Photoactivated riboflavin inhibits planktonic and biofilm growth of Candida albicans and non-albicans Candida species.

Fungal infections caused by Candida species pose a serious threat to humankind. Antibiotics abuse and the ability of Candida species to form biofilm have escalated the emergence of drug resistance in clinical settings and hence, rendered it more difficult to treat Candida-related diseases. Lethal effects of Candida infection are often due to inefficacy of antimicrobial treatments and failure of host immune response to clear infections. Previous studies have shown that a combination of riboflavin with UVA (riboflavin/UVA) light demonstrate candidacidal activity albeit its mechanism of actions remain elusive. Thus, this study sought to investigate antifungal and antibiofilm properties by combining riboflavin with UVA against Candida albicans and non-albicans Candida species. The MIC20 for the fluconazole and riboflavin/UVA against the Candida species tested was within the range of 0.125-2 µg/mL while the SMIC50 was 32 µg/mL. Present findings indicate that the inhibitory activities exerted by riboflavin/UVA towards planktonic cells are slightly less effective as compared to controls. However, the efficacy of the combination towards Candida species biofilms showed otherwise. Inhibitory effects exerted by riboflavin/UVA towards most of the tested Candida species biofilms points towards a variation in mode of action that could make it an ideal alternative therapeutic for biofilm-related infections.

Medicinal benefits, biological, and nanoencapsulation functions of riboflavin with its toxicity profile: A narrative review.

Riboflavin is a precursor of the essential coenzymes flavin mononucleotide and flavin adenine dinucleotide. Both possess antioxidant properties and are involved in oxidation-reduction reactions, which have a significant impact on energy metabolism. Also, the coenzymes participate in metabolism of pyridoxine, niacin, folate, and iron. Humans must obtain riboflavin through their daily diet because of the lack of programmed enzymatic machineries for de novo riboflavin synthesis. Because of its physiological nature and fast elimination from the human body when in excess, riboflavin consumed is unlikely to induce any negative effects or develop toxicity in humans. The use of riboflavin in pharmaceutical and clinical contexts has been previously explored, including for preventing and treating oxidative stress and reperfusion oxidative damage, creating synergistic compounds to mitigate colorectal cancer, modulating blood pressure, improving diabetes mellitus comorbidities, as well as neuroprotective agents and potent photosensitizer in killing bloodborne pathogens. Thus, the goal of this review is to provide a comprehensive understanding of riboflavin's biological applications in medicine, key considerations of riboflavin safety and toxicity, and a brief overview on the nanoencapsulation of riboflavin for various functions including the treatment of a range of diseases, photodynamic therapy, and cellular imaging.

Opportunities and challenges of 5G network technology toward precision medicine.

Moving away from traditional "one-size-fits-all" treatment to precision-based medicine has tremendously improved disease prognosis, accuracy of diagnosis, disease progression prediction, and targeted-treatment. The current cutting-edge of 5G network technology is enabling a growing trend in precision medicine to extend its utility and value to the smart healthcare system. The 5G network technology will bring together big data, artificial intelligence, and machine learning to provide essential levels of connectivity to enable a new health ecosystem toward precision medicine. In the 5G-enabled health ecosystem, its applications involve predictive and preventative measurements which enable advances in patient personalization. This review aims to discuss the opportunities, challenges, and prospects posed to 5G network technology in moving forward to deliver personalized treatments and patient-centric care via a precision medicine approach.

Prevalence of multi-antimicrobial resistant non-typhoidal Salmonella isolated from filth flies at wet markets in Klang, Malaysia, and their survival in the simulated gastric fluid.

Filth flies at wet markets can be a vector harbouring multiple antimicrobial-resistant (MAR) nontyphoidal Salmonella (NTS), and such strains are a significant threat to public health as they may cause severe infections in humans. This study aims to investigate the prevalence of antimicrobial-resistant NTS, especially Salmonella Enteritidis and S. Typhimurium harboured by filth flies at wet markets, and investigate their survival in the simulated gastric fluid (SGF). Filth flies (n = 90) were captured from wet markets in Klang, Malaysia, and processed to isolate Salmonella spp. The isolates (n = 16) were identified using the multiplex-touchdown PCR and assessed their antimicrobial susceptibility against 11 antimicrobial agents. Finally, three isolates with the highest MAR index were subjected to SGF survival tests. It was observed that 17.8 % of flies (n = 16/90) harbouring Salmonella, out of which 10 % (n = 9/90) was S. Enteritidis, 2.2 % (n = 2/90) was S. Typhimurium, and 5.6 % was unidentified serotypes of Salmonella enterica subsp. I. 43.8 % (n = 7/16) were confirmed as MAR, and they were observed to be resistant against ampicillin, chloramphenicol, kanamycin, streptomycin, and nalidixic acid. Three strains, F35, F75, and F85 demonstrated the highest MAR index and were able to survive (>6-log10) in the SGF (180 min), indicating their potential virulence and invasiveness. This study provides significant insights into the prevalence and severity of MAR nontyphoidal Salmonella harboured by filth flies in wet markets, which may help inform strategies for controlling the spread and outbreak of foodborne disease.

Genomic Surveillance of SARS-CoV-2 in Malaysia during the Era of Endemic COVID-19.

On 5 May 2023, WHO declared the end of coronavirus disease 2019 (COVID-19) as a public health emergency of international concern. However, the risk of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants causing rapid and high surges in cases and deaths remained. In Malaysia, five COVID-19 waves during the pandemic phase were well characterized, but similar studies focusing on the endemic phase were lacking. Hence, we retrieved 14,965 SARS-CoV-2 genomic sequences from the GISAID EpiCoV database for clade, lineage, and phylogenetic analysis in order to provide an insight into the population dynamics of SARS-CoV-2 that circulated in Malaysia from June 2022 to April 2023. The dominance of the Omicron variants was observed, and two new waves of infections driven by BA.5.2 and XBB.1, respectively, were detected. Data as of April 2023 also pointed to a possible eighth wave driven by XBB.1.9. Although new variants associated with higher transmissibility were behind the multiple surges, these subsequent waves had lower intensities as compared to the fourth and fifth waves. The on-going circulation and evolution of SARS-CoV-2 mean that COVID-19 still poses a serious threat, necessitating active genomic surveillance for early warning of potential new variants of concern.

Pathogenetic Mechanisms of Liver-Associated Injuries, Management, and Current Challenges in COVID-19 Patients.

The global outbreak of COVID-19 possesses serious challenges and adverse impacts for patients with progression of chronic liver disease and has become a major threat to public health. COVID-19 patients have a high risk of lung injury and multiorgan dysfunction that remains a major challenge to hepatology. COVID-19 patients and those with liver injury exhibit clinical manifestations, including elevation in ALT, AST, GGT, bilirubin, TNF-α, and IL-6 and reduction in the levels of CD4 and CD8. Liver injury in COVID-19 patients is induced through multiple factors, including a direct attack of SARS-CoV-2 on liver hepatocytes, hypoxia reperfusion dysfunction, cytokine release syndrome, drug-induced hepatotoxicity caused by lopinavir and ritonavir, immune-mediated inflammation, renin-angiotensin system, and coagulopathy. Cellular and molecular mechanisms underlying liver dysfunction are not fully understood in severe COVID-19 attacks. High mortality and the development of chronic liver diseases such as cirrhosis, alcoholic liver disease, autoimmune hepatitis, nonalcoholic fatty liver disease, and hepatocellular carcinoma are also associated with patients with liver damage. COVID-19 patients with preexisting or developing liver disease should be managed. They often need hospitalization and medication, especially in conjunction with liver transplants. In the present review, we highlight the attack of SARS-CoV-2 on liver hepatocytes by exploring the cellular and molecular events underlying the pathophysiological mechanisms in COVID-19 patients with liver injury. We also discuss the development of chronic liver diseases during the progression of SARS-CoV-2 replication. Lastly, we explore management principles in COVID-19 patients with liver injury and liver transplantation.

Explorations of CRISPR/Cas9 for improving the long-term efficacy of universal CAR-T cells in tumor immunotherapy.

Chimeric antigen receptor (CAR) T therapy has shown remarkable success in discovering novel CAR-T cell products for treating malignancies. Despite of successful results from clinical trials, CAR-T cell therapy is ineffective for long-term disease progression. Numerous challenges of CAR-T cell immunotherapy such as cell dysfunction, cytokine-related toxicities, TGF-ß resistance, GvHD risks, antigen escape, restricted trafficking, and tumor cell infiltration still exist that hamper the safety and efficacy of CAR-T cells for malignancies. The accumulated data revealed that these challenges could be overcome with the advanced CRISPR genome editing technology, which is the most promising tool to knockout TRAC and HLA genes, inhibiting the effects of dominant negative receptors (PD-1, TGF-ß, and B2M), lowering the risks of cytokine release syndrome (CRS), and regulating CAR-T cell function in the tumor microenvironment (TME). CRISPR technology employs DSB-free genome editing methods that robustly allow efficient and controllable genetic modification. The present review explored the innovative aspects of CRISPR/Cas9 technology for developing next-generation/universal allogeneic CAR-T cells. The present manuscript addressed the ongoing status of clinical trials of CRISPR/Cas9-engineered CAR-T cells against cancer and pointed out the off-target effects associated with CRISPR/Cas9 genome editing. It is concluded that CAR-T cells modified by CRISPR/Cas9 significantly improved antitumor efficacy in a cost-effective manner that provides opportunities for novel cancer immunotherapies.

Riboflavin as a promising antimicrobial agent? A multi-perspective review.

Riboflavin, or more commonly known as vitamin B2, forms part of the component of vitamin B complex. Riboflavin consisting of two important cofactors, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are involved in multiple oxidative-reduction processes and energy metabolism. Besides maintaining human health, different sources reported that riboflavin can inhibit or inactivate the growth of different pathogens including bacteria, viruses, fungi and parasites, highlighting the possible role of riboflavin as an antimicrobial agent. Moreover, riboflavin and flavins could produce reactive oxygen species (ROS) when exposed to light, inducing oxidative damage in cells and tissues, and thus are excellent natural photosensitizers. Several studies have illustrated the therapeutic efficacy of photoactivated riboflavin against nosocomial infections and multidrug resistant bacterial infections as well as microbial associated biofilm infections, revealing the potential role of riboflavin as a promising antimicrobial candidate, which could serve as one of the alternatives in fighting the global crisis of the emergence of antimicrobial resistance seen in different pathogenic microbes. Riboflavin could also be involved in modulating host immune responses, which might increase the pathogen clearance from host cells and increase host defense against microbial infections. Thus, the dual effects of riboflavin on both pathogens and host immunity, reflected by its potent bactericidal effect and alleviation of inflammation in host cells further imply that riboflavin could be a potential candidate for therapeutic intervention in resolving microbial infections. Hence, this review aimed to provide some insights on the promising role of riboflavin as an antimicrobial candidate and also a host immune-modulator from a multi-perspective view as well as to discuss the application and challenges on using riboflavin in photodynamic therapy against various pathogens and microbial biofilm-associated infections.

Human tuberculosis and Mycobacterium tuberculosis complex: A review on genetic diversity, pathogenesis and omics approaches in host biomarkers discovery.

Mycobacterium tuberculosis complex (MTBC) refers to a group of mycobacteria encompassing nine members of closely related species that causes tuberculosis in animals and humans. Among the nine members, Mycobacterium tuberculosis (M. tuberculosis) remains the main causative agent for human tuberculosis that results in high mortality and morbidity globally. In general, MTBC species are low in diversity but exhibit distinctive biological differences and phenotypes among different MTBC lineages. MTBC species are likely to have evolved from a common ancestor through insertions/deletions processes resulting in species speciation with different degrees of pathogenicity. The pathogenesis of human tuberculosis is complex and remains poorly understood. It involves multi-interactions or evolutionary co-options between host factors and bacterial determinants for survival of the MTBC. Granuloma formation as a protection or survival mechanism in hosts by MTBC remains controversial. Additionally, MTBC species are capable of modulating host immune response and have adopted several mechanisms to evade from host immune attack in order to survive in humans. On the other hand, current diagnostic tools for human tuberculosis are inadequate and have several shortcomings. Numerous studies have suggested the potential of host biomarkers in early diagnosis of tuberculosis, in disease differentiation and in treatment monitoring. "Multi-omics" approaches provide holistic views to dissect the association of MTBC species with humans and offer great advantages in host biomarkers discovery. Thus, in this review, we seek to understand how the genetic variations in MTBC lead to species speciation with different pathogenicity. Furthermore, we also discuss how the host and bacterial players contribute to the pathogenesis of human tuberculosis. Lastly, we provide an overview of the journey of "omics" approaches in host biomarkers discovery in human tuberculosis and provide some interesting insights on the challenges and directions of "omics" approaches in host biomarkers innovation and clinical implementation.

RAGE modulatory effects on cytokines network and histopathological conditions in malarial mice.

This study was aimed at investigating the involvement of Receptor for Advanced Glycation End Products (RAGE) during malaria infection and the effects of modulating RAGE on the inflammatory cytokines release and histopathological conditions of affected organs in malarial animal model. Plasmodium berghei (P. berghei) ANKA-infected ICR mice were treated with mRAGE/pAb and rmRAGE/Fc Chimera drugs from day 1 to day 4 post infection. Survival and parasitaemia levels were monitored daily. On day 5 post infection, mice were sacrificed, blood were drawn for cytokines analysis and major organs including kidney, spleen, liver, brain and lungs were extracted for histopathological analysis. RAGE levels were increased systemically during malaria infection. Positive correlation between RAGE plasma concentration and parasitaemia development was observed. Treatment with RAGE related drugs did not improve survival of malaria-infected mice. However, significant reduction on the parasitaemia levels were recorded. On the other hand, inhibition and neutralization of RAGE production during the infection significantly increased the plasma levels of interleukin (IL-4, IL-17A, IL-10 and IL-2) and reduced interferon (IFN)-γ secretion. Histopathological analysis revealed that all treated malarial mice showed a better outcome in histological assessment of affected organs (brain, liver, spleen, lungs and kidney). RAGE is involved in malaria pathogenesis and targeting RAGE could be beneficial in malaria infected host in which RAGE inhibition or neutralization increased the release of anti-inflammatory cytokines (IL-10 and IL-4) and reduce pro-inflammatory cytokine (IFNγ) which may help alleviate tissue injury and improve histopathological conditions of affected organs during the infection.

The Role, Involvement and Function(s) of Interleukin-35 and Interleukin-37 in Disease Pathogenesis.

The recently identified cytokines-interleukin (IL)-35 and interleukin (IL)-37-have been described for their anti-inflammatory and immune-modulating actions in numerous inflammatory diseases, auto-immune disorders, malignancies, infectious diseases and sepsis. Either cytokine has been reported to be reduced and in some cases elevated and consequently contributed towards disease pathogenesis. In view of the recent advances in utilizing cytokine profiles for the development of biological macromolecules, beneficial in the management of certain intractable immune-mediated disorders, these recently characterized cytokines (IL-35 and IL-37) offer potential as reasonable targets for the discovery of novel immune-modulating anti-inflammatory therapies. A detailed comprehension of their sophisticated regulatory mechanisms and patterns of expression may provide unique opportunities for clinical application as highly selective and target specific therapeutic agents. This review seeks to summarize the recent advancements in discerning the dynamics, mechanisms, immunoregulatory and anti-inflammatory actions of IL-35 and IL-37 as they relate to disease pathogenesis.

Critical Roles of IL-33/ST2 Pathway in Neurological Disorders.

Interleukin-33 (IL-33) is an IL-1 family member, which exhibits both pro- and anti-inflammatory properties solely based on the type of the disease itself. Generally, IL-33 is expressed by both endothelial and epithelial cells and mediates its function based on the interaction with various receptors, mainly with ST2 variants. IL-33 is a potent inducer for the Th2 immune response which includes defence mechanism in brain diseases. Thus, in this paper, we review the biological features of IL-33 and the critical roles of IL-33/ST2 pathway in selected neurological disorders including Alzheimer's disease, multiple sclerosis, and malaria infection to discuss the involvement of IL-33/ST2 pathway during these brain diseases and its potential as future immunotherapeutic agents or for intervention purposes.

Dissecting Candida albicans Infection from the Perspective of C. albicans Virulence and Omics Approaches on Host-Pathogen Interaction: A Review.

Candida bloodstream infections remain the most frequent life-threatening fungal disease, with Candida albicans accounting for 70% to 80% of the Candida isolates recovered from infected patients. In nature, Candida species are part of the normal commensal flora in mammalian hosts. However, they can transform into pathogens once the host immune system is weakened or breached. More recently, mortality attributed to Candida infections has continued to increase due to both inherent and acquired drug resistance in Candida, the inefficacy of the available antifungal drugs, tedious diagnostic procedures, and a rising number of immunocompromised patients. Adoption of animal models, viz. minihosts, mice, and zebrafish, has brought us closer to unraveling the pathogenesis and complexity of Candida infection in human hosts, leading towards the discovery of biomarkers and identification of potential therapeutic agents. In addition, the advancement of omics technologies offers a holistic view of the Candida-host interaction in a non-targeted and non-biased manner. Hence, in this review, we seek to summarize past and present milestone findings on C. albicans virulence, adoption of animal models in the study of C. albicans infection, and the application of omics technologies in the study of Candida-host interaction. A profound understanding of the interaction between host defense and pathogenesis is imperative for better design of novel immunotherapeutic strategies in future.

Correlation of BACH1 and Hemoglobin E/Beta-Thalassemia Globin Expression.

OBJECTIVE: The diverse clinical phenotype of hemoglobin E (HbE)/ß-thalassemia has not only confounded clinicians in matters of patient management but has also led scientists to investigate the complex mechanisms involved in maintaining the delicate red cell environment where, even with apparent similarities of α- and ß-globin genotypes, the phenotype tells a different story. The BTB and CNC homology 1 (BACH1) protein is known to regulate α- and ß-globin gene transcriptions during the terminal differentiation of erythroid cells. With the mutations involved in HbE/ß-thalassemia disorder, we studied the role of BACH1 in compensating for the globin chain imbalance, albeit for fine-tuning purposes. MATERIALS AND METHODS: A total of 47 HbE/ß-thalassemia samples were analyzed using real-time quantitative polymerase chain reaction and correlated with age, sex, red blood cell parameters, globin gene expressions, and some clinical data. RESULTS: The BACH1 expression among the ß-thalassemia intermedia patients varied by up to 2-log differences and was positively correlated to age; α-, ß-, and γ-globin gene expression level; and heme oxygenase 1 protein. BACH1 was also negatively correlated to reticulocyte level and had a significant correlation with splenectomy. CONCLUSION: This study indicates that the expression of BACH1 could be elevated as a compensatory mechanism to decrease the globin chain imbalance as well as to reduce the oxidative stress found in HbE/ß-thalassemia.