double-blind, double-dummy, multicenter, phase 3 clinical trial among non-Japanese Asian adults with endoscopically confirmed healed EE from April 2015 to February 2019. Patients from China, South Korea, and Malaysia were randomized to vonoprazan 10 mg or 20 mg once daily or lansoprazole 15 mg once daily for 24 weeks. The primary endpoint was endoscopically confirmed EE recurrence rate over 24 weeks with a noninferiority margin of 10% using a two-sided 95% confidence interval (CI). Treatment-emergent adverse events (TEAEs) were recorded.
RESULTS: Among 703 patients, EE recurrence was observed in 24/181 (13.3%) and 21/171 (12.3%) patients receiving vonoprazan 10 mg or 20 mg, respectively, and 47/184 (25.5%) patients receiving lansoprazole (differences: -12.3% [95% CI, -20.3% to -4.3%] and -13.3% [95% CI, -21.3% to -5.3%], respectively), meeting the primary endpoint of noninferiority to lansoprazole in preventing EE recurrence at 24 weeks. Evidence of superiority (upper bound of 95% CI <0%) was also observed. At 12 weeks, endoscopically confirmed EE recurrence was observed in 5/18, 2/20, and 7/20 of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. TEAEs were experienced by 66.8% (157/235), 69.0% (156/226), and 65.3% (158/242) of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. The most common TEAE was upper respiratory tract infection in 12.8% (30/235) and 12.8% (29/226) patients in vonoprazan 10 mg and 20 mg groups, respectively and 8.7% (21/242) patients in lansoprazole group.
CONCLUSION: Vonoprazan maintenance therapy was well-tolerated and noninferior to lansoprazole for preventing EE recurrence in Asian patients with healed EE.
TRIAL REGISTRATION: https://clinicaltrials.gov; NCT02388737.

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