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Fulltext WIN55,212-2 Attenuates Cognitive Impairments in AlCl3 + d-Galactose-Induced Alzheimer's Disease Rats by Enhancing Neurogenesis and Reversing Oxidative Stress

Mahdi O, Chiroma SM, Hidayat Baharuldin MT, Mohd Nor NH, Mat Taib CN, Jagadeesan S, et al.

Biomedicines, 2021 Sep 19;9(9).
PMID: 34572456 DOI: 10.3390/biomedicines9091270

Neurotransmission and cognitive dysfunctions have been linked to old age disorders including Alzheimer's disease (AD). Aluminium is a known neurotoxic metal, whereas d-galactose (d-gal) has been established as a senescence agent. WIN55,212-2 (WIN), is a potent cannabinoid agonist which partially restores neurogenesis in aged rats. The current study aimed to explore the therapeutic potentials of WIN on Aluminium chloride (AlCl3) and d-gal-induced rat models with cognitive dysfunction. Healthy male albino Wistar rats weighing between 200-250 g were injected with d-gal 60 mg/kg intra peritoneally (i.p), while AlCl3 (200 mg/kg) was orally administered once daily for 10 consecutive weeks. Subsequently, from weeks 8-11 rats were co-administered with WIN (0.5, 1 and 2 mg/kg/day) and donepezil 1 mg/kg. The cognitive functions of the rats were assessed with a Morris water maze (MWM). Furthermore, oxidative stress biomarkers; malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and neurogenesis markers: Nestin and glial fibrillary acidic protein (GFAP) were also evaluated, as well as the histology of the hippocampus. The results revealed that rats exposed to AlCl3 and d-gal alone showed cognitive impairments and marked neuronal loss (p < 0.05) in their hippocampal conus ammonis 1 (CA1). Additionally, a significant decrease in the expressions of GFAP and Nestin was also observed, including increased levels of MDA and decreased levels of SOD and GSH. However, administration of WIN irrespective of the doses given reversed the cognitive impairments and the associated biochemical derangements. As there were increases in the levels SOD, GSH, Nestin and GFAP (p < 0.05), while a significant decrease in the levels of MDA was observed, besides attenuation of the aberrant cytoarchitecture of the rat's hippocampi. The biochemical profiles of the WIN-treated rats were normal. Thus, these findings offer possible scientific evidence of WIN being an effective candidate in the treatment of AD-related cognitive deficits.
Fulltext Type II Collagen-Conjugated Mesenchymal Stem Cells Micromass for Articular Tissue Targeting

Sulaiman SB, Chowdhury SR, Busra MFBM, Abdul Rani RB, Mohamad Yahaya NHB, Tabata Y, et al.

Biomedicines, 2021 Jul 23;9(8).
PMID: 34440084 DOI: 10.3390/biomedicines9080880

The tissue engineering approach in osteoarthritic cell therapy often requires the delivery of a substantially high cell number due to the low engraftment efficiency as a result of low affinity binding of implanted cells to the targeted tissue. A modification towards the cell membrane that provides specific epitope for antibody binding to a target tissue may be a plausible solution to increase engraftment. In this study, we intercalated palmitated protein G (PPG) with mesenchymal stem cells (MSCs) and antibody, and evaluated their effects on the properties of MSCs either in monolayer state or in a 3D culture state (gelatin microsphere, GM). Bone marrow MSCs were intercalated with PPG (PPG-MSCs), followed by coating with type II collagen antibody (PPG-MSC-Ab). The effect of PPG and antibody conjugation on the MSC proliferation and multilineage differentiation capabilities both in monolayer and GM cultures was evaluated. PPG did not affect MSC proliferation and differentiation either in monolayer or 3D culture. The PPG-MSCs were successfully conjugated with the type II collagen antibody. Both PPG-MSCs with and without antibody conjugation did not alter MSC proliferation, stemness, and the collagen, aggrecan, and sGAG expression profiles. Assessment of the osteochondral defect explant revealed that the PPG-MSC-Ab micromass was able to attach within 48 h onto the osteochondral surface. Antibody-conjugated MSCs in GM culture is a potential method for targeted delivery of MSCs in future therapy of cartilage defects and osteoarthritis.
Fulltext Tissue Rigidity Increased during Carcinogenesis of NTCU-Induced Lung Squamous Cell Carcinoma In Vivo

Zakaria MA, Aziz J, Rajab NF, Chua EW, Masre SF

Biomedicines, 2022 Sep 23;10(10).
PMID: 36289644 DOI: 10.3390/biomedicines10102382

Increased tissue rigidity is an emerging hallmark of cancer as it plays a critical role in promoting cancer growth. However, the field lacks a defined characterization of tissue rigidity in dual-stage carcinogenesis of lung squamous cell carcinoma (SCC) in vivo. Pre-malignant and malignant lung SCC was developed in BALB/c mice using N-nitroso-tris-chloroethylurea (NTCU). Picro sirius red staining and atomic force microscopy were performed to measure collagen content and collagen (diameter and rigidity), respectively. Then, the expression of tenascin C (TNC) protein was determined using immunohistochemistry staining. Briefly, all tissue rigidity parameters were found to be increased in the Cancer group as compared with the Vehicle group. Importantly, collagen content (33.63 ± 2.39%) and TNC expression (7.97 ± 2.04%) were found to be significantly higher (p < 0.05) in the Malignant Cancer group, as compared with the collagen content (18.08 ± 1.75%) and TNC expression (0.45 ± 0.53%) in the Pre-malignant Cancer group, indicating increased tissue rigidity during carcinogenesis of lung SCC. Overall, tissue rigidity of lung SCC was suggested to be increased during carcinogenesis as indicated by the overexpression of collagen and TNC protein, which may warrant further research as novel therapeutic targets to treat lung SCC effectively.
Fulltext Tissue Engineering as a Promising Treatment for Glottic Insufficiency: A Review on Biomolecules and Cell-Laden Hydrogel

Ng WC, Lokanathan Y, Baki MM, Fauzi MB, Zainuddin AA, Azman M

Biomedicines, 2022 Nov 30;10(12).
PMID: 36551838 DOI: 10.3390/biomedicines10123082

Glottic insufficiency is widespread in the elderly population and occurs as a result of secondary damage or systemic disease. Tissue engineering is a viable treatment for glottic insufficiency since it aims to restore damaged nerve tissue and revitalize aging muscle. After injection into the biological system, injectable biomaterial delivers cost- and time-effectiveness while acting as a protective shield for cells and biomolecules. This article focuses on injectable biomaterials that transport cells and biomolecules in regenerated tissue, particularly adipose, muscle, and nerve tissue. We propose Wharton's Jelly mesenchymal stem cells (WJMSCs), induced pluripotent stem cells (IP-SCs), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin growth factor-1 (IGF-1) and extracellular vesicle (EV) as potential cells and macromolecules to be included into biomaterials, with some particular testing to support them as a promising translational medicine for vocal fold regeneration.
Fulltext The Role of Epigenetics in the Development and Progression of Multiple Myeloma

Ismail NH, Mussa A, Zakaria NA, Al-Khreisat MJ, Zahidin MA, Ramli NN, et al.

Biomedicines, 2022 Oct 31;10(11).
PMID: 36359286 DOI: 10.3390/biomedicines10112767

Multiple myeloma (MM) is an exceptionally complicated and heterogeneous disease that is caused by the abnormal proliferation of malignant monoclonal plasma cells initiated in the bone marrow. In disease progression, a multistep process including differentiation, proliferation, and invasion is involved. Despite great improvement in treatment outcomes in recent years due to the substantial discovery of novel therapeutic drugs, MM is still regarded as an incurable disease. Patients with MM are afflicted by confronting remission periods accompanied by relapse or progression outcomes, which inevitably progress to the refractory stage. In this regard, MM may need new medications or modifications in therapeutic strategies to overcome resistance. A variety of genetic abnormalities (e.g., point mutations, translocations, and deletions) and epigenetic changes (e.g., DNA methylation, histone modification, and non-coding RNA) contribute to the pathogenesis and development of MM. Here, we review the significant roles of epigenetic mechanisms in the development and progression of MM. We also highlight epigenetic pathways as potential novel treatment avenues for MM, including their interplay, use of epigenetic inhibitors, and major involvement in immuno-oncology.
Fulltext The NF-κB Transcriptional Network Is a High-Dose Vitamin C-Targetable Vulnerability in Breast Cancer

Mussa A, Afolabi HA, Syed NH, Talib M, Murtadha AH, Hajissa K, et al.

Biomedicines, 2023 Mar 30;11(4).
PMID: 37189677 DOI: 10.3390/biomedicines11041060

Breast cancer (BC) is the most common cancer type among women with a distinct clinical presentation, but the survival rate remains moderate despite advances in multimodal therapy. Consequently, a deeper understanding of the molecular etiology is required for the development of more effective treatments for BC. The relationship between inflammation and tumorigenesis is well established, and the activation of the pro-inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is frequently identified in BC. Constitutive NF-κB activation is linked to cell survival, metastasis, proliferation, and hormonal, chemo-, and radiotherapy resistance. Moreover, the crosstalk between NF-κB and other transcription factors is well documented. It is reported that vitamin C plays a key role in preventing and treating a number of pathological conditions, including cancer, when administered at remarkably high doses. Indeed, vitamin C can regulate the activation of NF-κB by inhibiting specific NF-κB-dependent genes and multiple stimuli. In this review, we examine the various NF-κB impacts on BC development. We also provide some insight into how the NF-κB network may be targeted as a potential vulnerability by using natural pro-oxidant therapies such as vitamin C.
The Modulation of NMDA and AMPA/Kainate Receptors by Tocotrienol-Rich Fraction and Α-Tocopherol in Glutamate-Induced Injury of Primary Astrocytes

Abedi Z, Khaza'ai H, Vidyadaran S, Mutalib MSA

Biomedicines, 2017 Dec 01;5(4).
PMID: 29194360 DOI: 10.3390/biomedicines5040068

Astrocytes are known as structural and supporting cells in the central nervous system (CNS). Glutamate, as a main excitatory amino acid neurotransmitter in the mammalian central nervous system, can be excitotoxic, playing a key role in many chronic neurodegenerative diseases. The aim of the current study was to elucidate the potential of vitamin E in protecting glutamate-injured primary astrocytes. Hence, primary astrocytes were isolated from mixed glial cells of C57BL/6 mice by applying the EasySep® Mouse CD11b Positive Selection Kit, cultured in Dulbecco's modified Eagle medium (DMEM) and supplemented with special nutrients. The IC20 and IC50 values of glutamate, as well as the cell viability of primary astrocytes, were assessed with 100 ng/mL, 200 ng/mL, and 300 ng/mL of tocotrienol-rich fraction (TRF) and alpha-tocopherol (α-TCP), as determined by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The mitochondrial membrane potential (MMP) detected in primary astrocytes was assessed with the same concentrations of TRF and α-TCP. The expression levels of the ionotropic glutamate receptor genes (Gria2, Grin2A, GRIK1) were independently determined using RT-PCR. The purification rate of astrocytes was measured by a flow-cytometer as circa 79.4%. The IC20 and IC50 values of glutamate were determined as 10 mM and 100 mM, respectively. Exposure to 100 mM of glutamate in primary astrocytes caused the inhibition of cell viability of approximately 64.75% and 61.10% in pre- and post-study, respectively (p < 0.05). Both TRF and α-TCP (at the lowest and highest concentrations, respectively) were able to increase the MMP to 88.46% and 93.31% pre-treatment, and 78.43% and 81.22% post-treatment, respectively. Additionally, the findings showed a similar pattern for the expression level of the ionotropic glutamate receptor genes. Increased extracellular calcium concentrations were also observed, indicating that the presence of vitamin E altered the polarization of astrocytes. In conclusion, α-TCP showed better recovery and prophylactic effects as compared to TRF in the pre-treatment of glutamate-injured primary astrocytes.
Fulltext The Effects of Probiotics on Small Intestinal Microbiota Composition, Inflammatory Cytokines and Intestinal Permeability in Patients with Non-Alcoholic Fatty Liver Disease

Ayob N, Muhammad Nawawi KN, Mohamad Nor MH, Raja Ali RA, Ahmad HF, Oon SF, et al.

Biomedicines, 2023 Feb 20;11(2).
PMID: 36831176 DOI: 10.3390/biomedicines11020640

The prevalence of non-alcoholic fatty liver disease (NAFLD) has soared globally. As our understanding of the disease grows, the role of the gut-liver axis (GLA) in NAFLD pathophysiology becomes more apparent. Hence, we focused mainly on the small intestinal area to explore the role of GLA. We looked at how multi-strain probiotics (MCP® BCMC® strains) containing six different Lactobacillus and Bifidobacterium species affected the small intestinal gut microbiota, inflammatory cytokines, and permeability in NAFLD patients. After six months of supplementation, biochemical blood analysis did not show any discernible alterations in either group. Five predominant phyla known as Actinobacteria, Proteobacteria, Firmicutes, Bacteroidota and Fusobacteria were found in NAFLD patients. The probiotics group demonstrated a significant cluster formation of microbiota composition through beta-diversity analysis (p < 0.05). This group significantly reduced three unclassifiable species: unclassified_Proteobacteria, unclassified_Streptococcus, and unclassified_Stenotrophomonas. In contrast, the placebo group showed a significant increase in Prevotella_melaninogenica and Rothia_mucilaginosa, which were classified as pathogens. Real-time quantitative PCR analysis of small intestinal mucosal inflammatory cytokines revealed a significant decrease in IFN-γ (-7.9 ± 0.44, p < 0.0001) and TNF-α (-0.96 ± 0.25, p < 0.0033) in the probiotics group but an increase in IL-6 (12.79 ± 2.24, p < 0.0001). In terms of small intestinal permeability analysis, the probiotics group, unfortunately, did not show any positive changes through ELISA analysis. Both probiotics and placebo groups exhibited a significant increase in the level of circulating zonulin (probiotics: 107.6 ng/mL ± 124.7, p = 0.005 vs. placebo: 106.9 ng/mL ± 101.3, p = 0.0002) and a significant decrease in circulating zonula occluden-1 (ZO-1) (probiotics: -34.51 ng/mL ± 18.38, p < 0.0001 vs. placebo: -33.34 ng/mL ± 16.62, p = 0.0001). The consumption of Lactobacillus and Bifidobacterium suggested the presence of a well-balanced gut microbiota composition. Probiotic supplementation improves dysbiosis in NAFLD patients. This eventually stabilised the expression of inflammatory cytokines and mucosal immune function. To summarise, more research on probiotic supplementation as a supplement to a healthy diet and lifestyle is required to address NAFLD and its underlying causes.
Fulltext Synchronous Breast and Cervical Carcinoma: A Genetic Point of View

Yahya MM, Ismail MP, Ramanathan S, Kadir MN, Azhar A, Ibrahim NBC, et al.

Biomedicines, 2023 Feb 11;11(2).
PMID: 36831061 DOI: 10.3390/biomedicines11020525

Breast carcinoma is the most common cancer of women in Malaysia. The most common sites of metastasis are the lung, liver, bone and brain. A 45-year-old lady was diagnosed with left invasive breast carcinoma stage IV (T4cN1M1) with axillary lymph nodes and lung metastasis. She was noted to have a cervical mass through imaging, and biopsy showed CIN III. Post chemotherapy, the patient underwent left simple mastectomy with examination under anaesthesia of the cervix, cystoscopy and staging. The cervical histopathological examination (HPE) showed squamous cell carcinoma, and clinical staging was 2A. The breast tissue HPE showed invasive carcinoma with triple receptors positivity. The patient was given tamoxifen and put on concurrent chemoradiotherapy (CCRT) for the cervical cancer. The management of each pathology of this patient involved a multi-disciplinary team that included surgeons, oncologists, gynaecologists, pathologists and radiologists. Due to the complexity of the case with two concurrent cancers, the gene expression profiles may help predict the patient's clinical outcome.
Fulltext Subchondral Bone Microarchitectural and Mineral Properties and Expression of Key Degradative Proteinases by Chondrocytes in Human Hip Osteoarthritis

Li Y, Liem Y, Zamli Z, Sullivan N, Dall'Ara E, Ahmed H, et al.

Biomedicines, 2021 Nov 01;9(11).
PMID: 34829822 DOI: 10.3390/biomedicines9111593

BACKGROUND: The purpose of this study was to investigate the relationship between the expression of key degradative enzymes by chondrocytes and the microarchitectural and mineral properties of subchondral bone across different stages of cartilage degradation in human hip osteoarthritis (OA).
METHODS: Osteochondral samples at different stages of cartilage degradation were collected from 16 femoral heads with OA. Osteochondral samples with normal cartilage were collected from seven femoral heads with osteoporosis. Microcomputed tomography was used for the investigation of subchondral bone microarchitecture and mineral densities. Immunohistochemistry was used to study the expression and distribution of MMP13 and ADAMTS4 in cartilage.
RESULTS: The microarchitecture and mineral properties of the subchondral plate and trabecular bone in OA varied with the severity of the degradation of the overlying cartilage. Chondrocytes expressing MMP13 and ADAMTS4 are mainly located in the upper zone(s) of cartilage regardless of the histopathological grades. The zonal expression of these enzymes in OA (i.e., the percentage of positive cells in the superficial, middle, and deep zones), rather than their overall expression (the percentage of positive cells in the full thickness of the cartilage), exhibited significant variation in relation to the severity of cartilage degradation. The associations between the subchondral bone properties and zonal and overall expression of these enzymes in the cartilage were generally weak or nonsignificant.
CONCLUSIONS: Phenotypic changes in chondrocytes and remodelling of subchondral bone proceed at different rates throughout the process of cartilage degradation. Biological influences are more important for cartilage degradation at early stages, while biomechanical damage to the compromised tissue may outrun the phenotypic change of chondrocytes and is critical in the advanced stages.
Fulltext Stem Cells and Cancer Stem Cells: The Jekyll and Hyde Scenario and Their Implications in Stem Cell Therapy

Wan Kamarul Zaman WS, Nurul AA, Nordin F

Biomedicines, 2021 Sep 17;9(9).
PMID: 34572431 DOI: 10.3390/biomedicines9091245

"Jekyll and Hyde" refers to persons with an unpredictably dual personality, who are battling between good and evil within themselves In this regard, even cells consist of good and evil counterparts. Normal stem cells (NSCs) and cancer stem cells (CSCs) are two types of cells that share some similar characteristics but have distinct functions that play a major role in physiological and pathophysiological development. In reality, NSCs such as the adult and embryonic stem cells, are the good cells and the ultimate treatment used in cell therapy. CSCs are the corrupted cells that are a subpopulation of cancer cells within the cancer microenvironment that grow into a massive tumour or malignancy that needs to be treated. Hence, understanding the connection between NSCs and CSCs is important not just in cancer development but also in their therapeutic implication, which is the focus of this review.
Fulltext Revisiting Resveratrol as an Osteoprotective Agent: Molecular Evidence from In Vivo and In Vitro Studies

Ahmad Hairi H, Jayusman PA, Shuid AN

Biomedicines, 2023 May 16;11(5).
PMID: 37239124 DOI: 10.3390/biomedicines11051453

Resveratrol (RSV) (3,5,4'-trihydroxystilbene) is a stilbene found in abundance in berry fruits, peanuts, and some medicinal plants. It has a diverse range of pharmacological activities, underlining the significance of illness prevention and health promotion. The purpose of this review was to delve deeper into RSV's bone-protective properties as well as its molecular mechanisms. Several in vivo studies have found the bone-protective effects of RSV in postmenopausal, senile, and disuse osteoporosis rat models. RSV has been shown to inhibit NF-κB and RANKL-mediated osteoclastogenesis, oxidative stress, and inflammation while increasing osteogenesis and boosting differentiation of mesenchymal stem cells to osteoblasts. Wnt/β-catenin, MAPKs/JNK/ERK, PI3K/AKT, FoxOs, microRNAs, and BMP2 are among the possible kinases and proteins involved in the underlying mechanisms. RSV has also been shown to be the most potent SIRT1 activator to cause stimulatory effects on osteoblasts and inhibitory effects on osteoclasts. RSV may, thus, represent a novel therapeutic strategy for increasing bone growth and reducing bone loss in the elderly and postmenopausal population.
Response Profiles of BV2 Microglia to IFN-γ and LPS Co-Stimulation and Priming

Pan ML, Ahmad Puzi NN, Ooi YY, Ramasamy R, Vidyadaran S

Biomedicines, 2023 Sep 27;11(10).
PMID: 37893022 DOI: 10.3390/biomedicines11102648

(1) Background: The latest research illustrates that microglia phenotype is not the binary 'resting' and 'activated' profiles. Instead, there is wide diversity in microglia states. Similarly, when testing different stimulation protocols for BV2 microglia, we discovered differences in the response of the cells in terms of the production of intracellular ROS (iROS), nitric oxide (NO), CD40 expression, and migratory capacity. (2) Methods: BV2 microglia were treated with single interferon gamma (IFN-γ) stimulation, LPS/IFN-γ co-stimulation, and priming with IFN-γ followed by stimulation with LPS for 24 h. The responses of BV2 microglia were then assessed using the H2DCFDA test for iROS, the Griess assay for NO, immunophenotyping for CD40/CD11b/MHC II, and migration using a transwell apparatus. (3) Results: Single stimulation with IFN-γ induced NO but not ROS in BV2 microglia. Co-stimulation with LPS200IFN-γ2.5 induced a higher iROS production (a 9.2-fold increase) and CD40 expression (28031 ± 8810.2 MFI), compared to priming with primedIFN-γ50LPS100 (a 4.0-fold increase in ROS and 16764 ± 1210.8 MFI of CD40). Co-stimulation also induced cell migration. On the other hand, priming BV2 microglia (primedIFN-γ50LPS100) resulted in a higher NO production (64 ± 1.4 µM) compared to LPS200IFN-γ2.5 co-stimulation (44 ± 1.7 µM). Unexpectedly, priming inhibited BV2 migration. (4) Conclusions: Taken together, the findings from this project reveal the ability of co-stimulation and priming in stimulating microglia into an inflammatory phenotype, and the heterogeneity of microglia responses towards different stimulating approaches.
Fulltext Recent Biomedical Applications of Coupling Nanocomposite Polymeric Materials Reinforced with Variable Carbon Nanofillers

Alosaimi AM, Alorabi RO, Katowah DF, Al-Thagafi ZT, Alsolami ES, Hussein MA, et al.

Biomedicines, 2023 Mar 21;11(3).
PMID: 36979948 DOI: 10.3390/biomedicines11030967

The hybridization between polymers and carbon materials is one of the most recent and crucial study areas which abstracted more concern from scientists in the past few years. Polymers could be classified into two classes according to the source materials synthetic and natural. Synthetic polymeric materials have been applied over a floppy zone of industrial fields including the field of biomedicine. Carbon nanomaterials including (fullerene, carbon nanotubes, and graphene) classified as one of the most significant sources of hybrid materials. Nanocarbons are improving significantly mechanical properties of polymers in nanocomposites in addition to physical and chemical properties of the new materials. In all varieties of proposed bio-nanocomposites, a considerable improvement in the microbiological performance of the materials has been explored. Various polymeric materials and carbon-course nanofillers were present, along with antibacterial, antifungal, and anticancer products. This review spots the light on the types of synthetic polymers-based carbon materials and presented state-of-art examples on their application in the area of biomedicine.
Fulltext Potential of Marine Terpenoids against SARS-CoV-2: An In Silico Drug Development Approach

Sahoo A, Fuloria S, Swain SS, Panda SK, Sekar M, Subramaniyan V, et al.

Biomedicines, 2021 Oct 20;9(11).
PMID: 34829734 DOI: 10.3390/biomedicines9111505

In an emergency, drug repurposing is the best alternative option against newly emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, several bioactive natural products have shown potential against SARS-CoV-2 in recent studies. The present study selected sixty-eight broad-spectrum antiviral marine terpenoids and performed molecular docking against two novel SARS-CoV-2 enzymes (main protease or Mpro or 3CLpro) and RNA-dependent RNA polymerase (RdRp). In addition, the present study analysed the physiochemical-toxicity-pharmacokinetic profile, structural activity relationship, and phylogenetic tree with various computational tools to select the 'lead' candidate. The genomic diversity study with multiple sequence analyses and phylogenetic tree confirmed that the newly emerged SARS-CoV-2 strain was up to 96% structurally similar to existing CoV-strains. Furthermore, the anti-SARS-CoV-2 potency based on a protein-ligand docking score (kcal/mol) exposed that the marine terpenoid brevione F (-8.4) and stachyflin (-8.4) exhibited similar activity with the reference antiviral drugs lopinavir (-8.4) and darunavir (-7.5) against the target SARS-CoV-Mpro. Similarly, marine terpenoids such as xiamycin (-9.3), thyrsiferol (-9.2), liouvilloside B (-8.9), liouvilloside A (-8.8), and stachyflin (-8.7) exhibited comparatively higher docking scores than the referral drug remdesivir (-7.4), and favipiravir (-5.7) against the target SARS-CoV-2-RdRp. The above in silico investigations concluded that stachyflin is the most 'lead' candidate with the most potential against SARS-CoV-2. Previously, stachyflin also exhibited potential activity against HSV-1 and CoV-A59 within IC50, 0.16-0.82 µM. Therefore, some additional pharmacological studies are needed to develop 'stachyflin' as a drug against SARS-CoV-2.
Fulltext Potential Effects of Non-Surgical Periodontal Therapy on Periodontal Parameters, Inflammatory Markers, and Kidney Function Indicators in Chronic Kidney Disease Patients with Chronic Periodontitis

Chaudhry A, Kassim NK, Zainuddin SLA, Taib H, Ibrahim HA, Ahmad B, et al.

Biomedicines, 2022 Oct 29;10(11).
PMID: 36359271 DOI: 10.3390/biomedicines10112752

Chronic kidney disease (CKD) and chronic periodontitis (CP) contribute to the increased level of inflammatory biomarkers in the blood. This study hypothesized that successful periodontal treatment would reduce the level of inflammatory biomarkers in CKD patients. This prospective study recruited two groups of CP patients: 33 pre-dialysis CKD patients and 33 non-CKD patients. All patients underwent non-surgical periodontal therapy (NSPT). Their blood samples and periodontal parameters were taken before and after six weeks of NSPT. The serum level of high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and periodontal parameters were compared between groups. On the other hand, kidney function indicators such as serum urea and estimated glomerular filtration rate (eGFR) were only measured in CKD patients. Clinical periodontal parameters and inflammatory markers levels at baseline were significantly higher (p < 0.05) in the CKD group than in the non-CKD group and showed significant reduction (p < 0.05) after six weeks of NSPT. CKD patients demonstrated a greater periodontitis severity and higher inflammatory burden than non-CKD patients. Additionally, CKD patients with CP showed a good response to NSPT. Therefore, CKD patients’ periodontal health needs to be screened for early dental interventions and monitored accordingly.
Fulltext Orthosiphon stamineus Proteins Alleviate Pentylenetetrazol-Induced Seizures in Zebrafish

Chung YS, Choo BKM, Ahmed PK, Othman I, Shaikh MF

Biomedicines, 2020 Jul 02;8(7).
PMID: 32630817 DOI: 10.3390/biomedicines8070191

The anticonvulsive potential of proteins extracted from Orthosiphon stamineus leaves (OSLP) has never been elucidated in zebrafish (Danio rerio). This study thus aims to elucidate the anticonvulsive potential of OSLP in pentylenetetrazol (PTZ)-induced seizure model. Physical changes (seizure score and seizure onset time, behavior, locomotor) and neurotransmitter analysis were elucidated to assess the pharmacological activity. The protective mechanism of OSLP on brain was also studied using mass spectrometry-based label-free proteomic quantification (LFQ) and bioinformatics. OSLP was found to be safe up to 800 µg/kg and pre-treatment with OSLP (800 µg/kg, i.p., 30 min) decreased the frequency of convulsive activities (lower seizure score and prolonged seizure onset time), improved locomotor behaviors (reduced erratic swimming movements and bottom-dwelling habit), and lowered the excitatory neurotransmitter (glutamate). Pre-treatment with OSLP increased protein Complexin 2 (Cplx 2) expression in the zebrafish brain. Cplx2 is an important regulator in the trans-SNARE complex which is required during the vesicle priming phase in the calcium-dependent synaptic vesicle exocytosis. Findings in this study collectively suggests that OSLP could be regulating the release of neurotransmitters via calcium-dependent synaptic vesicle exocytosis mediated by the "Synaptic Vesicle Cycle" pathway. OSLP's anticonvulsive actions could be acting differently from diazepam (DZP) and with that, it might not produce the similar cognitive insults such as DZP.
Novel Nematode-Killing Protein-1 (Nkp-1) from a Marine Epiphytic Bacterium Pseudoalteromonas tunicata

Salikin NH, Dubois M, Nappi J, Lebhar H, Marquis C, Egan S

Biomedicines, 2021 Oct 30;9(11).
PMID: 34829814 DOI: 10.3390/biomedicines9111586

Drug resistance among parasitic nematodes has resulted in an urgent need for the development of new therapies. However, the high re-discovery rate of anti-nematode compounds from terrestrial environments necessitates a new repository for future drug research. Marine epiphytes are hypothesised to produce nematicidal compounds as a defence against bacterivorous predators, thus representing a promising yet underexplored source for anti-nematode drug discovery. The marine epiphytic bacterium Pseudoalteromonas tunicata is known to produce several bioactive compounds. Screening heterologously expressed genomic libraries of P. tunicata against the nematode Caenorhabditis elegans, identified as an E. coli clone (HG8), shows fast-killing activity. Here we show that clone HG8 produces a novel nematode-killing protein-1 (Nkp-1) harbouring a predicted carbohydrate-binding domain with weak homology to known bacterial pore-forming toxins. We found bacteria expressing Nkp-1 were able to colonise the C. elegans intestine, with exposure to both live bacteria and protein extracts resulting in physical damage and necrosis, leading to nematode death within 24 h of exposure. Furthermore, this study revealed C. elegans dar (deformed anal region) and internal hatching may act as a nematode defence strategy against Nkp-1 toxicity. The characterisation of this novel protein and putative mode of action not only contributes to the development of novel anti-nematode applications in the future but reaffirms the potential of marine epiphytic bacteria as a new source of novel biomolecules.
Fulltext Neuroprotective and Anti-Inflammatory Effects of Rhus coriaria Extract in a Mouse Model of Ischemic Optic Neuropathy

Khalilpour S, Behnammanesh G, Suede F, Ezzat MO, Muniandy J, Tabana Y, et al.

Biomedicines, 2018 Apr 23;6(2).
PMID: 29690612 DOI: 10.3390/biomedicines6020048

Modulating oxidative stresses and inflammation can potentially prevent or alleviate the pathological conditions of diseases associated with the nervous system, including ischemic optic neuropathy. In this study we evaluated the anti-neuroinflammatory and neuroprotective activities of Rhus coriaria (R. coriaria) extract in vivo. The half maximal inhibitory concentration (IC50) for DPPH, ABTS and β⁻carotene were 6.79 ± 0.009 µg/mL, 10.94 ± 0.09 µg/mL, and 6.25 ± 0.06 µg/mL, respectively. Retinal ischemia was induced by optic nerve crush injury in albino Balb/c mice. The anti-inflammatory activity of ethanolic extract of R. coriaria (ERC) and linoleic acid (LA) on ocular ischemia was monitored using Fluorescence Molecular Tomography (FMT). Following optic nerve crush injury, the mice treated with 400 mg/kg of ERC and LA exhibited an 84.87% and 86.71% reduction of fluorescent signal (cathepsin activity) respectively. The results of this study provide strong scientific evidence for the neuroprotective activity of the ERC, identifying LA as one of the main components responsible for the effect. ERC may be useful and worthy of further development for its adjunctive utilization in the treatment of optic neuropathy.
Fulltext Nanoparticles Targeting Receptors on Breast Cancer for Efficient Delivery of Chemotherapeutics

Jahan S, Karim ME, Chowdhury EH

Biomedicines, 2021 Jan 26;9(2).
PMID: 33530291 DOI: 10.3390/biomedicines9020114

The journey of chemotherapeutic drugs from the site of administration to the site of action is confronted by several factors including low bioavailability, uneven distribution in major organs, limited accessibility of drug molecules to the distant tumor tissues, and lower therapeutic indexes. These unavoidable features of classical chemotherapeutics necessitate an additional high, repetitive dose of drugs to obtain maximum therapeutic responses with the result of unintended adverse side effects. An erratic tumor microenvironment, notable drawbacks of conventional chemotherapy, and multidrug-resistant mechanisms of breast cancer cells warrant precisely designed therapeutics for the treatment of cancers. In recent decades, nanoparticles have been deployed for the delivery of standard anticancer drugs to maximize the therapeutic potency while minimizing the adverse effects to increase the quality and span of life. Several organic and inorganic nanoplatforms that have been designed exploiting the distinctive features of the tumor microenvironment and tumor cells offer favorable physicochemical properties and pharmacokinetic profiles of a parent drug, with delivery of higher amounts of the drug to the pathological site and its controlled release, thereby improving the balance between its efficacy and toxicity. Advances to this front have included design and construction of targeted nanoparticles by conjugating homing devices like peptide, ligand, and Fab on the surface of nanomaterials to navigate nanoparticledrug complexes towards the target tumor cell with minimal destruction of healthy cells. Furthermore, actively targeting nanoparticles can facilitate the delivery and cellular uptake of nanoparticle-loaded drug constructs via binding with specific receptors expressed aberrantly on the surface of a tumor cell. Herein, we present an overview of the principle of targeted delivery approaches, exploiting drug-nanoparticle conjugates with multiple targeting moieties to target specific receptors of breast cancer cells and highlighting therapeutic evaluation in preclinical studies. We conclude that an understanding of the translational gap and challenges would show the possible future directions to foster the development of novel targeted nanotherapeutics.

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