Out of seven spp. isolated from infected faba bean roots, two were selected and showed faba bean-wilt disease severity with percentages of 68% and 47% under greenhouse conditions. The showed the highest wilt disease w...Out of seven spp. isolated from infected faba bean roots, two were selected and showed faba bean-wilt disease severity with percentages of 68% and 47% under greenhouse conditions. The showed the highest wilt disease was selected to complete the current study. Three rhizobacterial strains were isolated and identified as Vb1, Vb3, and Vb6. These strains showed the highest antagonistic activity by the dual-culture method against selected with inhibition percentages of 59±0.2, 46±0.3, and 52±0.3% for Vb1, Vb3, and Vb6, respectively. These rhizobacterial strains exhibit varied activity for nitrogen-fixing and phosphate-solubilizing. Moreover, these strains showed positive results for ammonia, HCN, and siderophores production. The phytohormones production (indole-3-acetic acid, ABA, benzyl, kinten, ziaten, and GA) and secretion of various lytic enzymes were recorded by these strains with varying degrees. Under greenhouse conditions, the rhizobacterial strains Vb1, Vb3, Vb6, and their consortium can protect faba bean from wilt caused by with percentages of 70, 60, 65, and 82%, respectively. Under field conditions, the inoculation with the rhizobacterial consortium (Vb1+Vb3+Vb6) significantly increases the growth performance of the -infected faba bean plant and recorded the highest wilt protection (83.3%).
Nowadays, mutations in the epidermal growth factor receptor (EGFR) kinase domain are studied in targeted therapy of non-small cell lung cancer (NSCLC) with EGFR tyrosine kinase inhibitors including gefitinib and erlotini...Nowadays, mutations in the epidermal growth factor receptor (EGFR) kinase domain are studied in targeted therapy of non-small cell lung cancer (NSCLC) with EGFR tyrosine kinase inhibitors including gefitinib and erlotinib. The present study reports a rare case of a patient harboring three simultaneous EGFR mutations (L718A, Q849H, and L858R). The development of erlotinib resistance was detected in the subsequent treatment. Using a computational approach, the current study investigated the conformational changes of wild-type and mutant EGFR's kinase domains in the interaction with erlotinib. Their binding modes with erlotinib were elucidated during molecular dynamics simulation, where higher fluctuations were detected in the mutated forms of the EGFR tyrosine kinase domain. Prediction of stability and functional effect of mutations revealed that amino acidic substitutions have decreased the protein stability as well as the binding affinity to erlotinib. These results may be useful for a recommendation of EGFR mutational analysis for patients with NSCLC carcinoma.
Studies published earlier this year demonstrated the association of the solute carrier gene with the risk and severity of COVID-19. The protein product (Sodium-dependent Imino Transporter 1 (SIT1)) is involved in the t...Studies published earlier this year demonstrated the association of the solute carrier gene with the risk and severity of COVID-19. The protein product (Sodium-dependent Imino Transporter 1 (SIT1)) is involved in the transport of amino acids, including glycine. Here we summarized the results of recent studies demonstrating the interaction of SIT1 with the ACE2 receptor for SARS-CoV-2 as well as an observed association of with the risk and traits of Type 2 diabetes (T2D). Recently, it was also proposed that represents the novel regulator of glycine levels and that glycine has beneficial effects against the proinflammatory cytokine secretion induced by SARS-CoV-2 infection. Ivermectin, as a partial agonist of glycine-gated chloride channels, was also recently suggested to interfere with the COVID-19 cytokine storm by inducing the activation of glycine receptors. Furthermore, plasma glycine levels are found to be decreased in diabetic patients. Thus, further clinical trials are warranted to confirm the potential favorable effects of targeting the SIT1 transporter and glycine levels in the treatment of COVID-19, particularly for the severe case of disease associated with hyperglycemia, inflammation, and T2D. These findings suggest that SIT1 may potentially represent one of the missing pieces in the complex puzzle observed between these two pandemic diseases and the potential novel target for their efficient treatment.
The BCR-ABL oncogene is a tyrosine kinase gene that is over-expressed in CML. It inhibits the TGF-β1 signaling pathway. Due to resistance of cells to the tyrosine kinase inhibitor, STI-571, the combined effect of STI-571...The BCR-ABL oncogene is a tyrosine kinase gene that is over-expressed in CML. It inhibits the TGF-β1 signaling pathway. Due to resistance of cells to the tyrosine kinase inhibitor, STI-571, the combined effect of STI-571 and TGF-β1 on K562 cells was studied in the present research. Results revealed that the TGF-β1 cell signaling pathway, which is activated in K562 cells treated with TGF-β1, activates collective cell signaling pathways involved in survival and apoptosis. It is noteworthy that treating K562 cells with STI-571 triggered apoptotic pathways, accompanied by a reduction in proteins such as Bcl-xL, Bcl-2, p-AKT, p-Stat5, p-FOXO3, and Mcl-1 and an increase in the pro-apoptotic proteins PARP cleavage, and p27, leading to an increase in sub-G1 phase-arrested and Annexin-positive cells. Interestingly, the proliferation behavior of TGF-β1-induced cells was changed with the combination therapy, and STI-571-induced apoptosis was also prompted by this combination. Thus, combination treatment appears to promote sub-G1 cell cycle arrest compared to individually treated cells. Furthermore, it strongly triggered apoptotic signaling. In conclusion, TGF-β1 did not negatively impact the effect of STI-571, based on positive annexin cells, and AKT protein phosphorylation remains effective in apoptosis.
Stromal cell-derived factor 1 (SDF-1) is known to influence bone marrow stromal cell (BMSC) migration, osteogenic differentiation, and fracture healing. We hypothesize that SDF-1 mediates some of its effects on BMSCs thr...Stromal cell-derived factor 1 (SDF-1) is known to influence bone marrow stromal cell (BMSC) migration, osteogenic differentiation, and fracture healing. We hypothesize that SDF-1 mediates some of its effects on BMSCs through epigenetic regulation, specifically via microRNAs (miRNAs). MiRNAs are small non-coding RNAs that target specific mRNA and prevent their translation. We performed global miRNA analysis and determined several miRNAs were differentially expressed in response to SDF-1 treatment. Gene Expression Omnibus (GEO) dataset analysis showed that these miRNAs play an important role in osteogenic differentiation and fracture healing. KEGG and GO analysis indicated that SDF-1 dependent miRNAs changes affect multiple cellular pathways, including fatty acid biosynthesis, thyroid hormone signaling, and mucin-type O-glycan biosynthesis pathways. Furthermore, bioinformatics analysis showed several miRNAs target genes related to stem cell migration and differentiation. This study's findings indicated that SDF-1 induces some of its effects on BMSCs function through miRNA regulation.
A unique feature of eukaryote initiation of protein translation is a so-called scanning of 5'-untranslated region (5'-UTR) by a ribosome initiation complex to enable bound Met-tRNA access to the initiation codon located...A unique feature of eukaryote initiation of protein translation is a so-called scanning of 5'-untranslated region (5'-UTR) by a ribosome initiation complex to enable bound Met-tRNA access to the initiation codon located further downstream. Here, we propose a universal scanning-free translation initiation model that is independent of 5'-UTR length and applicable to both 5'-mG (capped) and uncapped mRNAs.
Tuberculosis (TB) is a global health threat that affects 10 million people worldwide. Human Immunodeficiency Virus (HIV) remains one of the major contributors to the reactivation of asymptomatic latent tuberculosis (LTBI...Tuberculosis (TB) is a global health threat that affects 10 million people worldwide. Human Immunodeficiency Virus (HIV) remains one of the major contributors to the reactivation of asymptomatic latent tuberculosis (LTBI). Over the recent years, there has been a significant focus in developing in-vitro 3D models mimicking early events of (Mtb) pathogenesis, especially formation of the granuloma. However, these models are low throughput and require extracellular matrix. In this article, we report the generation of a matrix-free 3D model, using THP-1 human monocyte/macrophage cells and mCherry-expressing BCG (Bacilli Camille Guérin), henceforth referred as 3D spheroids, to study the host cell-bacterial interactions. Using mCherry-intensity-based tracking, we monitored the kinetics of BCG growth in the 3D spheroids. We also demonstrate the application of the 3D spheroids for testing anti-TB compounds such as isoniazid (INH), rifampicin (RIF), as well as a host-directed drug, everolimus (EVR) as single and combinational treatments. We further established a dual infection 3D spheroid model by coinfecting THP-1 macrophages with BCG mCherry and pseudotype HIV. In this HIV-TB co-infection model, we found an increase in BCG mCherry growth within the 3D spheroids infected with HIV pseudotype. The degree of disruption of the granuloma was proportional to the virus titers used for co-infection. In summary, this 3D spheroid assay is an useful tool to screen anti-TB response of potential candidate drugs and can be adopted to model HIV-TB interactions.
Previous studies associated plasma cathepsin D (CTSD) activity with hepatic insulin resistance in overweight and obese humans. Insulin resistance is a major feature of non-alcoholic fatty liver disease (NAFLD) and is one...Previous studies associated plasma cathepsin D (CTSD) activity with hepatic insulin resistance in overweight and obese humans. Insulin resistance is a major feature of non-alcoholic fatty liver disease (NAFLD) and is one of the multiple hits determining the progression towards non-alcoholic steatohepatitis (NASH). In line, we have previously demonstrated that plasma CTSD levels are increased in NASH patients. However, it is not known whether insulin resistance associates with plasma CTSD activity in NAFLD. To increase our understanding regarding the mechanisms by which insulin resistance mediates NAFLD, fifty-five liver biopsy or MRI-proven NAFLD patients (BMI>25kg/m) were included to investigate the link between plasma CTSD activity to insulin resistance in NAFLD. We concluded that HOMA-IR and plasma insulin levels are independently associated with plasma CTSD activity in NAFLD patients (standardized coefficient β: 0.412, 95% Cl: 0.142~0.679, p=0.004 and standardized coefficient β: 0.495, 95% Cl: 0.236~0.758, p=0.000, respectively). Together with previous studies, these data suggest that insulin resistance may link to NAFLD via elevation of CTSD activity in plasma. As such, these data pave the way for testing CTSD inhibitors as a pharmacological treatment of NAFLD.
We previously reported that on its own as well as together with HIV inhibits macrophage apoptosis by upregulating the expression of Bcl2 and Inhibitor of Apoptosis (IAP). In addition, recent reports from our lab showed...We previously reported that on its own as well as together with HIV inhibits macrophage apoptosis by upregulating the expression of Bcl2 and Inhibitor of Apoptosis (IAP). In addition, recent reports from our lab showed that stimulation of either macrophages or BMDCs results in the significant upregulation of Bcl2. In this report, we delineate the role of Bcl2 in mediating defense responses from dendritic cells (BMDCs) during mycobacterial infection. Inhibiting Bcl2 led to a significant decrease in intracellular bacterial burden in BMDCs. To further characterize the role of Bcl2 in modulating defense responses, we inhibited Bcl2 in BMDCs as well as human PBMCs to monitor their activation and functional status in response to mycobacterial infection and stimulation with antigen Rv3416. Inhibiting Bcl2 generated protective responses including increased expression of co-stimulatory molecules, oxidative burst, pro-inflammatory cytokine expression and autophagy. Finally, co-culturing human PBMCs and BMDCs with antigen-primed T cells increased their proliferation, activation and effector function. These results point towards a critical role for Bcl2 in regulating BMDCs defense responses to mycobacterial infection.
BACKGROUND: Trigger finger (TF), a painful condition involving a finger flexor tendon, is a common problem with a prevalence of ~2-3% in the general population. However, the TF prevalence is higher among diabetic patient...BACKGROUND: Trigger finger (TF), a painful condition involving a finger flexor tendon, is a common problem with a prevalence of ~2-3% in the general population. However, the TF prevalence is higher among diabetic patients-ranges from 6.7% to 10%. We have analyzed the expression of the extracellular matrix, inflammation, and epigenetic related genes in diabetic and non-diabetes TF. We hypothesized that Diabetes condition induces alter the expression of epigenetic modification genes in diabetic patients and one of the underlying determinants for more prevalence of TF in diabetic patients. METHOD: Tissues from the fingers of patients with symptomatic trigger fingers were collected. We had three groups: carpal tunnel syndrome (as a control), trigger finger, and diabetic trigger finger. A quantitative real-time polymerase chain reaction was performed. The gene expression of Extracellular matrix (ECM) components [COL-I, COL-II, COL-X, Aggrecan], DNA methyltransferases enzymes (DNMT1, DNMT3), growth factors (TGF-b, IGF), and Histone deacetylase enzymes (HDAC1, HDAC2) were evaluated in all groups. RESULTS: The mRNA expression of COL-I, COL-II, Aggrecan was significantly higher in the pully A1 of diabetic patients (p= 0.0164, p=0.0351, p=0.0399, respectively) as compared to non-diabetic TF patients. Diabetes was associated with a significant increase in the DNMT3 expression compared to non-diabetic TF patients (p=0.0485). HDAC1 and HDAC2 gene expression were up-regulated in diabetic TF than non-diabetic TF. CONCLUSION: The chronic state of hyperglycemia induces epigenetic modification of gene expressions in trigger fingers. This seems to have a significant impact on the development, recurrence, and progression of trigger finger in diabetic patients.
Liquid-liquid phase separation (LLPS) is a way to concentrate biochemical reactions while excluding noninteracting components. Disordered domains of proteins, as well as interaction with RNA, favor condensation but are n...Liquid-liquid phase separation (LLPS) is a way to concentrate biochemical reactions while excluding noninteracting components. Disordered domains of proteins, as well as interaction with RNA, favor condensation but are not mandatory for modulating this process. Recent insights about phase-separation mechanisms pointed to new fascinating models that could explain how cells could cope with DNA damage responses, conferring both spatial and temporal fine regulation. APE1 is a multifunctional protein belonging to the Base Excision Repair (BER) pathway, bearing additional 'non-canonical' DNA-repair functions associated with processes like RNA metabolism. Recently, it has been highlighted that several DNA repair enzymes, such as 53BP1 and APE1, are endowed with RNA binding abilities. In this work, after reviewing the recent literature supporting a role of LLPS in DDR, we analyze, as a proof of principle, the interactome of APE1 using a bioinformatics approach to look for clues of LLPS in BER. Some of the APE1 interactors are associated with cellular processes in which LLPS has been either proved or proposed and are involved in different pathogenic events. This work might represent a paradigmatical pipeline for evaluating the relevance of LLPS in DDR.
Natural products have served humanity as a valuable source for the discovery and development of therapeutic agents. In addition, these phytochemicals can function as lead compounds for the development of synthetic analog...Natural products have served humanity as a valuable source for the discovery and development of therapeutic agents. In addition, these phytochemicals can function as lead compounds for the development of synthetic analogs aimed at treating human diseases. In our aging society, Alzheimer's disease (AD) is the most common cause of dementia, which is characterized by a significant and progressive loss of memory and other cognitive functions. As society demographics change, the predominance of AD and other age-related dementias is increasing, with concurrent financial and societal costs.AD represents one of the most remarkable scientific challenges for drug discovery as the search for effective disease-modifying agents has been unsuccessful. Medicinal plants have been used for their "anti-aging" properties, and cognitive enhancing properties. In the past decades, natural products have been studied for their anti-AD properties, and their potential for developing therapeutic agents against several molecular targets has been evaluated. This insight evaluates the prospects of medicinal plants for providing disease-modifying, as well as disease-preventing, agents for AD.
Regenerative medicine and tissue engineering have been considered pioneer fields in the life sciences, with an ultimate goal of restoring or switching lost or impaired body parts. Graphene oxide (GO) is the product of gr...Regenerative medicine and tissue engineering have been considered pioneer fields in the life sciences, with an ultimate goal of restoring or switching lost or impaired body parts. Graphene oxide (GO) is the product of graphene oxidation and presents a great opportunity to make substantial progress in the field of regenerative medicine; for example, it supports the possibility of creating a cellular niche for stem cells on a nanoparticle surface. GO creates a fascinating structure for regulating stem cell behavior, as it can potentially applied to the noninvasive chase of stem cells , the liberation of active biological factors from stem cell-containing delivery systems, and the intracellular delivery of factors such as growth factors, DNA, or synthetic proteins in order to modulate stem cell differentiation and proliferation. Due to the interesting physicochemical properties of GO and its possible usage in tissue engineering approaches, the present review aims to elaborate on the ways in which GO can improve current regenerative strategies. In this respect, the applicability of GO to the repair and regeneration of various tissues and organs, including cardiac muscle, skeletal muscle, and nervous, bone, cartilage, adipose, and skin tissues, is discussed.
BACKGROUND: (1)Human periodontal ligament stem cells (HPDLSCs) are a unique population of mesenchymal stem cells (MSCs). Recently, the positive effects of photobiomodulation on the regulation of MSCs proliferation and os...BACKGROUND: (1)Human periodontal ligament stem cells (HPDLSCs) are a unique population of mesenchymal stem cells (MSCs). Recently, the positive effects of photobiomodulation on the regulation of MSCs proliferation and osteogenic differentiation have gained significant attention. This study aimed to assess the effects of photobiomodulation and vitamin D (as an anabolic factor) on HPDLSCs for bone regeneration. METHODS: (2)HPDLSCs were collected, isolated, and characterized and then divided into six groups: groups I and II, control and (10 Mol) vitamin D, respectively; group III, irradiation at 1 J/cm of 808-nm diode laser; group IV, irradiation at 1 J/cm and culture with vitamin D; group V, irradiation at 2 J/cm, and group VI, irradiation at 2 J/cm and culture with vitamin D. Cell viability assay was measured through MTT assay and cell growth curve. Alkaline phosphatase (ALP) enzyme activity and mRNA levels of RUNX2, collagen 1 (Col-1), ALP, and osteonectin were also assessed. RESULTS: (3)Photobiomodulation at 1 and 2 J/cm combined with vitamin D significantly promoted HPDLSC proliferation (in MTT assay and cell growth curve results) and osteogenic differentiation (through the gene expression of RUNX2, Col-1, ALP, and osteonectin levels (p < 0.05). CONCLUSION: (4)Laser irradiation at 2 J/cm combined with vitamin D3 enhanced osteoblast differentiation and proliferation of cultured HPDLSCs and thus could further substitute bone grafting.
is considered to be an important food poisoning agent causing diarrhea and vomiting. In this study, the occurrence of bacteriophages in Thai fermented soybean products (Thua Nao) was studied using five indicator strain...is considered to be an important food poisoning agent causing diarrhea and vomiting. In this study, the occurrence of bacteriophages in Thai fermented soybean products (Thua Nao) was studied using five indicator strains (four strains and one strain). In a total of 26 Thua Nao samples, there were only two bacteriophages namely BaceFT01 and BaceCM02 exhibiting lytic activity against . Morphological analysis revealed that these two bacteriophages belonged to the . Both phages were specific to and not able to lyse other tested bacteria including and . The two phages were able to survive in a pH range between 5 and 12. However, both phages were inactive either by treatment of 50°C for 2 h or exposure of UV for 2 h. It should be noted that both phages were chloroform-insensitive, however. This is the first report describing the presence of bacteriophages in Thua Nao products. The characterization of these two phages is expected to be useful in the food industry for an alternative strategy including the potential use of the phages as a biocontrol candidate against foodborne pathogenic bacteria.
Protein therapeutics are in great demand due to their effectiveness towards hard-to-treat diseases. Despite their high demand, these bio-therapeutics are very susceptible to degradation aggregation, fragmentation, oxida...Protein therapeutics are in great demand due to their effectiveness towards hard-to-treat diseases. Despite their high demand, these bio-therapeutics are very susceptible to degradation aggregation, fragmentation, oxidation, and reduction, all of which are very likely to affect the quality and efficacy of the product. Mechanisms and modelling of these degradation (aggregation and fragmentation) pathways is critical for gaining a deeper understanding of stability of these products. This review aims to provide a summary of major developments that have occurred towards unravelling the mechanisms of size-based protein degradation (particularly aggregation and fragmentation), modelling of these size-based degradation pathways, and their control. Major caveats that remain in our understanding and control of size-based protein degradation have also been presented and discussed.
Abdominal aortic aneurysm (AAA) is a complex degenerative vascular disease, with considerable morbidity and mortality rates among the elderly population. The mortality of AAA is related to aneurysm expansion (the enlarge...Abdominal aortic aneurysm (AAA) is a complex degenerative vascular disease, with considerable morbidity and mortality rates among the elderly population. The mortality of AAA is related to aneurysm expansion (the enlargement of the aortic diameter up to 30 mm and above) and the subsequent rupture. The pathogenesis of AAA involves several biological processes, including aortic mural inflammation, oxidative stress, vascular smooth muscle cell apoptosis, elastin depletion, and degradation of the extracellular matrix. Mitochondrial dysfunction was also found to be associated with AAA formation. The evidence accumulated to date supports a close relationship between environmental and genetic factors in AAA initiation and progression. However, a comprehensive pathophysiological understanding of AAA formation remains incomplete. The open surgical repair of AAA is the only therapeutic option currently available, while a specific pharmacotherapy is still awaited. Therefore, there is a great need to clarify pathophysiological cellular and molecular mechanisms underlying AAA formation that would help to develop effective pharmacological therapies. In this review, pathophysiological aspects of AAA development with a special focus on mitochondrial dysfunction and genetic associations were discussed.
Weight-related disorders affect more than half of the adult population worldwide; they are also concomitant with a state of chronic low-grade inflammation manifesting in abnormal cytokine production. The present study ev...Weight-related disorders affect more than half of the adult population worldwide; they are also concomitant with a state of chronic low-grade inflammation manifesting in abnormal cytokine production. The present study evaluated the effect of polyphenol and flavonoid extract from (granadilla) on low-grade inflammation and body weight in overweight Wistar rats. To induce weight-gain, rats were fed a chow diet with 30% sucrose water and supplemented with 2.0, 2.5, and 3.0 g/L polyphenol extracts ( = 16). The design was a 3 +1 factorial model performed for 42 days (granadilla polyphenols, 3 levels of supplementation, and 1 control group). In addition to total polyphenol and total flavonoid content, the major identified and quantified polyphenol, via UHPLC, was ferulic acid. Interleukin 6 (IL-6), and cytokine tumor necrosis factor-alpha (TNF-α) were evaluated in serum. A decline in the concentration of TNF-α and in weight-gain was found in (granadilla) groups treated with the 2.5 g/L dose. Consumption of polyphenol extracts from granadilla inhibits interleukin-activity as an indicator of inflammation and aids in body-weight control, considering similar food intake, in overweight Wistar rats.
Cao R, To K, Kachour N
… +7 more, Beever A, Owens J, Sathananthan A, Singh P, Kolloli A, Subbian S, Venketaraman V
Biomol Concepts
· 2021 Jun · PMID 34062056
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With a disease as widespread and destructive as tuberculosis, more effective drugs and healthcare strategies, in addition to the current antibiotics regimen, are crucial for the enhanced well-being of millions of people...With a disease as widespread and destructive as tuberculosis, more effective drugs and healthcare strategies, in addition to the current antibiotics regimen, are crucial for the enhanced well-being of millions of people suffering from the disease. Host-directed therapy is a new and emerging concept in treating chronic infectious diseases, such as tuberculosis. Repurposing of anti-cancer drugs, such as everolimus, may be an effective way to supplement the standard antibiotic treatment. Individuals with type 2 diabetes are increasingly susceptible to co-morbidities and co-infections including the causative agent of tuberculosis. We demonstrated in this study that everolimus treatment of granulomas from individuals with type 2 diabetes caused significant reduction in the viability of Further investigations revealed the effects of everolimus in targeting foamy macrophages, a macrophage phenotype that forms around granulomas, and is characterized by a higher lipid accumulation inside the cells. These foamy macrophages are thought to harbor dormant bacilli, which are potential sources of disease reactivation. Therefore, blocking foamy macrophage formation would help better killing of intracellular bacteria. Here, we report the potential of everolimus treatment to downregulate lipid content within the foamy macrophages of granulomas, thus leading to a potential decrease in the number of foamy macrophages and a more robust response to .