Oleuropein activates autophagy to circumvent anti-plasmodial defense.

Antimalarial drug resistance and unavailability of effective vaccine warrant for newer drugs and drug targets. Hence, anti-inflammatory activity of phyto-compound (oleuropein; OLP) was determined in antigen (LPS)-stimulated human THP-1 macrophages (macrophage model of inflammation; MMI). Reduction in the inflammation was controlled by the PI3K-Akt1 signaling to establish the "immune-homeostasis." Also, OLP treatment influenced the cell death/autophagy axis leading to the modulated inflammation for extended cell survival. The findings with MII prompted us to detect the antimalarial activity of OLP in the wild type (3D7), D10-expressing GFP-Atg18 parasite, and chloroquine-resistant (Dd2) parasite. OLP did not show the parasite inhibition in the routine in vitro culture of P. falciparum whereas OLP increased the antimalarial activity of artesunate. The molecular docking of autophagy-related proteins, investigations with MMI, and parasite inhibition assays indicated that the host activated the autophagy to survive OLP pressure. The challenge model of P. berghei infection showed to induce autophagy for circumventing anti-plasmodial defenses.

Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events. Methods: We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)-loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund's adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA. Results: Higher permeation of ACE-NLCs/CE across skin layers confirming the greater "therapeutic index" of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations. Conclusion: Our findings confirmed the use of co-delivery of drug nanoformulations as the "combination drug regimen" to treat RA.

Re-evaluation of dietary interventions in rheumatoid arthritis: can we improve patient conversations around food choices?

Rheumatoid arthritis (RA) is one of over 100 different types of autoimmune conditions. In RA, the cells of the immune system attack the tissue lining the joints, triggering inflammation. A large body of research suggests that the underlying trigger(s) of RA are unique to an individual. For example, increased risk of RA can be driven by smoking tobacco in one individual and mercury exposure in another. Due to the development of next-generation sequencing technology, the critical role of the microbiota in shaping RA risk has been elucidated. Therefore, it is surprising that diet, arguably the most important lever in shaping the gut microbiota, is ineffective in the treatment of RA, even in a sub-set of patients. To attempt to rationalise this apparent paradox, we conducted an umbrella review to address the question as to whether diet can affect outcomes in RA.

Unlocking the Potential of Type 2 Diabetes Mellitus Remission.

Diabetes was considered manageable but not curable, but now there are methods by which diabetes can be reversed. The twin cycle hypothesis provides a bird's eye view on the pathogenesis of the onset of diabetes, which is necessary to understand for reversing the disease: it states that diabetes occurs due to a substantial accumulation of fat in the pancreas and liver, impairing the ß-cell function. Thus, we can infer that diabetes and obesity are two aspects of the same problem. Thus, the key to diabetes reversal is to reverse obesity. Bariatric surgery has shown promising results. Diabetes remission can also be achieved by reducing calories. A very low-calorie diet (VLCD) results in rapid weight loss. ß-cell recovery is possible if early-diagnosed individuals are treated with intensive insulin therapy. New drugs like liraglutide and tirzepatide also have the potential for diabetes reversal. Thus the age-old myth of diabetes being incurable is proven wrong.

Aceclofenac and methotrexate combination therapy could influence Th1/Th17 axis to modulate rheumatoid-arthritis-induced inflammation.

Rheumatoid arthritis (RA) is an inflammatory, autoimmune and connective-tissue arthropathy. The methotrexate (MTX) and aceclofenac (ACL) combination drug regimen is known to regulate the immunological pathways. Also, RA-elicited inflammation is decreased by the combination drug treatment. ACL and MTX combination treatment has been shown to regulate the signaling pathway controlled by NF-κB and FOXO1. The present manuscript reviews the importance of the combination drug regimen to treat and/or manage RA. The combination drug regimen could affect the Th1/Th17 axis to switch the balance toward the immunoregulatory (Th1) phenotype for establishing immune homeostasis. In conclusion, we propose the study of the immunological signaling pathways in experimental humanized RA mice.

Understanding Mutations in Human SARS-CoV-2 Spike Glycoprotein: A Systematic Review & Meta-Analysis.

Genetic variant(s) of concern (VoC) of SARS-CoV-2 have been emerging worldwide due to mutations in the gene encoding spike glycoprotein. We performed comprehensive analyses of spike protein mutations in the significant variant clade of SARS-CoV-2, using the data available on the Nextstrain server. We selected various mutations, namely, A222V, N439K, N501Y, L452R, Y453F, E484K, K417N, T478K, L981F, L212I, N856K, T547K, G496S, and Y369C for this study. These mutations were chosen based on their global entropic score, emergence, spread, transmission, and their location in the spike receptor binding domain (RBD). The relative abundance of these mutations was mapped with global mutation D614G as a reference. Our analyses suggest the rapid emergence of newer global mutations alongside D614G, as reported during the recent waves of COVID-19 in various parts of the world. These mutations could be instrumentally imperative for the transmission, infectivity, virulence, and host immune system's evasion of SARS-CoV-2. The probable impact of these mutations on vaccine effectiveness, antigenic diversity, antibody interactions, protein stability, RBD flexibility, and accessibility to human cell receptor ACE2 was studied in silico. Overall, the present study can help researchers to design the next generation of vaccines and biotherapeutics to combat COVID-19 infection.

Co-inoculation of biochar and arbuscular mycorrhizae for growth promotion and nutrient fortification in soybean under drought conditions.

Drought is significant abiotic stress that affects the development and yield of many crops. The present study is to investigate the effect of arbuscular mycorrhizal fungi (AMF) and biochar on root morphological traits, growth, and physiological traits in soybean under water stress. Impact of AMF and biochar on development and root morphological traits in soybean and AMF spores number and the soil enzymes' activities were studied under drought conditions. After 40 days, plant growth parameters were measured. Drought stress negatively affected soybean growth, root parameters, physiological traits, microbial biomass, and soil enzyme activities. Biochar and AMF individually increase significantly plant growth (plant height, root dry weight, and nodule number), root parameters such as root diameter, root surface area, total root length, root volume, and projected area, total chlorophyll content, and nitrogen content in soybean over to control in water stress. In drought conditions, dual applications of AMF and biochar significantly enhanced shoot and root growth parameters, total chlorophyll, and nitrogen contents in soybean than control. Combined with biochar and AMF positively affects AMF spores number, microbial biomass, and soil enzyme activities in water stress conditions. In drought stress, dual applications of biochar and AMF increase microbial biomass by 28.3%, AMF spores number by 52.0%, alkaline phosphomonoesterase by 45.9%, dehydrogenase by 46.5%, and fluorescein diacetate by 52.2%, activities. The combined application of biochar and AMF enhance growth, root parameters in soybean and soil enzyme activities, and water stress tolerance. Dual applications with biochar and AMF benefit soybean cultivation under water stress conditions.

Above-Ground Biomass Estimation in Oats Using UAV Remote Sensing and Machine Learning.

Current strategies for phenotyping above-ground biomass in field breeding nurseries demand significant investment in both time and labor. Unmanned aerial vehicles (UAV) can be used to derive vegetation indices (VIs) with high throughput and could provide an efficient way to predict forage yield with high accuracy. The main objective of the study is to investigate the potential of UAV-based multispectral data and machine learning approaches in the estimation of oat biomass. UAV equipped with a multispectral sensor was flown over three experimental oat fields in Volga, South Shore, and Beresford, South Dakota, USA, throughout the pre- and post-heading growth phases of oats in 2019. A variety of vegetation indices (VIs) derived from UAV-based multispectral imagery were employed to build oat biomass estimation models using four machine-learning algorithms: partial least squares (PLS), support vector machine (SVM), Artificial neural network (ANN), and random forest (RF). The results showed that several VIs derived from the UAV collected images were significantly positively correlated with dry biomass for Volga and Beresford (r = 0.2-0.65), however, in South Shore, VIs were either not significantly or weakly correlated with biomass. For Beresford, approximately 70% of the variance was explained by PLS, RF, and SVM validation models using data collected during the post-heading phase. Likewise for Volga, validation models had lower coefficient of determination (R2 = 0.20-0.25) and higher error (RMSE = 700-800 kg/ha) than training models (R2 = 0.50-0.60; RMSE = 500-690 kg/ha). In South Shore, validation models were only able to explain approx. 15-20% of the variation in biomass, which is possibly due to the insignificant correlation values between VIs and biomass. Overall, this study indicates that airborne remote sensing with machine learning has potential for above-ground biomass estimation in oat breeding nurseries. The main limitation was inconsistent accuracy in model prediction across locations. Multiple-year spectral data, along with the inclusion of textural features like crop surface model (CSM) derived height and volumetric indicators, should be considered in future studies while estimating biophysical parameters like biomass.

Disinfectant-like activity of lipopeptide biosurfactant produced by Bacillus tequilensis strain SDS21.

Antiseptics and disinfectants are widely applied for eliminating microorganisms. However, microorganisms dwelling in the biofilm are less susceptible and in some cases resistant to biocide treatment. The present study describes isolation and characterization of lipopeptide biosurfactant exhibiting disinfectant-like activity. Biosurfactant was produced by an endo-rhizospheric bacterium Bacillus tequilensis strain SDS21. Biosurfactant reduced the surface tension of water from 72 to 30 mN/m with CMC of 40 mg/l. The Liquid Chromatography-Mass Spectrometry analysis of biosurfactant suggested it to be a mixture of C14, C15, C16 and C17 surfactin homologues. The lipopeptide biosurfactant exhibited bactericidal activity against planktonic cells and biofilm residing sessile cells. The biosurfactant treatment eradicated more than 99% of bacterial biofilm present on polystyrene, glass and stainless steel surface. The biosurfactant retained its bactericidal and biofilm eradicating activities even after exposure to extreme conditions like high temperate and extreme pH. Unlike some of the commonly used disinfectant, biosurfactant retained its bactericidal and biofilm removing activity even in the hard water containing Mg2+ and Ca2+ ions. Thus, suggesting that biosurfactant produced by strain SDS21 can be used as a disinfectant or in disinfectant-like formulations effective against both planktonic and biofilm residing bacteria.