Oral squamous cell carcinoma (OSCC) is a prevalent type of head and neck cancer, ranked as the sixth most common cancer worldwide, accounting for approximately 300,000 new cases and 145,000 deaths annually. Early detection using biomarkers significantly increases the 5-year survival rate of OSCC by up to 80-90%. Clusterin (CLU), also known as apolipoprotein J, is a sulfated chaperonic glycoprotein expressed in all tissues and human fluids and has been reported to be a potential biomarker of OSCC. CLU has been implicated as playing a vital role in many biological processes such as apoptosis, cell cycle, etc. Abnormal CLU expression has been linked with the development and progression of cancers. Despite the fact that there are many studies that have reported the involvement of CLU and its isoforms in OSCC, the exact roles of CLU and its isoforms in OSCC carcinogenesis have not been fully explored. This article aims to provide a comprehensive review of the current understanding of CLU structure and genetics and its correlation with OSCC tumorigenesis to better understand potential diagnostic and prognostic biomarker development. The relationship between CLU and chemotherapy resistance in cancer will also be discussed to explore the therapeutic application of CLU and its isoforms in OSCC.
Diabetic foot ulcers (DFU) are a predominant impediment among diabetic patients, increasing morbidity and wound care costs. There are various strategies including using biomaterials have been explored for the management of DFU. This paper will review the injectable hydrogel application as the most studied polymer-based hydrogel based on published journals and articles. The main key factors that will be discussed in chronic wounds focusing on diabetic ulcers include the socioeconomic burden of chronic wounds, biomaterials implicated by the government for DFU management, commercial hydrogel product, mechanism of injectable hydrogel, the current study of novel injectable hydrogel and the future perspectives of injectable hydrogel for the management of DFU.
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.
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.
Metabolic syndrome (MetS) refers to a cluster of metabolic dysregulations, which include insulin resistance, obesity, atherogenic dyslipidemia and hypertension. The complex pathogenesis of MetS encompasses the interplay between environmental and genetic factors. Environmental factors such as excessive nutrients and sedentary lifestyle are modifiable and could be improved by lifestyle modification. However, genetic susceptibility to MetS, a non-modifiable factor, has attracted the attention of researchers, which could act as the basis for future diagnosis, prognosis, and therapy for MetS. Several cholesterol-related genes associated with each characteristic of MetS have been identified, such as apolipoprotein, lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and adiponectin. This review aims to summarize the genetic information of cholesterol-related genes in MetS, which may potentially serve as biomarkers for early prevention and management of MetS.
"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.
Vitamin D plays a role in regulating the immune system and can be linked to the alteration of the gut microbiome, which leads to several immunological diseases. This systematic review aims to explore the relationship between Vitamin D and children's gut microbiome, as well as its impact towards the immune system. We have systematically collated relevant studies from different databases concerning changes in the gut microbiome of children from infants to 18 years old associated with Vitamin D and the immunological pathways. The studies utilized 16S rRNA sequencing analysis of fecal matter with or without Vitamin D supplementation and Vitamin D levels. Ten studies were selected for the review, among which eight studies showed significant alterations in the gut microbiome related to Vitamin D supplementation or Vitamin D levels. The taxa of the phylum Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria are the most altered in these studies. The alteration of the taxa alters the Th1 and Th2 pathways and changes the immune response. We will discuss how Vitamin D may contribute to the activation of immune pathways via its effects on intestinal barrier function, microbiome composition, and/or direct effects on immune responses. In conclusion, the studies examined in this review have provided evidence that Vitamin D levels may have an impact on the composition of children's gut microbiomes.
Skin squamous cell carcinoma (SCC) is a type of non-melanoma skin cancer. Pterostilbene is a natural compound proven to exhibit various pharmacological properties, including chemo-preventive effects. This study aimed to explore the chemo-preventive effect of oral pterostilbene during initiation, promotion or continuous on multistage skin SCC mouse models induced by 7,12-Dimethylbenz(a)anthracene (DMBA)/12-O-Tetradecanoylphorbol-13-acetate (TPA). The experimental design consists of five groups of female Institute of Cancer Research (ICR) mice, with two control groups of vehicle and cancer. Three oral pterostilbene groups consisted of orally administered pterostilbene during initiation, promotion, or continuously. Oral pterostilbene significantly reduced the number and volume of tumours. Oral pterostilbene demonstrated less severe skin histology changes compared to the cancer control group, with less pleomorphic in the cells and nuclei, and the basement membrane remained intact. Our results showed fewer invasive tumours in oral PT-treated groups than in cancer groups that displayed mitotic bodies, highly pleomorphic cells and nuclei, and basement membrane invasion. The cell proliferation marker (Ki-67) was reduced in oral pterostilbene-treated groups. Overall, oral pterostilbene is a promising chemo-preventive intervention due to its anti-initiation and anti-promotion on skin carcinogenesis. Thus, the potential molecular mechanisms of oral pterostilbene chemo-prevention agent should be explored.
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.
Background: Breast cancer developed at a young age (≤45 years) is hypothesized to have unique biology; however, findings in this field are controversial. Methods: We compared the whole transcriptomic profile of young vs. old-age breast cancer using DNA microarray. RNA was extracted from 13 fresh estrogen receptor (ER)-positive primary breast cancer tissues of untreated patients (7 = young age ≤45 years and 6 = old age ≥55 years). In silico validation for the differentially expressed genes (DEGs) by young-age patients was conducted using The Cancer Genome Atlas (TCGA) database. Next, we analyzed the protein expression encoded by two of the significantly down-regulated genes by young-age patients, Glycine N-acyltransferase-like 1 (GLYATL-1) and Ran-binding protein 3 like (RANBP3L), using immunohistochemical analysis in an independent cohort of 56 and 74 ER-positive pre-therapeutic primary breast cancer tissues, respectively. Results: 12 genes were significantly differentially expressed by young-age breast cancers (fold change >2 or <2- with FDR p-value < 0.05). TCGA data confirmed the differential expression of six genes. Protein expression analysis of GLYATL-1 and RANBP3L did not show heterogeneous expression between young and old-age breast cancer tissues. Loss of expression of GLYATL-1 was significantly (p-value 0.005) associated with positive lymph node status. Higher expression of RANBP3L was significantly associated with breast cancers with lower histopathological grades (p-value 0.038). Conclusions: At the transcriptomic level, breast cancer developed in young and old age patients seems homogenous. The variation in the transcriptomic profiles can be attributed to the other clinicopathological characteristics rather than the age of the patient.
BPA is identified as an endocrine-disrupting chemical that deteriorates the physiological function of the hormones of the male reproductive system. Bisphenol F (BPF), bisphenol S (BPS), and bisphenol AF (BPAF) are actively explored as substitutes for BPA and are known as BPA analogues in most manufacturing industries. These analogues may demonstrate the same adverse effects as BPA on the male reproductive system; however, toxicological data explaining the male reproductive hormones' physiological functions are still limited. Hence, this mini-review discusses the effects of BPA and its analogues on the physiological functions of hormones in the male reproductive system, focusing on the hypothalamus-pituitary-gonad (HPG) axis, steroidogenesis, and spermatogenesis outcomes. The BPA analogues mainly show a similar negative effect on the hormones' physiological functions, proven by alterations in the HPG axis and steroidogenesis via activation of the aromatase activity and reduction of spermatogenesis outcomes when compared to BPA in in vitro and in vivo studies. Human biomonitoring studies also provide significant adverse effects on the physiological functions of hormones in the male reproductive system. In conclusion, BPA and its analogues deteriorate the physiological functions of hormones in the male reproductive system as per in vitro, in vivo, and human biomonitoring studies.
Tissue engineering products have grown rapidly as an alternative solution available for chronic wound and burn treatment. However, some drawbacks include additional procedures and a lack of antibacterial properties that can impair wound healing, which are issues that need to be tackled effectively for better wound recovery. This study aimed to develop a functionalized dual-layered hybrid biomatrix composed of collagen sponge (bottom layer) to facilitate cell proliferation and adhesion and gelatin/cellulose hydrogel (outer layer) incorporated with graphene oxide and silver nanoparticles (GC-GO/AgNP) to prevent possible external infections post-implantation. The bilayer hybrid scaffold was crosslinked with 0.1% (w/v) genipin for 6 h followed by advanced freeze-drying technology. Various characterisation parameters were employed to investigate the microstructure, biodegradability, surface wettability, nanoparticles antibacterial activity, mechanical strength, and biocompatibility of the bilayer bioscaffold towards human skin cells. The bilayer bioscaffold exhibited favourable results for wound healing applications as it demonstrated good water uptake (1702.12 ± 161.11%), slow rate of biodegradation (0.13 ± 0.12 mg/h), and reasonable water vapour transmission rate (800.00 ± 65.85 gm−2 h−1) due to its porosity (84.83 ± 4.48%). The biomatrix was also found to possess hydrophobic properties (48.97 ± 3.68°), ideal for cell attachment and high mechanical strength. Moreover, the hybrid GO-AgNP promoted antibacterial properties via the disk diffusion method. Finally, biomatrix unravelled good cellular compatibility with human dermal fibroblasts (>90%). Therefore, the fabricated bilayer scaffold could be a potential candidate for skin wound healing application.
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.
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.
MicroRNAs (miRNAs) are short non-coding RNAs involved in post-transcriptional gene regulation. Over the past years, various studies have demonstrated the role of aberrant miRNA expression in the onset of cancer. The mechanisms by which miRNA exerts its cancer-promoting or inhibitory effects are apparent through the various cancer hallmarks, which include selective proliferative advantage, altered stress response, vascularization, invasion and metastasis, metabolic rewiring, the tumor microenvironment and immune modulation; therefore, this review aims to highlight the association between miRNAs and the various cancer hallmarks by dissecting the mechanisms of miRNA regulation in each hallmark separately. It is hoped that the information presented herein will provide further insights regarding the role of cancer and serve as a guideline to evaluate the potential of microRNAs to be utilized as biomarkers and therapeutic targets on a larger scale in cancer research.
Molecular hydrogen is renowned as an odorless and colorless gas. The recommendations developed by China suggest that the inhalation of hydrogen molecules is currently advised in COVID-19 pneumonia treatment. The therapeutic effects of molecular hydrogens have been confirmed after numerous clinical trials and animal-model-based experiments, which have expounded that the low molecular weight of hydrogen enables it to easily diffuse and permeate through the cell membranes to produce a variety of biological impacts. A wide range of both chronic and acute inflammatory diseases, which may include sepsis, pancreatitis, respiratory disorders, autoimmune diseases, ischemia-reperfusion damages, etc. may be treated and prevented by using it. H2 can primarily be inoculated through inhalation, by drinking water (which already contains H2), or by administrating the injection of saline H2 in the body. It may play a pivotal role as an antioxidant, in regulating the immune system, in anti-inflammatory activities (mitochondrial energy metabolism), and cell death (apoptosis, pyroptosis, and autophagy) by reducing the formation of excessive reactive O2 species and modifying the transcription factors in the nuclei of the cells. However, the fundamental process of molecular hydrogen is still not entirely understood. Molecular hydrogen H2 has a promising future in therapeutics based on its safety and possible usefulness. The current review emphasizes the antioxidative, anti-apoptotic, and anti-inflammatory effects of hydrogen molecules along with the underlying principle and fundamental mechanism involved, with a prime focus on the coronavirus disease of 2019 (COVID-19). This review will also provide strategies and recommendations for the therapeutic and medicinal applications of the hydrogen molecule.
(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.
Osteoarthritis (OA) has traditionally been known as a "wear and tear" disease, which is mainly characterized by the degradation of articular cartilage and changes in the subchondral bone. Despite the fact that OA is often thought of as a degenerative disease, the catabolic products of the cartilage matrix often promote inflammation by activating immune cells. Current OA treatment focuses on symptomatic treatment, with a primary focus on pain management, which does not promote cartilage regeneration or attenuate joint inflammation. Since articular cartilage have no ability to regenerate, thus regeneration of the tissue is one of the key targets of modern treatments for OA. Cell-based therapies are among the new therapeutic strategies for OA. Mesenchymal stem cells (MSCs) have been extensively researched as potential therapeutic agents in cell-based therapy of OA due to their ability to differentiate into chondrocytes and their immunomodulatory properties that can facilitate cartilage repair and regeneration. In this review, we emphasized current knowledge and future perspectives on the use of MSCs by targeting their regeneration potential and immunomodulatory effects in the treatment of OA.
Cytokines play an important role in modulating inflammation during viral infection, including hepatitis C virus (HCV) infection. Genetic polymorphisms of cytokines can alter the immune response against this infection. The objective of this study was to investigate the possible association between chronic hepatitis C virus infection susceptibility and cytokine gene polymorphism for interleukin-10 (IL-10) rs1800896 and rs1800871, interleukin 6 (IL-6) rs1800795, TNF-α rs1800629, and TGF-β1 rs1800471 in Malay male drug abusers. The study was conducted on 76 HCV-positive (HP) male drug abusers and 40 controls (HCV-negative male drug abusers). We found that there were significant differences in the frequencies of genotype for IL-10 rs1800871 (p = 0.0386) and at the allelic level for IL-10 rs1800896 A versus G allele (p = 0.0142) between the HP group and the control group. However, there were no significant differences in gene polymorphism in interleukin 6 rs1800795, TNF-α rs1800629 and TGF-β1 rs1800471. These findings suggest significant associations between gene polymorphism for IL-10 rs1800871, IL-10 rs1800896 (at the allelic level) and susceptibility to HCV infection among Malay male drug abusers.
Borrelia burgdorferi sensu lato (B. burgdorferi s.l.), which is predominantly spread by ticks, is the cause of Lyme disease (LD), also known as Lyme borreliosis, one of the zoonotic diseases affecting people. In recent years, LD has become more prevalent worldwide, even in countries with no prior records. Currently, Lyme Borrelia detection is achieved through nucleic acid amplification, antigen detection, microscopy, and in vitro culture. Nevertheless, these methods lack sensitivity in the early phase of the disease and, thus, are unable to confirm active infection. This review briefly discusses the existing direct detection methods of LD. Furthermore, this review also introduces the use of aptamer technology integrated with biosensor platforms to detect the Borrelia antigen. This aptamer technology could be explored using other biosensor platforms targeting whole Borrelia cells or specific molecules to enhance Borrelia detection in the future.