An insights into emerging trends to control the threats of antimicrobial resistance (AMR): an address to public health risks.

Antimicrobial agents are used to treat microbial ailments, but increased use of antibiotics and exposure to infections in healthcare facilities and hospitals as well as the excessive and inappropriate use of antibiotics at the society level lead to the emergence of multidrug-resistant (MDR) bacteria. Antimicrobial resistance (AMR) is considered a public health concern and has rendered the treatment of different infections more challenging. The bacterial strains develop resistance against antimicrobial agents by limiting intracellular drug accumulation (increasing efflux or decreasing influx of antibiotics), modification and inactivation of drugs and its targets, enzymatic inhibition, and biofilm formation. However, the driving factors of AMR include the sociocultural and economic circumstances of a country, the use of falsified and substandard medicines, the use of antibiotics in farm animals, and food processing technologies. These factors make AMR one of the major menaces faced by mankind. In order to promote reciprocal learning, this article summarizes the current AMR situation in Pakistan and how it interacts with the health issues related to the COVID-19 pandemic. The COVID-19 pandemic aids in illuminating the possible long-term impacts of AMR, which are less immediate but not less severe since their measures and effects are equivalent. Impact on other sectors, including the health industry, the economy, and trade are also discussed. We conclude by summarizing the several approaches that could be used to address this issue.

Financial development, resource richness, eco-innovation, and sustainable development: Does geopolitical risk matter?

Financial development and geopolitical risks can significantly affect sustainable development. However, the roles of these factors in sustainable development are rarely investigated. Thus, this study takes into account the role of geopolitical risk while exploring the effects of financial development, natural resource rents, and eco-innovation on sustainable development in the Organization for Economic Co-operation and Development (OECD) countries. To this end, yearly data from 1990 to 2019 is analyzed using advanced econometric tests. The Common Correlated Effects Mean Group (CCEMG) results indicate that financial development and eco-innovation are significantly and positively related to sustainable development. Natural resource rents have a detrimental impact on sustainable development which confirms the presence of the resource curse hypothesis in OECD countries. Furthermore, the results revealed that controlling geopolitical risk is useful in fostering sustainable development. Lastly, the panel Granger causality test unveiled one-way causality from financial development, eco-innovation, natural resource rents, and geopolitical risk to sustainable development. Moreover, causalities are found from geopolitical risk to financial development, eco-innovation and natural resources. These findings suggest that OECD countries should prioritize financial development and eco-innovation policies for sustainable development while mitigating the negative effects of natural resource rents. The geopolitical risk can harm sustainable development, so policymakers should promote international cooperation and risk-sharing.

A Winning New Combination? Toward Clinical Application in Oncology.

Immunotherapy has substantial attention in oncology due to the success of CTLA-4 and PD-1 inhibitors in the treatment of melanoma, lung cancer, head and neck cancer, renal cell carcinoma, and Hodgkin's lymphoma. A deeper understanding of interaction of tumor with its environment and the immune system provides best guide for oncology research. Recent studies in oncology have explained how a tumor alters antigen presentation, avoids detection, and activation of the host immune system to live and develop. Understanding the connections between the tumor and the immune system has resulted in several innovative therapy options. The extensive field of gene therapy has provided a number of cutting-edge medicines that are expected to play an important role in lowering cancer-related mortality. This article explains the history, important breakthroughs, and future prospects for three separate gene therapy treatment modalities: immunotherapy, oncolytic virotherapy, and gene transfer. Immunotherapies have completely changed how cancer is treated, especially for individuals whose condition was previously thought to be incurable. Examples include ACT (adoptive cell therapy) and ICB (immune checkpoint blockade). This review article will discuss the relationship between the immune response to cancer and the mechanisms of immunotherapy resistance. It will cover combination drugs authorized by the US Food and Drug Administration and provide a thorough overview of how these drugs are doing clinically right now. Cytokines, vaccines, and other soluble immunoregulatory agents, innate immune modifiers, ACT, virotherapy, and other treatment modalities will all be covered in detail.

Bioengineered microbial strains for detoxification of toxic environmental pollutants.

Industrialization and other anthropogenic human activities pose significant environmental risks. As a result of the hazardous pollution, numerous living organisms may suffer from undesirable diseases in their separate habitats. Bioremediation, which removes hazardous compounds from the environment using microbes or their biologically active metabolites, is one of the most successful remediation approaches. According to the United Nations Environment Program (UNEP), deteriorating soil health negatively impacts food security and human health over time. Soil health restoration is critical right now. Microbes are widely known for their importance in cleaning up toxins present in the soil, such as heavy metals, pesticides, and hydrocarbons. However, the capacity of local bacteria to digest these pollutants is limited, and the process takes an extended time. Genetically modified organisms (GMOs), whose altered metabolic pathways promote the over-secretion of a variety of proteins favorable to the bioremediation process, can speed up the breakdown process. The need for remediation procedures, degrees of soil contamination, site circumstances, broad adoptions, and numerous possibilities occurring at various cleaning stages are all studied in detail. Massive efforts to restore contaminated soils have also resulted in severe issues. This review focuses on the enzymatic removal of hazardous pollutants from the environment, such as pesticides, heavy metals, dyes, and plastics. There are also in-depth assessments of present discoveries and future plans for efficient enzymatic degradation of hazardous pollutants.

Development of zinc ferrite nanoparticles with enhanced photocatalytic performance for remediation of environmentally toxic pharmaceutical waste diclofenac sodium from wastewater.

Diclofenac sodium is an anti-inflammatory drug commonly used to cure pain in various treatments. The remarkable potential of this pain-killer leads to its excessive use and, therefore, a persistent water contaminant. Its presence in aqueous bodies is hazardous for both humans and the environment because it causes the growth of harmful drug-resistant bacteria in water. Herein, we present a comparative study of the ZnO and ZnFe2O4 as photocatalysts for the degradation of diclofenac sodium, along with their structural and morphological studies. A simple co-precipitation method was used for the synthesis of ZnO and ZnFe2O4 and characterized by various analytical techniques. For instance, the UV-Vis study revealed the absorption maxima of ZnO at 320 nm, which was shifted to a longer wavelength region at 365 nm for zinc ferrite. The optical band gaps obtained from the Tauc plot indicated that the incorporation of iron has led to a decreased band gap of zinc ferrite (2.89 eV) than pure ZnO (3.14 eV). The metal-oxygen linkages shown by FTIR indicated the formation of desired ZnO and ZnFe2O4, which was further confirmed by XRD. It elucidated the typical hexagonal structure for ZnO and spinel cubic structure for ZnFe2O4 with an average crystallite of 31 nm and 44 nm for ZnO and ZnFe2O4, respectively. The micrographs obtained by SEM showed rough spherical particles of ZnO, whereas for ZnFe2O4 flower-like clustered particles were observed. The photocatalytic investigation against diclofenac sodium revealed the higher degradation efficiency of ZnFe2O4 (61.4%) in only 120 min, whereas ZnO degraded only 48.9% of the drug. Moreover, zinc ferrite has shown good recyclability and was stable up to five runs of photodegradation with a small loss (3.9%) of photocatalytic activity. The comparison of two catalysts has suggested the promising role of zinc ferrite in wastewater remediation to eliminate hazardous pharmaceuticals.

Comparative Analysis of IgG Antibody Titers Induced by Three Different SARS-COV-2 Vaccines in Healthy Adults of Pakistan.

Covid-19 is a contagious disease caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). In order to control this disease, different effective vaccines have been developed. This study is an attempt to determine the strength and duration of immunogenicity of various established vaccines. This cross-sectional, observational study was conducted to compare the efficacy of three different vaccines; Pfizer BNT 162b2, Sinovac, and CanSino, respectively, after a duration of 3 months, in the healthy adult population of Pakistan. In this study 371 healthy participants (aged 12-25 years) of both genders (male and females) were enrolled. The blood sample was drawn 90 days after the complete vaccination process. The humoral response (IgG) was analyzed by electrochemiluminescence immunoassay (ECLIA) method with Roche Anti-SARS-CoV-2 S analyzer kit. Descriptive statistical analysis was performed using IBM SPSS statistics version 22 and P < 0.05 was considered significant. The mean antibody titer in Pfizer-group was 12,536.35 U/mL, followed by 5168.68 U/mL in the Sinovac group and 4284.32 U/mL in the CanSino group. The Pfizer-group showed gender-specific significant differences, with higher antibody levels in males (P = 0.006) as compared to Sinovac and Cansino groups. The Mean IgG antibody levels of the Pfizer-vaccinated group were significantly higher than the Sinovac-vaccinated group and the CanSino-vaccinated group (P = 0.000, each). However, the mean difference between the Sinovac-vaccinated group and the CanSino-vaccinated group was not significant. Vaccine-induced seropositivity was found in the whole cohort. The mRNA-based vaccine produced the highest immune response, and thus, it is recommended for future application.

Sustainable production of biofuels from the algae-derived biomass.

The worldwide fossil fuel reserves are rapidly and continually being depleted as a result of the rapid increase in global population and rising energy sector needs. Fossil fuels should not be used carelessly since they produce greenhouse gases, air pollution, and global warming, which leads to ecological imbalance and health risks. The study aims to discuss the alternative renewable energy source that is necessary to meet the needs of the global energy industry in the future. Both microalgae and macroalgae have great potential for several industrial applications. Algae-based biofuels can surmount the inadequacies presented by conventional fuels, thereby reducing the 'food versus fuel' debate. Cultivation of algae can be performed in all three systems; closed, open, and hybrid frameworks from which algal biomass is harvested, treated and converted into the desired biofuels. Among these, closed photobioreactors are considered the most efficient system for the cultivation of algae. Different types of closed systems can be employed for the cultivation of algae such as stirred tank photobioreactor, flat panel photobioreactor, vertical column photobioreactor, bubble column photobioreactor, and horizontal tubular photobioreactor. The type of cultivation system along with various factors, such as light, temperature, nutrients, carbon dioxide, and pH affect the yield of algal biomass and hence the biofuel production. Algae-based biofuels present numerous benefits in terms of economic growth. Developing a biofuel industry based on algal cultivation can provide us with a lot of socio-economic advantages contributing to a publicly maintainable result. This article outlines the third-generation biofuels, how they are cultivated in different systems, different influencing factors, and the technologies for the conversion of biomass. The benefits provided by these new generation biofuels are also discussed. The development of algae-based biofuel would not only change environmental pollution control but also benefit producers' economic and social advancement.

Novel strategies for extraction, purification, processing, and stability improvement of bioactive molecules.

Bioactive molecules gain significance in pharmaceutical and nutraceutical industries for showcasing various beneficial biological properties including but not limited to anticancer, antimicrobial, antioxidant, antifungal, anti-inflammatory, cardioprotective, neuroprotective, and antidiabetic. However, the practice of using traditional approaches to produce bioactive molecules is gradually declining due to various limitations such as low product quality, high toxicity, low product yield, low efficiency, and product degradation. Thus, with the escalating demand for these bioactive molecules and active agents in food and other food-related industries, it has become a dire need for the scientific world to come up with novel approaches and strategies that cannot just improve the quality of these bioactives but also prepare them in a comparatively shorter time span. This review includes the latest approaches and techniques used either independently or in combinations for the extraction, purification, processing, and stability improvement of general bioactive molecules. Different parameters of these versatile techniques have been discussed with their effectiveness and work principles.

Novel strategies and advancement in reducing heavy metals from the contaminated environment.

The most contemporary ecological issues are the dumping of unprocessed factories' effluent. As a result, there is an increasing demand for creative, practical, environmentally acceptable, and inexpensive methodologies to remediate inorganic metals (Hg, Cr, Pb, and Cd) liquidated into the atmosphere, protecting ecosystems. Latest innovations in biological metals have driven natural treatment as a viable substitute for traditional approaches in this area. To eliminate pesticide remains from soil/water sites, technologies such as oxidation, burning, adsorption, and microbial degradation have been established. Bioremediation is a more cost-effective and ecologically responsible means of removing heavy metals than conventional alternatives. As a result, microorganisms have emerged as a necessary component of methyl breakdown and detoxification via metabolic reactions and hereditary characteristics. The utmost operative variant for confiscating substantial metals commencing contaminated soil was A. niger, which had a maximum bioaccumulation efficiency of 98% (Cd) and 43% (Cr). Biosensor bacteria are both environmentally sustainable and cost-effective. As a result, microbes have a range of metal absorption processes that allow them to have higher metal biosorption capabilities. Additionally, the biosorption potential of bacterium, fungus, biofilm, and algae, inherently handled microorganisms that immobilized microbial cells for the elimination of heavy metals, was reviewed in this study. Furthermore, we discuss some of the challenges and opportunities associated with producing effective heavy metal removal techniques, such as those that employ different types of nanoparticles.

Identification of NS5B resistance against SOFOSBUVIR in hepatitis C virus genotype 3a, naive and treated patients.

AIMS: Pakistan has the second highest prevalence of HCV with genotype 3a (GT-3a) being the most frequently circulating genotype. Currently, resistance-associated substitutions (RASs) are a major challenge in HCV treatment with direct-acting antivirals (DAAs). Sofosbuvir (SOF) is an FDA-approved NS5B nucleotide inhibitor. The aim of this study was to identify these RASs in the NS5B gene in naive and treated Pakistani HCV 3a isolates against SOF. METHODS AND RESULTS: Blood samples were collected from anti-HCV-positive patients, followed by HCV RNA isolation and real-time PCR quantification. HCV-positive patients were processed for HCV RNA genotyping, patients with genotype 3a were processed for NS5B gene amplification and sequencing. GT-3a was the most prevalent genotype (62.2%). S282T was identified in 2 (8.7%) patients, C316Y/G/R in 3 (13%), V321A and L320P in 1 (4.3%) each in SOF/RBV-resistant patients. Variants of S282 were detected in 3 (13%) of SOF/RBV-treated patients. While INF/RBV-associated mutations were also analysed, D244N, A333R and A334E were identified in 2 (9.5%), 3 (14.2%) and 7 (33.3%) in treatment-naive and 15 (65.2%), 7 (30.4%) and 5 (21.7%) treated patients, respectively. Q309R was observed only in one treatment-experienced patients. Some substitutions were present at higher frequency in both groups like N307G, K304R, A272D and R345H, considered that they do not have any role in sofosbuvir resistance. CONCLUSION: It was concluded that sofosbuvir RASs are present in Pakistani HCV GT-3a isolates, and they should be monitored carefully, especially in treatment-experienced patients, for further selection of treatment regimens. SIGNIFICANCE AND IMPACT OF STUDY: HCV RASs have been studied very well across the world but there is scarcity of data regarding this topic in Pakistani population, this study provides data regarding the prevalence of these RASs in Pakistani HCV isolates emphasizing the fact that these RASs must be carefully monitored before starting HCV treatment, especially in treatment failure patients.

Citric acid-capped NiWO4/Bi2S3 and rGO-doped NiWO4/Bi2S3 nanoarchitectures for photocatalytic decontamination of emerging pollutants from the aqueous environment.

Herein, we describe the successful synthesis of NiWO4/Bi2S3 and reduced graphene oxide (rGO-NiWO4/Bi2S3) nanocomposites through a simple green sol-gel approach. The fabricated composites were subsequently characterized by Fourier transform infrared (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), Energy Dispersive X-Ray Analysis (EDX) and ultraviolet-visible spectroscopy (UV-VIS) spectroscopic analyses. Dielectric properties were done by a precision impedance analyzer. Tanδ and dielectric constant for NiWO4/Bi2S3 and rGO-NiWO4/Bi2S3 were 1.811, 292818, and 0.2970, 344574, respectively, at 20 Hz. The photocatalytic performance of NiWO4/Bi2S3 and rGO-NiWO4/Bi2S3 was investigated against methylene blue and methyl orange dyes in an aqueous medium. NiWO4-Bi2S3 showed degradation of methylene blue 15.52% after 20 min, 21.8% after 30 min and 46.8% after 40 min. Similarly, for methyl orange dye it was 18.1% after 20 min, 54% after 30 min and 59.36% after 40 min. Compared to NiWO4/Bi2S3, rGO-NiWO4/Bi2S3 exhibited superior degradation efficiency of 7.5% (20 min), 25.24% (30 min) and 57.71% (40 min) for methylene blue, and 35.7% (20 min), 56.98% (30 min) and 72.42% (40 min) for methyl orange under sunlight. This enhancement in photocatalytic and dielectric properties might be attributed to the presence of graphene in rGO-NiWO4/Bi2S3 nanococomposite. Different factors such as effect of time, pH, dose of catalyst, concentration of dye were optimized and the reusability of superior catalyst rGO-NiWO4/Bi2S3 was also checked for four cycles. In conclusion, promising photocatalytic and dielectric properties of rGO-NiWO4/Bi2S3 suggest its potential applications in the photocatalytic degradation of organic pollutants and energy storage materials. This study provides a well-developed route to exploit metal sulphide/oxide nanocomposites in environmental remediation and energy storage devices.

Multifunctional nanomaterials and nanocomposites for sensing and monitoring of environmentally hazardous heavy metal contaminants.

The applications of conventional sensors are limited by the long response time, high cost, large detection limit, low sensitivity, complicated usage and low selectivity. These sensors are nowadays replaced by Nanocomposite-based modalities and nanomaterials which are known for their high selectivity and physical and chemical properties. These nanosensors effectively detect heavy metal contaminants in the environment as the discharge of heavy metals into natural water as a result of human activity has become a global epidemic. Exposure to these toxic metals might induce many health-related complications, including kidney failure, brain injury, immune disorders, muscle paleness, cardiac damage, nervous system impairment and limb paralysis. Therefore, designing and developing novel sensing systems for the detection and recognition of these harmful metals in various environmental matrices, particularly water, is of extremely important. Emerging nanotechnological approaches in the past two decades have played a key role in overcoming environmentally-related problems. Nanomaterial-based fabrication of chemical nanosensors has widely been applied as a powerful analytical tool for sensing heavy metals. Portability, high sensitivity, on-site detection capability, better device performance and selectivity are all advantages of these nanosensors. The detection and selectivity have been improved using molecular recognition probes for selective binding on different nanostructures. This study aims to evaluate the sensing properties of various nanomaterials such as metal-organic frameworks, fluorescent materials, metal-based nanoparticles, carbon-based nanomaterials and quantum dots and graphene-based nanomaterials and quantum dots for heavy metal ions recognition. All these nano-architectures are frequently served as effective fluorescence probes to directly (or by modification with some large or small biomolecules) sense heavy metal ions for improved selectivity. However, efforts are still needed for the simultaneous designing of multiple metal ion-based detection systems, exclusively in colorimetric or optical fluorescence nanosensors for heavy metal cations.

Development of reduced graphene oxide-supported novel hybrid nanomaterials (Bi2WO6@rGO and Cu-WO4@rGO) for green and efficient oxidative desulfurization of model fuel oil for environmental depollution.

For the first time, two new kinds of inorganic-organic hybrid nanomaterials (Bi2WO6@rGO and Cu-WO4@rGO) were fabricated by simple hydrothermal treatment and employed for green and efficient oxidative desulfurization of real fuel. The characterization of newly synthesized nanocomposites was performed by SEM, EDX, P-XRD, FT-IR and TGA. SEM and XRD analyses revealed well decoration of dopants (Cu-WO4 and Bi-WO3) on the surface of rGO with a crystallite size of <50 nm. The catalytic activity of both nanocatalysts was examined for model (dibenzothiophene) and real fuel (kerosene and diesel) by oxidative desulfurization route. Experimental findings revealed a high efficiency of over 90% under optimal reaction conditions of 0.1 g catalyst, 1 mL of oxidant, and 100 mg/L after 120 min at 30 °C. The major factors affecting desulfurization efficiency (time, temperature, catalyst amount, dibenzothiophene (DBT) concentration and amount of oxidant) and kinetic studies were described. The DBT removal via oxidative desulfurization followed pseudo first-order kinetics with an activation energy of 14.57 and 16.91 kJ/mol for Cu-WO4@rGO and Bi2WO6@rGO, respectively. The prepared catalysts showed promising reusability for the ODS process up to 5 times with no significant decrease in efficiency. In conclusion, the findings confirm the robustness of newly prepared nanocomposite for efficient production of sulfur-free oil.

Bioprospecting microalgae and cyanobacteria for biopharmaceutical applications.

Microalgae and cyanobacteria have sparked a lot of interest due to their potential in various industries like biorefineries, biopharmaceuticals, food supplements, nutraceuticals, and other high-value products. Polysaccharides, vitamins, proteins, enzymes, and steroids are valuable products isolated from microalgae and cyanobacteria and potentially used in health and biomedical applications. Bioactive compounds derived from microalgae and cyanobacteria exhibit various pharmaceutical properties like antibacterial, anticancer, antiviral, antialgal, and antioxidant. From the properties listed above, the research for novel antibiotics has become particularly appropriate. In addition, the possible emergence of resistance against pathogens, as well as the potential decline in antibiotic efficacy, has prompted researchers to look for a new source of antibiotics. Microalgae and cyanobacteria have indicated a great and unexplored potential among these sources. For this reason, microalgae and cyanobacteria have been highlighted for their efficiency in different industrial sectors, as well as for their potential uses in the betterment of human and environmental health. This review gives an overview of bioactive compounds and metabolites with several biological properties isolated from microalgae and cyanobacteria for treating different animal and human diseases.

Expression profiling of miRNA-196a biomarker in naïve hepatitis C virus-infected and Sofosbuvir plus Daclatasvir-treated patients.

Micro-RNA (miRNA) is a short stretch of nucleotides that can regulate many genes associated with the various stages of the hepatitis C virus (HCV) life cycle and disease progression. This study evaluates the expression profiling of miRNA-196a in naïve HCV-infected, and Sofosbuvir plus Daclatasvir-treated patients. MiRNA-196a can inhibit HCV replication by silencing the HCV NS5A protein or downregulating the human BACH-I mRNA. The expression level of miRNA-196a was determined by quantitative reverse transcription PCR (RT-qPCR) using the whole RNA extracted from the recruited participant's serum. Results showed a 0.83-fold decrease in the miRNA-196a level in naïve HCV-infected than controls. On the contrary, an increase in the expression level by 0.06-fold was observed in Sofosbuvir plus Daclatasvir-treated patients. A negative but significant correlation was recorded between the HCV-RNA load and miRNA-196a expression level in the naïve-infected patients. Serum miRNA-196a ROC curve analysis revealed an area under the curve of 0.8278 (95% CI 0.7033-0.9524, p < 0.0001) with 82.05% sensitivity and 76.19% specificity in discriminating the healthy controls from the HCV-infected samples. In conclusion, our study explored the comparative expression levels of miRNA-196a in HCV-infected and Sofosbuvir plus Daclatasvir patients. Further studies are needed to examine the possible role of miR-196a as a therapeutic agent for treating HCV-infected patients.

Isolation and functional characterization of exopolysaccharide produced by Lactobacillus plantarum S123 isolated from traditional Chinese cheese.

During the past few years, there are growing interests in the potential use of exopolysaccharide (EPS) in the food industry as an efficient biopolymer because of its exceptional biological features. Therefore, the aim of the present study is EPS production by Lactobacillus Plantarum S123 (S123 EPS), its partial structural and biopotential characterization. The results from this study suggested that the major portion of S123 EPS has an amorphous sponge-like structure with partial crystalline nature. The FTIR and NMR results suggested that the S123 EPS consists of carbonyl and hydroxyl groups, respectively. Furthermore, the results of technological as well as biotechnological characterization suggested that the S123 EPS was exhibited excellent antibacterial activity against Gram-positive (7.2 mm) and Gram-negative bacteria (11.5 mm), DPPH radical scavenging activity (> 65%), water holding capacity (326.6 ± 0.5%), oil holding capacity (995.3 ± 0.2%), flocculation (89.5 ± 0.6%), and emulsifying (80.1 ± 1.1%) activities. Overall, the present results suggested that due to the highly porous structure and efficient biotechnological potential, S123 EPS from Lactobacillus plantarum S123 (L. plantarum S123) can be used in the functional food product.

Abnormal Expression of DICER1 Leads to Dysregulation of Inflammatory Effectors in Human Synoviocytes.

Dysregulation of multiple microRNAs widely takes place during rheumatoid arthritis (RA) and experimental arthritides. This study is performed to explore the possible mechanism underlying DICER1 deficiency-mediated inflammation in human synoviocytes SW982. Firstly, RNAi of DICER1 led to increased COX2, MMP3, and MMP13 protein production, while DICER1 overexpression could reduce MMP13 expression. Secondly, the increase of IL-8 and decrease of TGF-ß1 and TIMP1 were determined in the supernatant derived from DICER1 siRNA-treated cells, while DICER1 overexpression was found capable to reverse this effect. Ingenuity pathway analysis (IPA) software predicted that the Dicer1 deficiency-induced dysregulated cytokines in synoviocytes could possibly lead to the inflammatory disorders in the synovial tissue. Moreover, DICER1 deficiency could also reduce apoptosis, while DICER1 overexpression was found to decrease the proliferation and enhance apoptosis. In addition, DICER1 deficiency could lower the expression of multiple RA-related miRNAs such as miR-155. Meanwhile, DICER1 overexpression could rescue their low expression levels. And then, gain or loss of miR-155 function could regulate the protein levels of MMP3 and MMP13. These results indicated that DICER1 might play its role through regulating its downstream RA-related miRNAs. Our data demonstrated that DICER1 deficiency could cause multiple proinflammatory events in human synoviocytes SW982. This mechanism study might provide the possible target molecule to modify the inflammatory destruction and overproliferation in synoviocytes.

Down-regulation of miR-10a-5p in synoviocytes contributes to TBX5-controlled joint inflammation.

MicroRNAs are considered to play critical roles in the pathogenesis of human inflammatory arthritis, including rheumatoid arthritis (RA). The purpose of this study was to determine the relationship between miR-10a-5p and TBX5 in synoviocytes and evaluate their contribution to joint inflammation. The expression of miR-10a-5p and TBX5 in the synovium of RA and human synovial sarcoma cell line SW982 stimulated by IL-1ß was determined by RT-qPCR and Western blotting. The direct interaction between miR-10a-5p and TBX5 3'UTR was determined by dual-luciferase reporter assay in HeLa cells. Mimics and inhibitors of miR-10a-5p were transfected into SW982 cells. TBX5 was overexpressed by plasmid transfection or knocked down by RNAi. Proinflammatory cytokines and TLR3 and MMP13 expressions were determined by RT-qPCR and Western blotting. Down-regulated expression of miR-10a-5p and up-regulation of TBX5 in human patients with RA were found compared to patients with OA. IL-1ß could reduce miR-10a-5p and increase TBX5 expression in SW982 cells in vitro. The direct target relationship between miR-10a-5p and 3'UTR of TBX5 was confirmed by luciferase reporter assay. Alterations of miR-10-5p after transfection with its mimic and inhibitor caused the related depression and re-expression of TBX5 and inflammatory factors in SW982 cells. Overexpression of TBX5 after pCMV3-TBX5 plasmid transfection significantly promoted the production of TLR3, MMP13 and various inflammatory cytokines, while this effect was rescued after knocking down of TBX5 with its specific siRNA. We conclude that miR-10a-5p in a relation with TBX5 regulates joint inflammation in arthritis, which would serve as a diagnostic and therapeutic target for RA treatment.

Down-regulated in OA cartilage, SFMBT2 contributes to NF-κB-mediated ECM degradation.

The interplay between anabolic and catabolic factors regulates cartilage matrix homoeostasis. In OA, this balance is disrupted which results in cartilage degradation involving a plethora of inflammatory factors. Here, we identify a novel gene "Scm-like with four MBT domains protein 2" (SFMBT2) negatively regulated in OA cartilage. Articular cartilage from human OA patients undergoing knee arthroplasty surgery exhibited significantly decreased levels of SFMBT2 compared to the normal controls. Down-regulation of SFMBT2 by specific siRNA disturbed the metabolic homoeostasis and led to decreased expression of anabolic genes (SOX9, COL2A1) while increasing the expression of catabolic genes (MMP13 and ADAMTS4), in human chondrocytes. Finally, we revealed that SFMBT2 intervention by siRNA contributed to the catabolic phenotype of human chondrocytes mediated by NF-kB pathway.

TRANSPARENT TESTA 4-mediated flavonoids negatively affect embryonic fatty acid biosynthesis in Arabidopsis.

Flavonoids are involved in many physiological processes in plants. TRANSPARENT TESTA 4 (TT4) acts at the first step of flavonoid biosynthesis, and the loss of TT4 function causes a lack of flavonoid. Flavonoid deficiency is reportedly the main cause of increased fatty acid content in pale-coloured oilseeds, but details regarding the relationship between seed flavonoids and fatty acid biosynthesis are elusive. In this work, we applied a genetic strategy combined with biochemical and cytological assays to determine the effect of seed flavonoids on the biosynthesis of fatty acids in Arabidopsis thaliana. We showed that TT4-mediated flavonoids negatively affect embryonic fatty acid biosynthesis. A crossing experiment indicated that seed flavonoid biosynthesis and the impact of this process on fatty acid biosynthesis were controlled in a maternal line-dependent manner. Loss of TT4 function activated glycolysis in seed embryos, thereby enhancing fatty acid biosynthesis, but did not improve seed mucilage production. Moreover, loss of TT4 function reduced PIN-FORMED 4 expression and subsequently increased auxin accumulation in embryos. Pharmacologically and genetically elevated auxin levels enhanced seed fatty acid biosynthesis. These results indicated that flavonoids affect fatty acid biosynthesis by carbon source reallocation via regulation of WRINKLE1 and auxin transport.