miRNA in Ischemic Heart Disease and Its Potential as Biomarkers: A Comprehensive Review.

Ischemic heart disease (IHD) constitutes the leading global cause of mortality and morbidity. Although significant progress has been achieved in the diagnosis, treatment, and prognosis of IHD, more robust diagnostic biomarkers and therapeutic interventions are still needed to circumvent the increasing incidence of IHD. MicroRNAs (miRNAs) are critical regulators of cardiovascular function and are involved in various facets of cardiovascular biology. While the knowledge of the role of miRNAs in IHD as diagnostic biomarkers has improved, research emphasis on how miRNAs can be effectively used for diagnosis and prognosis of IHD is crucial. This review provides an overview of the biology, therapeutic and diagnostic potential, as well as the caveats of using miRNAs in IHD based on existing research.

Identification of NRAS Diagnostic Biomarkers and Drug Targets for Endometrial Cancer-An Integrated in Silico Approach.

The diagnosis of endometrial cancer involves sequential, invasive tests to assess the thickness of the endometrium by a transvaginal ultrasound scan. In 6−33% of cases, endometrial biopsy results in inadequate tissue for a conclusive pathological diagnosis and 6% of postmenopausal women with non-diagnostic specimens are later discovered to have severe endometrial lesions. Thus, identifying diagnostic biomarkers could offer a non-invasive diagnosis for community or home-based triage of symptomatic or asymptomatic women. Herein, this study identified high-risk pathogenic nsSNPs in the NRAS gene. The nsSNPs of NRAS were retrieved from the NCBI database. PROVEAN, SIFT, PolyPhen-2, SNPs&GO, PhD-SNP and PANTHER were used to predict the pathogenicity of the nsSNPs. Eleven nsSNPs were identified as "damaging", and further stability analysis using I-Mutant 2.0 and MutPred 2 indicated eight nsSNPs to cause decreased stability (DDG scores < −0.5). Post-translational modification and protein−protein interactions (PPI) analysis showed putative phosphorylation sites. The PPI network indicated a GFR-MAPK signalling pathway with higher node degrees that were further evaluated for drug targets. The P34L, G12C and Y64D showed significantly lower binding affinity towards GTP than wild-type. Furthermore, the Kaplan−Meier bioinformatics analyses indicated that the NRAS gene deregulation affected the overall survival rate of patients with endometrial cancer, leading to prognostic significance. Findings from this could be considered novel diagnostic and therapeutic markers.

Contribution of Aldehydes and Their Derivatives to Antimicrobial and Immunomodulatory Activities.

Essential oils (EOs) are intricate combinations of evaporative compounds produced by aromatic plants and extracted by distillation or expression. EOs are natural secondary metabolites derived from plants and have been found to be useful in food and nutraceutical manufacturing, perfumery and cosmetics; they have also been found to alleviate the phenomenon of antimicrobial resistance (AMR) in addition to functioning as antibacterial and antifungal agents, balancing menstrual cycles and being efficacious as an immune system booster. Several main aldehyde constituents can be found in different types of EOs, and thus, aldehydes and their derivatives will be the main focus of this study with regard to their antimicrobial, antioxidative, anti-inflammatory and immunomodulatory effects. This brief study also explores the activity of aldehydes and their derivatives against pathogenic bacteria for future use in the clinical setting.

Circulation of at Least Six Distinct Groups of Pigeon-Derived Newcastle Disease Virus in Iran Between 1996 and 2019.

According to the latest Newcastle disease virus (NDV) classification system, Iranian PPMV-1 isolates were classified as either XXI.1.1 or XXI.2 subgenotypes only. However, a few recent studies have suggested the possible existence of other Iranian PPMV-1 genotypes/subgenotypes. Recently, we isolated a PPMV-1 closely related to the African origin subgenotype VI.2.1.2 from an ill captive pigeon in a park aviary in central Tehran (Pg/IR/AMMM160/2019). This subgenotype had never been reported from Iran or neighboring countries. We also isolated a subgenotype VII.1.1 NDV (Pg/IR/AMMM117/2018), usually reported from non-pigeon birds in Iran. The nucleotide distance of AMMM117 was 1.0-2.5% compared to other Iranian subgenotypes VII.1.1 isolates. However, usually the same year VII.1.1 viruses that we isolate from Iranian poultry farms show negligible distances (0.0-0.5%). More isolates are required to study if this difference is due to subgenotype VII.1.1 being circulated and mutated in pigeons. Here, we also characterized two other isolates, namely Pg/IR/AMMM168/2019 and Pg/IR/MAM39/2017. The latter is the first Iranian subgenotype XXI.1.1 to be featured in the NDV datasets of the international NDV consortium. We also investigated the phylogenetic relation of all the published Iranian pigeon-derived NDV to date and updated the grouping according to the latest classification system. We have concluded that at least six different groups of pigeon-derived NDV have been circulating in Iran since 1996, four of which have been reported from just one city over the last seven years. This study suggests that the Iranian pigeon-origin NDV have been more diverse than the Iranian poultry-derived NDV in recent years.

Predominance of Fourth Panzootic Newcastle Disease Virus Subgenotype VII.1.1 in Iran and Its Relation to the Genotypes Circulating in the Region.

Following recent Newcastle disease virus (NDV) outbreaks in Iranian poultry farms which were mostly associated with lesions of the avian gastrointestinal tract, it was speculated that the scale of the outbreaks could be attributed in part to co-circulating infectious agents or a new NDV genotype/subgenotype. This speculation was due to the isolation of a few 5th panzootic subgenotype VII.2 viruses from Iranian poultry farms in 2017. Samples from different species of commercial and domestic birds were collected from different provinces of Iran, 19 of which were selected for the current study. Phylogenetic analyses showed that the recent outbreaks have been caused by only one agent, i.e. the distinctive NDV subgenotype VII.1.1 (previously known VIIl) viruses that seem to be circulating predominantly in Iran, but have also been sporadically reported from Iraq among neighbouring countries. At most, 96.3-96.7% BLAST identity to non-Iranian VII.1.1 isolates was observed. Genetic distance values of <1% were indicative of high similarity between the isolates, but the values were approaximately 2% when the current isolates were compared to the earliest recorded Iranian VII.1.1 viruses isolated in 2010. Using Bayesian analysis, annual mutation rates of 1.7156E-3 (strict) and 1.9902E-3 (relaxed) over 11 years were obtained. In addition, we report that our laboratories have not detected any genotype XIII strains since 2011. Following up on previous reports, we concluded that currently, and except in Columbiforms, subgenotype VII.1.1 may likely be the predominant subgenotype in many bird species in Iran despite the subgenotype VII.2 being predominant in neighbouring countries.

Bioactive Compounds from Marine Sponges: Fundamentals and Applications.

Marine sponges are sessile invertebrates that can be found in temperate, polar and tropical regions. They are known to be major contributors of bioactive compounds, which are discovered in and extracted from the marine environment. The compounds extracted from these sponges are known to exhibit various bioactivities, such as antimicrobial, antitumor and general cytotoxicity. For example, various compounds isolated from Theonella swinhoei have showcased various bioactivities, such as those that are antibacterial, antiviral and antifungal. In this review, we discuss bioactive compounds that have been identified from marine sponges that showcase the ability to act as antibacterial, antiviral, anti-malarial and antifungal agents against human pathogens and fish pathogens in the aquaculture industry. Moreover, the application of such compounds as antimicrobial agents in other veterinary commodities, such as poultry, cattle farming and domesticated cats, is discussed, along with a brief discussion regarding the mode of action of these compounds on the targeted sites in various pathogens. The bioactivity of the compounds discussed in this review is focused mainly on compounds that have been identified between 2000 and 2020 and includes the novel compounds discovered from 2018 to 2021.

An Overview of the Potential Therapeutic Applications of Essential Oils.

The emergence of antimicrobial resistance (AMR) has urged researchers to explore therapeutic alternatives, one of which includes the use of natural plant products such as essential oils (EO). In fact, EO obtained from clove, oregano, thymus, cinnamon bark, rosemary, eucalyptus, and lavender have been shown to present significant inhibitory effects on bacteria, fungi, and viruses; many studies have been done to measure EO efficacy against microorganisms. The strategy of combinatory effects via conventional and non-conventional methods revealed that the combined effects of EO-EO or EO-antibiotic exhibit enhanced efficacy. This paper aims to review the antimicrobial effects of EO, modes of EO action (membrane disruption, efflux inhibition, increase membrane permeability, and decrease in intracellular ATP), and their compounds' potential as effective agents against bacteria, fungi, and viruses. It is hoped that the integration of EO applications in this work can be used to consider EO for future clinical applications.

Nutraceuticals: Transformation of Conventional Foods into Health Promoters/Disease Preventers and Safety Considerations.

Nutraceuticals are essential food constituents that provide nutritional benefits as well as medicinal effects. The benefits of these foods are due to the presence of active compounds such as carotenoids, collagen hydrolysate, and dietary fibers. Nutraceuticals have been found to positively affect cardiovascular and immune system health and have a role in infection and cancer prevention. Nutraceuticals can be categorized into different classes based on their nature and mode of action. In this review, different classifications of nutraceuticals and their potential therapeutic activity, such as anti-cancer, antioxidant, anti-inflammatory and anti-lipid activity in disease will be reviewed. Moreover, the different mechanisms of action of these products, applications, and safety upon consumers including current trends and future prospect of nutraceuticals will be included.

Application, monitoring and adverse effects in pesticide use: The importance of reinforcement of Good Agricultural Practices (GAPs).

This review intends to integrate the relevant information that is related to pesticide applications in food commodities and will cover three main sections. The first section encompasses some of the guidelines that have been implemented on management of pesticide application worldwide, such as the establishment of a value called Maximum Residue Level (MRL) through the application of Good Agricultural Practices (GAPs) into daily agricultural activities. A brief overview of the methods adopted in quantification of these trace residues in different food samples will also be covered. Briefly, pesticide analysis is usually performed in two stages: sample preparation and analytical instrumentation. Some of the preparation methods such as QuEChERs still remain as the technique of choice for most of the analytical scientists. In terms of the instrumentation such as the gas chromatography-mass spectrophotometry (GC-MS) and high performance-liquid chromatography (HPLC), these are still widely used, in spite of new inventions that are more sustainable and efficient such as the capillary electrophoresis (CE). Finally, the third section emphasizes on how pesticides can affect our health significantly whereby different types of pesticides result in different adverse health implications, despite its application benefits in agriculture in controlling pests. To date, there are limited reviews on pesticide usage in many agricultural-based nations; for the purpose of this review, Malaysia is selected to better illustrate pesticide regulations and implementation of policies. Finally, the review aims to provide an insight on how implementation of GAP and food safety assurance are inter-related and with this established correlation, to identify further measures for improvement to enable reinforcement of optimised agricultural practices specifically in these countries.

Middle Eastern Plant Extracts: An Alternative to Modern Medicine Problems.

Middle Eastern countries are primarily known for their dry sand deserts; however, they have a wider physiographic range which includes upland plateau and mountain ranges. The Middle East is home to various types of plants, such as Phoenix dactylifera (date palm tree), Scrophularia striata (herbaceous plants), and Opuntia ficus-indica (cactus). These plants have been found to have various types of bioactivities, such as antimicrobial activities against both bacteria and fungi, in addition to exhibiting anti-inflammatory effects and anti-cancer characteristics which can be utilized in the clinical setting for treatment. Due to limited reviews focusing on plant extracts from the Middle East, we aim to provide a discourse on plants from this region which have various bioactivities and to provide information on the compounds that can be identified from these plants. This is to enhance our understanding to improve modern medicine problems such as antimicrobial resistance and to find an alternative cure for cancer. It is hoped that the collation of information from this review will enable an assessment of the direct role of Middle Eastern plants in providing therapeutic options to address the predicaments in the medical field.

Virotherapy: Current Trends and Future Prospects for Treatment of Colon and Rectal Malignancies.

Colorectal cancer (CRC) is one of the most common malignancies. In recent decades, early diagnosis and conventional therapies have resulted in a significant reduction in mortality. However, late stage metastatic disease still has very limited effective treatment options. There is a growing interest in using viruses to help target therapies to tumour sites. In recent years the evolution of immunotherapy has emphasised the importance of directing the immune system to eliminate tumour cells; we aim to give a state-of-the-art over-view of the diverse viruses that have been investigated as potential oncolytic agents for the treatment of CRC.

The synergism of Clinacanthus nutans Lindau extracts with gemcitabine: downregulation of anti-apoptotic markers in squamous pancreatic ductal adenocarcinoma.

BACKGROUND: Clinacanthus nutans extracts have been consumed by the cancer patients with the hope that the extracts can kill cancers more effectively than conventional chemotherapies. Our previous study reported its anti-inflammatory effects were caused by inhibiting Toll-like Receptor-4 (TLR-4) activation. However, we are unsure of its anticancer effect, and its interaction with existing chemotherapy. METHODS: We investigated the anti-proliferative efficacy of polar leaf extracts (LP), non-polar leaf extracts (LN), polar stem extract (SP) and non-polar stem extracts (SN) in human breast, colorectal, lung, endometrial, nasopharyngeal, and pancreatic cancer cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT assay. The most potent extracts was tested along with gemcitabine using our established drug combination analysis. The effect of the combinatory treatment in apoptosis were quantified using enzyme-linked immunosorbent assay (ELISA), Annexin V assay, antibody array and immunoblotting. Statistical significance was analysed using one-way analysis of variance (ANOVA) and post hoc Dunnett's test. A p-value of less than 0.05 (p < 0.05) was considered statistical significance. RESULTS: All extracts tested were not able to induce potent anti-proliferative effects. However, it was found that pancreatic ductal adenocarcinoma, PDAC (AsPC1, BxPC3 and SW1990) were the cell lines most sensitive cell lines to SN extracts. This is the first report of C. nutans SN extracts acting in synergy with gemcitabine, the first line chemotherapy for pancreatic cancer, as compared to conventional monotherapy. In the presence of SN extracts, we can reduce the dose of gemcitabine 2.38-5.28 folds but still maintain the effects of gemcitabine in PDAC. SN extracts potentiated the killing of gemcitabine in PDAC by apoptosis. Bax was upregulated while bcl-2, cIAP-2, and XIAP levels were downregulated in SW1990 and BxPC3 cells treated with gemcitabine and SN extracts. The synergism was independent of TLR-4 expression in pancreatic cancer cells. CONCLUSION: These results provide strong evidence of C. nutans extracts being inefficacious as monotherapy for cancer. Hence, it should not be used as a total substitution for any chemotherapy agents. However, SN extracts may synergise with gemcitabine in the anti-tumor mechanism.

Terpene Derivatives as a Potential Agent against Antimicrobial Resistance (AMR) Pathogens.

The evolution of antimicrobial resistance (AMR) in pathogens has prompted extensive research to find alternative therapeutics. Plants rich with natural secondary metabolites are one of the go-to reservoirs for discovery of potential resources to alleviate this problem. Terpenes and their derivatives comprising of hydrocarbons, are usually found in essential oils (EOs). They have been reported to have potent antimicrobial activity, exhibiting bacteriostatic and bactericidal effects against tested pathogens. This brief review discusses the activity of terpenes and derivatives against pathogenic bacteria, describing the potential of the activity against AMR followed by the possible mechanism exerted by each terpene class. Finally, ongoing research and possible improvisation to the usage of terpenes and terpenoids in therapeutic practice against AMR are discussed.

NDV subgenotype VII(L) is currently circulating in commercial broiler farms of Iran, 2017-2018.

BACKGROUND: Based on our previous work, it was discovered that some Newcastle disease virus (NDV) isolates from backyard poultry between 2011 and 2013 in Iran formed a new separate cluster when phylogenetic analysis based on the complete F gene sequence was carried out. The novel cluster was designated subgenotype VII(L) and published. AIM: In the current study, for further validation, we initiated a comprehensive epidemiological study to identify the dominant NDV genotype(s) circulating within the country. Collection of samples was executed between October 2017 and February 2018 from 108 commercial broiler farms which reported clinical signs of respiratory disease in their broilers. RESULT: We report that 38 of the farms (> 35%) tested positive for NDV. The complete F gene sequences of seven of the isolates are shown as representative sequences in this study. According to the phylogenetic tree constructed, the recent broiler farm isolates clustered into the newly designated cluster VII(L) together with the older Iranian backyard poultry isolates in our previous work. All the sequences shared the same virulence-associated F cleavage site of 112RRQKR↓F117. CONCLUSION: Our phylogenetic analysis suggested that the NDV subgenotype VII(L) may have been derived from subgenotype VIId, and contrary to popular belief, subgenotype VIId may not be the dominant subgenotype in Iran. Tracking of the subgenotype on BLAST suggested that the NDV subgenotype VII(L), although previously unidentified, may have been circulating in this region as an endemic virus for at least a decade. Other NDV genotypes, however, have also been reported in Iran in recent years. Hence, ongoing study is aimed at determining the exact dominant NDV genotypes and subgenotypes in the country. This will be crucial in effective mitigation of outbreaks in Iranian broiler farms.

Prevalence of avian influenza (H9N2) in commercial quail, partridge, and turkey farms in Iran, 2014-2015.

Avian influenza virus (AIV) H9N2 subtype is endemic in Iran and causes substantial economic loss to the growing poultry industry within the country. In this study, a cross-sectional analysis was carried out to determine the sero-prevalence of H9N2 in several commercial farms between the years 2014 and 2015. The comparison of the mean of serum titers and the ratio of sero-positive birds between all units were analyzed using one-way ANOVA test. In 2014, a total of 77 farms (58 turkey farms, 14 quail farms, and 5 partridge farms) and 894 birds (682 turkeys, 154 quails, and 58 partridges) were sampled while in 2015, a total of 69 farms (54 turkey farms, 8 quail farms, and 7 partridge farms) and 856 birds (675 turkeys, 105 quails, and 76 partridges) were sampled. Of that, 52 of 77 sampled farms (67.5%) and 437 of 894 samples (48.9%) were positive for H9N2 in 2014 while. Forty-one of 69 farms (59.4%) and 307 of 856 sera (35.9%) were positive in 2015. Furthermore, the mean titer of partridge farms was significantly lower than that of turkey farms (p < 0.01) and the mean percentage of sero-positive turkey farms was significantly higher than partridge farms (p < 0.01) in 2014. In 2015, no significant difference was observed between the mean sera titer amongst farms and percentage of sero-positive birds (p > 0.05). Our results indicated that H9N2 is circulating in these farms. Since many more such farms are being established for operations, in addition to the threat of emergence and continuous reemergence of the disease in these farms, enhanced veterinary biosecurity measures on farms are required for mitigation.

A review on Lactococcus lactis: from food to factory.

Lactococcus lactis has progressed a long way since its discovery and initial use in dairy product fermentation, to its present biotechnological applications in genetic engineering for the production of various recombinant proteins and metabolites that transcends the heterologous species barrier. Key desirable features of this gram-positive lactic acid non-colonizing gut bacteria include its generally recognized as safe (GRAS) status, probiotic properties, the absence of inclusion bodies and endotoxins, surface display and extracellular secretion technology, and a diverse selection of cloning and inducible expression vectors. This have made L. lactis a desirable and promising host on par with other well established model bacterial or yeast systems such as Escherichia coli, Saccharomyces [corrected] cerevisiae and Bacillus subtilis. In this article, we review recent technological advancements, challenges, future prospects and current diversified examples on the use of L. lactis as a microbial cell factory. Additionally, we will also highlight latest medical-based applications involving whole-cell L. lactis as a live delivery vector for the administration of therapeutics against both communicable and non-communicable diseases.

Additivity vs Synergism: Investigation of the Additive Interaction of Cinnamon Bark Oil and Meropenem in Combinatory Therapy.

Combinatory therapies have been commonly applied in the clinical setting to tackle multi-drug resistant bacterial infections and these have frequently proven to be effective. Specifically, combinatory therapies resulting in synergistic interactions between antibiotics and adjuvant have been the main focus due to their effectiveness, sidelining the effects of additivity, which also lowers the minimal effective dosage of either antimicrobial agent. Thus, this study was undertaken to look at the effects of additivity between essential oils and antibiotic, via the use of cinnamon bark essential oil (CBO) and meropenem as a model for additivity. Comparisons between synergistic and additive interaction of CBO were performed in terms of the ability of CBO to disrupt bacterial membrane, via zeta potential measurement, outer membrane permeability assay and scanning electron microscopy. It has been found that the additivity interaction between CBO and meropenem showed similar membrane disruption ability when compared to those synergistic combinations which was previously reported. Hence, results based on our studies strongly suggest that additive interaction acts on a par with synergistic interaction. Therefore, further investigation in additive interaction between antibiotics and adjuvant should be performed for a more in depth understanding of the mechanism and the impacts of such interaction.

In-silico identification of deleterious non-synonymous SNPs of TBX1 gene: Functional and structural impact towards 22q11.2DS.

The TBX1 gene plays a critical role in the development of 22q11.2 deletion syndrome (22q11.2DS), a complex genetic disorder associated with various phenotypic manifestations. In this study, we performed in-silico analysis to identify potentially deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) within the TBX1 gene and evaluate their functional and structural impact on 22q11.2DS. A comprehensive analysis pipeline involving multiple computational tools was employed to predict the pathogenicity of nsSNPs. This study assessed protein stability and explored potential alterations in protein-protein interactions. The results revealed the rs751339103(C>A), rs780800634(G>A), rs1936727304(T>C), rs1223320618(G>A), rs1248532217(T>C), rs1294927055 (C>T), rs1331240435 (A>G, rs1601289406 (A>C), rs1936726164 (G>A), and rs911796187(G>A) with a high-risk potential for affecting protein function and stability. These nsSNPs were further analyzed for their impact on post-translational modifications and structural characteristics, indicating their potential disruption of molecular pathways associated with TBX1 and its interacting partners. These findings provide a foundation for further experimental studies and elucidation of potential therapeutic targets and personalized treatment approaches for individuals affected by 22q11.2DS.

Aflatoxin Contamination: An Overview on Health Issues, Detection and Management Strategies.

Aflatoxins (AFs) represent one of the main mycotoxins produced by Aspergillus flavus and Aspergillus parasiticus, with the most prevalent and lethal subtypes being AFB1, AFB2, AFG1, and AFG2. AFs are responsible for causing significant public health issues and economic concerns that affect consumers and farmers globally. Chronic exposure to AFs has been linked to liver cancer, oxidative stress, and fetal growth abnormalities among other health-related risks. Although there are various technologies, such as physical, chemical, and biological controls that have been employed to alleviate the toxic effects of AF, there is still no clearly elucidated universal method available to reduce AF levels in food and feed; the only mitigation is early detection of the toxin in the management of AF contamination. Numerous detection methods, including cultures, molecular techniques, immunochemical, electrochemical immunosensor, chromatographic, and spectroscopic means, are used to determine AF contamination in agricultural products. Recent research has shown that incorporating crops with higher resistance, such as sorghum, into animal feed can reduce the risk of AF contamination in milk and cheese. This review provides a current overview of the health-related risks of chronic dietary AF exposure, recent detection techniques, and management strategies to guide future researchers in developing better detection and management strategies for this toxin.