Inhibition of SARS-CoV-2 3CL protease by the anti-viral chimeric protein RetroMAD1.

COVID-19 results from SARS-CoV-2, which mutates frequently, challenging current treatments. Therefore, it is critical to develop new therapeutic drugs against this disease. This study explores the interaction between SARS-CoV-2 3CLpro and RetroMAD1, a well-characterized coronavirus protein and potential drug target, using in-silico methods. The analysis through the HDOCK server showed stable complex formation with a binding energy of -12.3, the lowest among reference drugs. The RetroMAD1-3CLpro complex underwent a 100 ns molecular dynamics simulation (MDS) in an explicit solvation system, generating various trajectories, including RMSD, RMSF, hydrogen bonding, radius of gyration, and ligand binding energy. MDS results confirmed intact interactions within the RetroMAD1-3CLpro complex during simulations. In vitro experiments validated RetroMAD1's ability to inhibit 3CLpro enzyme activity and prevent SARS-CoV-2 infection in human bronchial cells. RetroMAD1 exhibited antiviral efficacy comparable to Remdesivir without cytotoxicity at effective concentrations. These results suggest RetroMAD1 as a potential drug candidate against SARS-CoV-2, warranting further in vivo and clinical studies to assess its efficiency.

Rice Bran: From Waste to Nutritious Food Ingredients.

Rice (Oryza sativa L.) is a principal food for more than half of the world's people. Rice is predominantly consumed as white rice, a refined grain that is produced during the rice milling process which removes the bran and germ and leaves the starchy endosperm. Rice bran is a by-product produced from the rice milling process, which contains many bioactive compounds, for instance, phenolic compounds, tocotrienols, tocopherols, and γ-oryzanol. These bioactive compounds are thought to protect against cancer, vascular disease, and type 2 diabetes. Extraction of rice bran oil also generates various by-products including rice bran wax, defatted rice bran, filtered cake, and rice acid oil, and some of them exert bioactive substances that could be utilized as functional food ingredients. However, rice bran is often utilized as animal feed or discarded as waste. Therefore, this review aimed to discuss the role of rice bran in metabolic ailments. The bioactive constituents and food product application of rice bran were also highlighted in this study. Collectively, a better understanding of the underlying molecular mechanism and the role of these bioactive compounds exerted in the rice bran would provide a useful approach for the food industry and prevent metabolic ailments.

Persistent Newcastle disease virus infection in bladder cancer cells is associated with putative pro-survival and anti-viral transcriptomic changes.

BACKGROUND: Newcastle disease virus (NDV) is an oncolytic virus with excellent selectivity against cancer cells, both in vitro and in vivo. Unfortunately, prolonged in vitro NDV infection results in the development of persistent infection in the cancer cells which are then able to resist NDV-mediated oncolysis. However, the mechanism of persistency of infection remains poorly understood. METHODS: In this study, we established persistently NDV-infected EJ28 bladder cancer cells, designated as EJ28P. Global transcriptomic analysis was subsequently carried out by microarray analysis. Differentially expressed genes (DEGs) between EJ28 and EJ28P cells identified by the edgeR program were further analysed by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) analyses. In addition, the microarray data were validated by RT-qPCR. RESULTS: Persistently NDV-infected EJ28 bladder cancer cells were successfully established and confirmed by flow cytometry. Microarray analysis identified a total of 368 genes as differentially expressed in EJ28P cells when compared to the non-infected EJ28 cells. GSEA revealed that the Wnt/ß-catenin and KRAS signalling pathways were upregulated while the TGF-ß signalling pathway was downregulated. Findings from this study suggest that the upregulation of genes that are associated with cell growth, pro-survival, and anti-apoptosis may explain the survivability of EJ28P cells and the development of persistent infection of NDV. CONCLUSIONS: This study provides insights into the transcriptomic changes that occur and the specific signalling pathways that are potentially involved in the development and maintenance of NDV persistency of infection in bladder cancer cells. These findings warrant further investigation and is crucial towards the development of effective NDV oncolytic therapy against cancer.

The findings of 18F-fluorodeoxyglucose positron emission tomography-computed tomography scan in patients with hidradenitis suppurativa in Malaysia: A multicenter study.

Hidradenitis suppurativa (HS) is known to have association with systemic diseases with chronic inflammation such as psoriasis. We aim to describe the concomitant systemic inflammation in patients with HS using 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) scan. This was a case-control study conducted in three tertiary hospitals in Northern Malaysia from January to December 2017, involving HS patients aged 18 years and above. Thirty-two HS patients with age- and sex-matched controls were recruited with a mean age of 31.4 years (range: 18-56). Numerous cutaneous inflammatory foci were detected on FDG-PET/CT scan in clinically unapparent sites (27/32, 84.4%). Approximately 90.6%, 93.8%, and 50.0% of the patients had significantly higher cutaneous uptake over nasal, mandibular, and scalp regions, respectively (P < 0.0001). PET/CT scan did not detect any systemic inflammation unlike those found in psoriasis. Three (9.4%) patients had thyroid nodules with high uptake (maximum standard uptake values ranging from 2.9 to 11.3). Two of them were confirmed to have papillary thyroid carcinoma, while the third patient has inconclusive finding. 18F-FDG PET/CT scan may be useful to map disease burden of HS. Nonlesional inflammatory foci on the skin of the nose, mandibular, and scalp are probably significant. The association of thyroid carcinoma in HS warrants further evaluation.

Consensus Guidelines in Usage of Biologics in Dermatology during COVID-19 Pandemic: Biologic Advisory Group Malaysia

@#The aim of this Biologic Advisory Group (BAG) Malaysia consensus guideline is to provide clinicians managing cutaneous diseases with biologics relevant parameters to consider prior to initiating or stopping or continuing any biologic treatment in the current landscape of the COVID-19 pandemic. Besides reviewing the medical literatures on COVID-19 and evidences related to other human coronavirus or influenza, expert opinions and clinical experiences are shared and debated in formulation of this biologic consensus guideline.

Position Statement on Secukinumab in the Management of Plaque Psoriasis: The Malaysian Perspective.

Psoriasis is a chronic inflammatory skin disease affecting nearly 10% of dermatologic patients in Malaysia. Treatment options include topical agents and phototherapy as well as nonbiologic and biologic systemic therapy. Mild psoriasis can often be managed with topical agents. However, managing moderate to severe psoriasis is more challenging and may require systemic treatment with nonbiologics or biologics. Despite the availability of several biologics, there are many unmet clinical needs, which may be addressed by secukinumab, an IL-17A inhibitor. This position statement is based on an expert panel discussion and is intended to provide dermatologists an overview of existing options as well as to provide a better understanding of secukinumab and how it can be integrated into current practice. During the discussion, panel members examined current approaches and the role of secukinumab in plaque psoriasis management. Panel members estimated that up to 30% of patients have moderate to severe psoriasis but only 1-2% receive biologics. Highlights from the discussion were that (i) the threshold for biologic use should be lower, in line with international guidelines; (ii) studies have shown that secukinumab has several advantages over other biologics which are greater efficacy, sustained efficacy over time, rapid onset of action, and early evidence of possible disease-modifying potential; and (iii) ideal candidates for secukinumab are all patients of moderate to severe psoriasis, including those with history of treatment failure, difficult-to-treat patterns of psoriasis (nail, scalp, and palmoplantar psoriasis), psoriatic arthritis, and comorbidities and those aiming for clear skin. Panel members recommend that secukinumab be considered first line option among biologic therapies.

Induction of cell cycle arrest and apoptosis by copper complex Cu(SBCM)2 towards oestrogen-receptor positive MCF-7 breast cancer cells.

Copper complexes have the potential to be developed as targeted therapy for cancer because cancer cells take up larger amounts of copper than normal cells. Copper complex Cu(SBCM)2 has been reported to induce cell cycle arrest and apoptosis towards triple-negative breast cancer cells. Nevertheless, its effect towards other breast cancer subtypes has not been explored. Therefore, the present study was conducted to investigate the effect of Cu(SBCM)2 towards oestrogen-receptor positive MCF-7 breast cancer cells. Growth inhibition of Cu(SBCM)2 towards MCF-7 and human non-cancerous MCF-10A breast cells was determined by MTT assay. Morphological changes of Cu(SBCM)2-treated-MCF-7 cells were observed under an inverted microscope. Annexin V/PI apoptosis assay and cell cycle analysis were evaluated by flow cytometry. The expression of wild-type p53 protein was evaluated by Western blot analysis. The intracellular ROS levels of MCF-7 treated with Cu(SBCM)2 were detected using DCFH-DA under a fluorescence microscope. The cells were then co-treated with Cu(SBCM)2 and antioxidants to evaluate the involvement of ROS in the cytotoxicity of Cu(SBCM)2. Docking studies of Cu(SBCM)2 with DNA, DNA topoisomerase I, and human ribonucleotide reductase were also performed. The growth of MCF-7 cells was inhibited by Cu(SBCM)2 in a dose-dependent manner with less toxicity towards MCF-10A cells. It was found that Cu(SBCM)2 induced G2/M cell cycle arrest and apoptosis in MCF-7 cells, possibly via a p53 pathway. Induction of intracellular ROS was not detected in MCF-7 cells. Interestingly, antioxidants enhance the cytotoxicity of Cu(SBCM)2 towards MCF-7 cells. DNA topoisomerase I may be the most likely target that accounts for the cytotoxicity of Cu(SBCM)2.

Manilkara zapota (L.) P. Royen Leaf Water Extract Induces Apoptosis in Human Hepatocellular Carcinoma (HepG2) Cells via ERK1/2/Akt1/JNK1 Signaling Pathways.

Manilkara zapota (L.) P. Royen, called sapodilla, or locally known as ciku, belongs to the family Sapotaceae. We found that Manilkara zapota leaf water extract has cytotoxic effect against human hepatocellular carcinoma (HepG2) cell line in our earlier study. Therefore, this study aimed to explore the anticancer properties of Manilkara zapota leaf water extract in HepG2 cells. We also aimed to unravel yet undiscovered mechanisms and identified several expressed genes whose functions in cytotoxicity activity of Manilkara zapota leaf water extract in HepG2 cells have not been well-studied. The apoptosis and intracellular reactive oxygen species (ROS) activities were analyzed using Annexin V-propidium iodide staining and dichlorodihydrofluorescein diacetate, respectively, by NovoCyte Flow Cytometer. Bax and Bcl-2 expression were assessed using Enzyme-Linked Immunosorbent Assay. The associated molecular pathways were evaluated by quantitative real-time PCR. Overall analyses revealed that Manilkara zapota leaf water extract can increase percentage of early apoptotic cells, induce the formation of ROS, upregulate c-Jun N-terminal kinase 1 (JNK1) and inducible nitric oxide synthase (iNOS), and reduce Akt1 and vascular endothelial growth factor A (VEGFA) transcriptional activities. Our data suggest that Manilkara zapota leaf water extract can suppress the growth of HepG2 cells via modulation of ERK1/2/Akt1/JNK1 transcriptional expression.

An Intrinsic Mitochondrial Pathway Is Required for Phytic Acid-Chitosan-Iron Oxide Nanocomposite (Phy-CS-MNP) to Induce G0/G1 Cell Cycle Arrest and Apoptosis in the Human Colorectal Cancer (HT-29) Cell Line.

Magnetic iron oxide nanoparticles are among the most useful metal nanoparticles in biomedical applications. A previous study had confirmed that phytic acid-chitosan-iron oxide nanocomposite (Phy-CS-MNP) exhibited antiproliferative activity towards human colorectal cancer (HT-29) cells. Hence, in this work, we explored the in vitro cytotoxicity activity and mechanistic action of Phy-CS-MNP nanocomposite in modulating gene and protein expression profiles in HT-29 cell lines. Cell cycle arrest and apoptosis were evaluated by NovoCyte Flow Cytometer. The mRNA changes (cyclin-dependent kinase 4 (Cdk4), vascular endothelial growth factor A (VEGFA), c-Jun N-terminal kinase 1 (JNK1), inducible nitric oxide synthase (iNOS), and matrix metallopeptidase 9 (MMP9)) and protein expression (nuclear factor-kappa B (NF-κB) and cytochrome c) were assessed by quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. The data from our study demonstrated that treatment with Phy-CS-MNP nanocomposite triggered apoptosis and G0/G1 cell cycle arrest. The transcriptional activity of JNK1 and iNOS was upregulated after treatment with 90 µg/mL Phy-CS-MNP nanocomposite. Our results suggested that Phy-CS-MNP nanocomposite induced apoptosis and cell cycle arrest via an intrinsic mitochondrial pathway through modulation of Bax and Bcl-2 and the release of cytochrome c from the mitochondria into the cytosol.

The clinical, biochemical, and ultrasonographic characteristics of patients with hidradenitis suppurativa in Northern Peninsular Malaysia: a multicenter study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disorder of follicular occlusion, resulting in abscesses with tunnel formation and severe scarring. Our objectives were to identify the clinical patterns and the prevalence of metabolic syndrome (MetS) among our HS patients and to determine the role of ultrasonography in the clinical assessment of HS. METHODS: This was a cross-sectional study carried out from September 2016 to August 2017 at three tertiary hospitals in Northern Peninsular Malaysia. RESULTS: A total of 62 patients were recruited, 83.9% of whom were male. The mean age was 29.2 with the median age of onset at 18 years old. The median duration of delay in diagnosis was 3 years. A quarter of them had positive family history. Nearly three-quarters were overweight and obese. About 12/62 (19.4%) had MetS, and it was comparable to healthy controls (15/62, 24.2%). HS patients had a significant higher risk of low-high-density lipoprotein (HDL) and obesity. Based on Hurley staging, 15/62 (24.2%) were in stage I, 38/62 (61.3%) and 9/62 (14.5%) in stages II and III, respectively. However, sonographic scoring showed 50% had severe stage of disease, and 56.9% of the patients had subclinical lesions. There was only a fair agreement between ultrasonography and Hurley staging of disease severity (k = 0.25; P = 0.004). CONCLUSION: There was a male preponderance among HS patients in Northern Peninsular Malaysia with early age of onset and more severe disease. Only one-fifth had MetS, but they had significantly higher risks of obesity and low HDL. Ultrasonography examination was useful to detect subclinical lesions and providing a better understanding on disease severity.

ROS-Mediated Mitochondrial Pathway is Required for Manilkara Zapota (L.) P. Royen Leaf Methanol Extract Inducing Apoptosis in the Modulation of Caspase Activation and EGFR/NF-κB Activities of HeLa Human Cervical Cancer Cells.

Manilkara zapota (L.) P. Royen (family: Sapotaceae) is commonly called sapodilla, or locally known as ciku. The detailed mechanisms underlying Manilkara zapota leaf methanol extract against HeLa human cervical cancer cells have yet to be investigated. Therefore, our present study is designed to investigate the ability to induce apoptosis and the underlying mechanisms of Manilkara zapota leaf methanol extract inducing cytotoxicity in HeLa cells. The apoptotic cell death was assessed using Annexin V-propidium iodide staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential activities were measured using dichlorodihydrofluorescein diacetate and MitoLite Orange, respectively, by NovoCyte Flow Cytometer. Bax and Bcl-2 expression were evaluated using Enzyme-Linked Immunosorbent Assay. Caspase-3 activity was determined using a colorimetric assay. The associated biological interaction pathways were evaluated using quantitative real-time PCR. Our data showed that HeLa cells were relatively more sensitive to Manilkara zapota leaf methanol extract than other cancer cell lines studied. Overall analyses revealed that Manilkara zapota leaf methanol extract can inhibit the viability of HeLa cells, induce mitochondrial ROS generation, and inhibit nuclear factor-kappa B (NF-κB) and epidermal growth factor receptor (EGFR) transcriptional activities. Our results suggested that Manilkara zapota leaf methanol extract might represent a potential anticervical cancer agent.

Copper complex derived from S-benzyldithiocarbazate and 3-acetylcoumarin induced apoptosis in breast cancer cell.

Copper complexes have been widely studied for the anti-tumour application as cancer cells are reported to take up greater amounts of copper than normal cells. Preliminary study revealed that the newly synthesised copper complex [Cu(SBCM)2] displayed marked anti-proliferative towards triple-negative MDA-MB-231 breast cancer cells. Therefore, Cu(SBCM)2 has great potential to be developed as an agent for the management of breast cancer. The present study was carried out to investigate the mode of cell death induced by Cu(SBCM)2 towards MDA-MB-231 breast cancer cells. The inhibitory and morphological changes of MDA-MB-231 cells treated with Cu(SBCM)2 was determined by using MTT assay and inverted light microscope, respectively. The safety profile of Cu(SBCM)2 was also evaluated towards human dermal fibroblast (HDF) normal cells. Confirmation of apoptosis and cell cycle arrest were determined by flow cytometry analysis. The expression of p53, Bax, Bcl-2 and MMP2 protein were detected with western blot analysis. Cu(SBCM)2 significantly inhibited the growth of MDA-MB-231 cells in a dose-dependent manner with GI50 18.7 ± 3.06 µM. Indeed, Cu(SBCM)2 was less toxic towards HDF normal cells with GI50 31.8 ± 4.0 µM. Morphological study revealed that Cu(SBCM)2-treated MDA-MB-231 cells experienced cellular shrinkage, membrane blebbing, chromatin condensation and formation of apoptotic bodies, suggesting that Cu(SBCM)2 induced apoptosis in the cells, which was confirmed by Annexin-V/PI flow cytometry analysis. It was also found that Cu(SBCM)2 induced G2/M phase cell cycle arrest towards MDA-MB-231 cells. The induction of apoptosis and cell cycle arrest in the present study is possibly due to the down-regulation of the mutant p53 and MMP2 protein. In conclusion, Cu(SBCM)2 can be developed as a targeted therapy for the treatment of triple-negative breast cancer.

South-East Asia study alliance guidelines on the management of acne vulgaris in South-East Asian patients.

The management of acne in South-East Asia is unique, as Asian skin and local variables require a clinical approach unlike that utilized in other parts of the world. There are different treatment guidelines per country in the region, and a group of leading dermatologists from these countries convened to review these guidelines, discuss current practices and recent advances, and formulate consensus guidelines to harmonize the management of acne vulgaris in the region. Emphasis has been placed on formulating recommendations to impede the development of antibiotic resistance in Propionibacterium acnes. The group adopted the Acne Consensus Conference system for grading acne severity. The group recommends that patients may be treated with topical medications including retinoids, benzoyl peroxide (BPO), salicylic acid, a combination of retinoid and BPO, or a combination of retinoids and BPO with or without antibiotics for mild acne; topical retinoid with topical BPO and a oral antibiotic for moderate acne; and oral isotretinoin if the patient fails first-line treatment (a 6- or 8-week trial of combined oral antibiotics and topical retinoids with BPO) for severe acne. Maintenance acne treatment using topical retinoids with or without BPO is recommended. To prevent the development of antibiotic resistance, topical antibiotics should not be used as monotherapy or used simultaneously with oral antibiotics. Skin care, comprised of cleansing, moisturizing and sun protection, is likewise recommended. Patient education and good communication is recommended to improve adherence, and advice should be given about the characteristics of the skin care products patients should use.

Quality of life and cost of illness in patients with psoriasis in Malaysia: a multicenter study.

BACKGROUND: Psoriasis is an immune-mediated, chronic, inflammatory skin disease which affects approximately 2% of the world's population. It has a major impact on the patient's quality of life (QoL), influencing career, social activities, family relationships, and all other aspects of life. Many studies have described the various ways in which psoriasis can affect a patient's life. Very little is known, however, about the impact of psoriasis on the QoL of patients treated in Malaysia and the cost of illness in this region. OBJECTIVES: This study aims to describe the extent to which psoriasis affects the QoL of patients treated in government-run dermatology clinics in Malaysia and to estimate the cost of illness. METHODS: A total of 250 psoriasis patients treated at eight dermatology clinics in government-run hospitals in Malaysia were studied. The severity of psoriasis was assessed by dermatologists. Quality of life was evaluated using the Dermatology Life Quality Index (DLQI) and Version 2 of the 12-Item Short-Form Health Survey (SF-12v2). Scores on the SF-12v2 of healthy subjects and of patients with other medical conditions, such as depression, diabetes mellitus, hypertension, and ischemic heart disease, were also assessed for comparison. The costs of dermatology outpatient consultant fees, medications, investigations, procedures, transportation, over-the-counter medications, and hospitalization were retrospectively estimated using questionnaires. RESULTS: The cohort studied had a median Psoriasis Area Severity Index (PASI) score of 9.9 and a median DLQI score of 10.0. The average SF-12v2 scores were 43.68 (standard deviation [SD] 9.23) and 42.25 (SD 10.7) on the Physical Health Summary and Mental Health Summary, respectively. The impact of disease on QoL was found to be greater in those with more extensive psoriatic lesion involvement, in younger patients, and in those with psoriatic arthropathy. Psoriasis was found to affect QoL in both genders equally. Body mass index had no effect on the severity of psoriasis or QoL. Patients with psoriasis had a significantly lower SF-12v2 score than healthy subjects. Comparisons with data for patients with other chronic medical conditions demonstrated that psoriasis has a negative effect on health-related QoL similar to the impact of other chronic conditions. The estimated cost of illness for psoriasis in the current cohort was ringgit Malaysia (RM) 1307.47 per person per year excluding costs of hospitalization. Patients were noted to spend a large amount of money on over-the-counter products obtained without doctors' prescriptions. CONCLUSIONS: The QoL of patients with psoriasis was significantly impaired compared with that of healthy subjects and was comparable with that of patients with other chronic medical illnesses. The estimated cost of illness of psoriasis in the current study was lower than in other countries, mainly because healthcare costs in public hospitals are heavily subsidized by government and because usage of newer but more expensive treatment options is low in Malaysia.

Paronychia induced by the epidermal growth factor receptor inhibitor cetuximab.

While the development of epidermal growth factor receptor inhibitors has been hailed as a remarkable triumph in the field of oncology, it has inherited with it a host of cutaneous side-effects that have been increasingly observed in a substantial number of patients in the recent years. One cutaneous manifestation that may inflict significant pain and affect activities of daily living among some of the patients receiving epidermal growth factor receptor inhibitors is paronychia. A case of paronychia associated with the use of cetuximab in the management of KRAS wild-type midrectal adenocarcinoma along with its management has been described.