Visceral leishmaniasis is a life-threatening infectious disease worldwide. Extensive experiments have been done to introduce potential vaccine candidates to combat leishmaniasis. The present study was done to evaluate Leishmania donovani hydrophilic acylated surface protein B1 as a potential vaccine candidate using in silico methods. For this aim, server-based predictions were performed regarding physicochemical characteristics, solubility, antigenicity, allergenicity, signal peptide, transmembrane domain, and posttranslational modifications (PTMs). Also, secondary and tertiary structures were predicted using NetSurfP-3.0 and I-TASSER, respectively. The 3D model was further subjected to refinement and validation, and promising B-cell, cytotoxic T-lymphocyte (CTL; human, dog), and helper T-lymphocyte (HTL; human) epitopes were predicted. The protein had a molecular weight of 42.19 kDa, with high solubility (0.749), stability (instability index: 21.34), and hydrophilicity (GRAVY: -2.322). No signal peptide or transmembrane domain was predicted, and the most abundant PTMs were phosphorylation, O-glycosylation, and acetylation. Many coils and disordered regions existed in the secondary structure analysis, and the tertiary model had a good confidence score (-0.79). Next, the ProSA-web and PROCHECK tools showed adequate improvements in the refined model compared to the crude model. Only 4 shared B-cell epitopes among three web servers (ABCpred, BepiPred 2.0, and SVMTriP) were shown to be antigenic, nonallergenic, and with good water solubility. Also, five potent CTL epitopes in dogs and five in humans were predicted. Notably, two HTL epitopes were found to be potential IFN-γ inducers. In conclusion, our results demonstrated several immunogenic epitopes in this protein, which could be directed towards multiepitope vaccine design.

Background. Nowadays, the immunomodulatory properties of plants have been studied extensively with greater interest due to increasing awareness and combating the severity of immunomodulatory diseases. Scope and Approach. This paper highlights the efficacy of the available literature evidence on natural immunomodulators of plant origin and synthetic ones. In addition, several aspects of plants and their phytoconstituents responsible for immunomodulation have been discussed. Moreover, this review also discusses the mechanism involved in immunomodulation. Key Findings. One hundred fifty medicinal immunomodulatory plants are currently identified to find novel immunomodulatory drugs. Of these plants, the plant family Asteraceae also takes the first rank by offering 18 plant species (12%). Similarly of the plants studied so far, 40% belong to the Asteraceae family. Echinacea purpurea of this family is most known for its immunostimulating activity. The most prominent immune-active bioactive molecules are polyphenols, terpenoids, and alkaloids. Also, eight plant bioactive immunomodulators were checked for clinical trials and found in the market. These are six immunosuppressants, resveratrol, epigallocatechin-3-gallate, quercetin, colchicine, capsaicin, and andrographolide, and two immunostimulants, curcumin and genistein. Nowadays, there are a lot of polyherbal traditional medicinal products sold in the market and claimed to their immunomodulators. However, much work is still needed to find more active immunomodulatory agents. The mechanism by which immunomodulatory medicinal plant exert their effect is through the induction of cytokines and phagocyte cells and the inhibition of iNOS, PGE, and COX-2 synthesis.

Metformin is a multipotential compound for treating diabetes II and controlling hormonal acne and skin cancer. This study was designed to enhance metformin skin penetration in melanoma using nanoparticles containing biocompatible polymers. Formulations with various concentrations of chitosan, hyaluronic acid, and sodium tripolyphosphate were fabricated using an ionic gelation technique tailored by the Box-Behnken design. The optimal formulation was selected based on the smallest particle size and the highest entrapment efficiency (EE%) and used in ex vivo skin penetration study. In vitro antiproliferation activity and apoptotic effects of formulations were evaluated using MTT and flow cytometric assays, respectively. The optimized formulation had an average size, zeta potential, EE%, and polydispersity index of 329 ± 6.30 nm, 21.94 ± 0.05 mV, 64.71 ± 6.12%, and 0.272 ± 0.010, respectively. The release profile of the optimized formulation displayed a biphasic trend, characterized by an early burst release, continued by a slow and sustained release compared to free metformin. The ex vivo skin absorption exhibited 1142.5 ± 156.3 μg/cm2 of metformin deposited in the skin layers for the optimized formulation compared to 603.2 ± 93.1 μg/cm2 for the free metformin. Differential scanning calorimetry confirmed the deformation of the drug from the crystal structure to an amorphous state. The attenuated total reflection Fourier transform infrared results approved no chemical interaction between the drug and other ingredients of the formulations. According to the MTT assay, metformin in nanoformulation exhibited a higher cytotoxic effect against melanoma cancer cells than free metformin (IC50: 3.94 ± 0.57 mM vs. 7.63 ± 0.26 mM, respectively, P < 0.001). The results proved that the optimized formulation of metformin could efficiently decrease cell proliferation by promoting apoptosis, thus providing a promising strategy for melanoma therapy.

Current approaches are incurable for rheumatoid arthritis (RA). Regulatory T (Treg) cells and T helper cells (Th1 and Th17) are crucial in controlling the process of RA, which is characterized by inflammatory cell infiltration and bone destruction. Carnosol is an orthodiphenolic diterpene that has been extensively applied in traditional medicine for the treatment of multiple autoimmune and inflammatory diseases. Herein, we indicate that administration of carnosol dramatically alleviated the severity of collagen-induced arthritis (CIA) model with a decreased clinical score and inflammation reduction. Cellular mechanistically, carnosol inhibits the Th17 cell differentiation and maintains Treg cell suppressive function in vitro and in vivo. Meanwhile, it also restrains Treg cells from transdifferentiation into Th17 cells under inflammatory milieu. Furthermore, carnosol modulates the function of Th17 and Treg cells possibly via limiting IL-6R (CD126) expression. Collectively, our results suggest that carnosol can alleviate the severity of CIA via hiding Th17 cell differentiation and maintain the stability of Treg cells. Administration of carnosol can be applied as a potential therapy for patients with RA.

Antibiotic resistance is a major public health concern that has resulted in high healthcare costs, increased mortality, and the emergence of novel bacterial diseases. Cardiobacterium valvarum, an antibiotic-resistant bacterium, is one of the leading causes of heart disease. Currently, there is no licensed vaccination against C. valvarum. In this research, an in silico-based vaccine was designed against C. valvarum using reverse vaccinology, bioinformatics, and immunoinformatics techniques. 4206 core proteins, 2027 nonredundant proteins, and 2179 redundant proteins were predicted. Among nonredundant proteins, 23 proteins were predicted in an extracellular membrane, 30 in the outer membrane, and 62 in the periplasmic membrane region. After applying several subtractive proteomics filters, two proteins, TonB-dependent siderophore receptor and hypothetical protein, were chosen for epitope prediction. In the epitope selection phase, B and T-cellepitopes were analyzed and shortlisted for vaccine design. The vaccine model was designed by linking selected epitopes with GPGPG linkers to avoid flexibility. Furthermore, the vaccine model was linked to cholera toxin B adjuvant to induce a proper immune response. The docking approach was utilized to analyze binding affinity to immune cell receptors. Molecular docking results predicted 12.75 kcal/mol for a Vaccine with MHC-I, 6.89 for a vaccine with MHC-II, and 19.51 vaccine with TLR-4. The MMGBSA estimated -94, -78, and -76 kcal/mol for TLR-4 and vaccine, MHC-I and vaccine, and MHC-II and vaccine, while the MMPBSA analysis estimated -97, -61, and -72 kcal/mol for TLR-4 with the vaccine, MHC-I with vaccine, and MHC-II with a vaccine. Molecular dynamic simulation analysis revealed that the designed vaccine construct has proper stability with immune cell receptors as it is essential for inducing an immune response. In conclusion, we observed that the model vaccine candidate has the potency to induce an immune response in the host. However, the study is designed purely on a computational basis; hence, experimental validation is strongly recommended.

OBJECTIVE: It is essential to be aware of the potential effects of orthodontic treatment on tissues and anatomical structures associated with the masticatory system, especially the temporomandibular joint (TMJ). Little information is available about the consequences of molar distalization on the TMJ. Therefore, this study is aimed at investigating the changes of the condyle-fossa relationship after molar distalization using the distal jet appliance. MATERIALS AND METHODS: The sample consisted of twenty-five patients (mean age 20.4 ± 2.6) who underwent molar distalization by the distal jet appliance. CBCT scans were taken before (T0) and after (T1) the completion of the molar distalization. Joint spaces (anterior, superior, and posterior) and cephalometric vertical angles (SN.GOME and Björk sum) were measured and compared at T0 and T1. RESULTS: Superior and posterior joint spaces increased significantly after molar distalization (PS 0.29 mm, P < 0.001, SS 0.06 mm, P < 0.5). Vertical cephalometric angles also increased after molar distalization by the distal jet appliance (SN.GOME 0.92°, Björk 1.11°). CONCLUSION: There was a statistically significant increase in the superior and posterior joint spaces after molar distalization. However, this increase may not be of clinical importance. The vertical dimension has also increased.

BACKGROUND: Both high-fat diet (HFD) and 4-nonylphenol (4-NP) could affect fat formation in adipose tissue individually. We investigated whether HFD promote abnormal adipose tissue formation caused by early exposure to 4-NP in life and preliminarily explore the possible mechanisms involved. METHODS: The first-generation rats were treated with HFD on postnatal day after pregnant rats exposure to 5 ug/kg/day 4-NP. Then, the second generation rats started to only receive normal diet without 4-NP or HFD. We analyzed organ coefficient and histopathology of fat tissues, biochemical index, and gene level involved in lipid metabolism in female offspring rats. RESULTS: HFD and 4-NP interaction synergistically increased birth weight, body weight, and organ coefficients of adipose tissue in offspring female rats. HFD accelerately aggravated abnormal lipid metabolism and increased the adipocyte mean areas around the uterus of the offspring female rats induced by prenatal exposure to 4-NP. HFD also facilitate the regulation of gene expression involved lipid metabolism in offspring female rats induced by perinatal exposure to 4-NP, even passed on to the second generation of female rats. Moreover, HFD and 4-NP interaction synergistically declined the gene and protein expression of estrogen receptor (ER) in the adipose tissue of second-generation female rats. CONCLUSION: HFD and 4-NP synergistically regulate the expression of lipid metabolism genes in adipose tissue of F2 female rats and promote adipose tissue generation, leading to obesity in offspring rats, which is closely related to low expression of ER. Therefore, ER genes and proteins may be involved in the synergistic effect of HFD and 4-NP.

Nanotechnology has become one of the most extensive fields of research. Nanoparticles (NPs) form the base for nanotechnology. Recently, nanomaterials (NMs) are widely used due to flexible chemical, biological, and physical characteristics with improved efficacy in comparison to bulk counterparts. The significance of each class of NMs is enhanced by identifying their properties. Day by day, there is an emergence of various applications of NMs, but the toxic effects associated with them cannot be avoided. NMs demonstrate therapeutic abilities by enhancing the drug delivery system, diagnosis, and therapeutic effects of numerous agents, but determining the benefits of NMs over other clinical applications (disease-specific) or substances is an ongoing investigation. This review is aimed at defining NMs and NPs and their types, synthesis, and pharmaceutical, biomedical, and clinical applications.

[This retracts the article DOI: 10.1155/2022/6539917.].

[This retracts the article DOI: 10.1155/2022/9933387.].

[This retracts the article DOI: 10.1155/2022/9248972.].

[This retracts the article DOI: 10.1155/2022/6871623.].

[This retracts the article DOI: 10.1155/2022/2560053.].

[This retracts the article DOI: 10.1155/2022/9687345.].

[This retracts the article DOI: 10.1155/2022/4165839.].

[This retracts the article DOI: 10.1155/2022/5027024.].

[This retracts the article DOI: 10.1155/2022/1869922.].

[This retracts the article DOI: 10.1155/2022/4801703.].

[This retracts the article DOI: 10.1155/2022/9910841.].

[This retracts the article DOI: 10.1155/2022/6293095.].

[This retracts the article DOI: 10.1155/2022/3002353.].

[This retracts the article DOI: 10.1155/2022/9777817.].

[This retracts the article DOI: 10.1155/2022/7848771.].

[This retracts the article DOI: 10.1155/2022/9943598.].

[This retracts the article DOI: 10.1155/2022/1201129.].

[This retracts the article DOI: 10.1155/2022/8645183.].

[This retracts the article DOI: 10.1155/2022/9190241.].

[This retracts the article DOI: 10.1155/2022/8012018.].

[This retracts the article DOI: 10.1155/2022/4278048.].

[This retracts the article DOI: 10.1155/2022/6383893.].

[This retracts the article DOI: 10.1155/2022/1495807.].

[This retracts the article DOI: 10.1155/2022/3862122.].

[This retracts the article DOI: 10.1155/2023/1176232.].

[This retracts the article DOI: 10.1155/2022/5260231.].

[This retracts the article DOI: 10.1155/2022/4632453.].

[This retracts the article DOI: 10.1155/2022/1041688.].

[This retracts the article DOI: 10.1155/2022/1636301.].

[This retracts the article DOI: 10.1155/2022/1569084.].

[This retracts the article DOI: 10.1155/2022/2417523.].

[This retracts the article DOI: 10.1155/2022/3261213.].

[This retracts the article DOI: 10.1155/2022/7922906.].

[This retracts the article DOI: 10.1155/2022/4589191.].

[This retracts the article DOI: 10.1155/2022/9914173.].

[This retracts the article DOI: 10.1155/2022/9343951.].

[This retracts the article DOI: 10.1155/2023/1816818.].

[This retracts the article DOI: 10.1155/2022/3156093.].

[This retracts the article DOI: 10.1155/2022/8626234.].

[This retracts the article DOI: 10.1155/2022/8246761.].

[This retracts the article DOI: 10.1155/2022/2102795.].

[This retracts the article DOI: 10.1155/2022/4704107.].

[This retracts the article DOI: 10.1155/2022/8975435.].

[This retracts the article DOI: 10.1155/2022/2337447.].

[This retracts the article DOI: 10.1155/2022/6997221.].

[This retracts the article DOI: 10.1155/2022/3529499.].

[This retracts the article DOI: 10.1155/2022/5693994.].

[This retracts the article DOI: 10.1155/2022/6098799.].

[This retracts the article DOI: 10.1155/2022/2550686.].

[This retracts the article DOI: 10.1155/2022/1447388.].

[This retracts the article DOI: 10.1155/2022/9449497.].

[This retracts the article DOI: 10.1155/2022/1231446.].

[This retracts the article DOI: 10.1155/2022/5861928.].

[This retracts the article DOI: 10.1155/2022/4625719.].

[This retracts the article DOI: 10.1155/2023/3158486.].

[This retracts the article DOI: 10.1155/2022/7191178.].

[This retracts the article DOI: 10.1155/2022/1451881.].

[This retracts the article DOI: 10.1155/2022/7833516.].

[This retracts the article DOI: 10.1155/2022/7378953.].

[This retracts the article DOI: 10.1155/2022/8480106.].

Malaria is a devastating disease, and its management is only achieved through chemotherapy. However, resistance to available medication is still a challenge; therefore, there is an urgent need for the discovery and development of therapeutics with a novel mechanism of action to counter the resistance scourge consistent with the currently available antimalarials. Recently, plasmepsin V was validated as a therapeutic target for the treatment of malaria. The pepsin-like aspartic protease anchored in the endoplasmic reticulum is responsible for the trafficking of parasite-derived proteins to the erythrocytic surface of the host cells. In this study, a small library of compounds was preliminarily screened in vitro to identify novel modulators of Plasmodium falciparum plasmepsin V (PfPMV). The results obtained revealed kaempferol, quercetin, and shikonin as possible PfPMV inhibitors, and these compounds were subsequently probed for their inhibitory potentials using in vitro and in silico methods. Kaempferol and shikonin noncompetitively and competitively inhibited the specific activity of PfPMV in vitro with IC50 values of 22.4 and 43.34 μM, respectively, relative to 62.6 μM obtained for pepstatin, a known aspartic protease inhibitor. Further insight into the structure-activity relationship of the compounds through a 100 ns molecular dynamic (MD) simulation showed that all the test compounds had a significant affinity for PfPMV, with quercetin (-36.56 kcal/mol) being the most prominent metabolite displaying comparable activity to pepstatin (-35.72 kcal/mol). This observation was further supported by the compactness and flexibility of the resulting complexes where the compounds do not compromise the structural integrity of PfPMV but rather stabilized and interacted with the active site amino acid residues critical to PfPMV modulation. Considering the findings in this study, quercetin, kaempferol, and shikonin could be proposed as novel aspartic protease inhibitors worthy of further investigation in the treatment of malaria.

The 32 bp deletion in the chemokine receptor (C-C motif) 5 gene (CCR5Δ32) is a natural loss of function polymorphism that prevents the protein from locating on the cell surface. This genetic variation acts as a double-edge sword in the pathogenesis/defense mechanism of different health conditions, such as viral infections, autoimmune diseases, and cancers. Here, we evaluated the prevalence of the CCR5Δ32 polymorphism in the Turkmen population of Golestan province, northeast of Iran. Blood samples were collected from 400 randomly selected Turkmen populations (199 women and 201 men), and genomic DNA was extracted. Characterization of CCR5Δ32 genotypes was performed by PCR using primers flanking the 32-nucleotide deletion in the CCR5 gene. The amplified DNA fragments were visualized on 2% agarose gel electrophoresis with cybergreen staining under UV light. All individuals were of Turkmen ethnicity and lived in the Golestan province, northeast of Iran. The mean age of all participants was 35.46 years, with a 20-45 year range. All the studied subjects were healthy without any severe conditions such as autoimmune disease and viral infections. All individuals had no history of HIV infection. The PCR product visualization showed that all the samples are at the 330 bp size, which means the CCR5Δ32 allele was utterly absent from the study population. The presence of the CCR5Δ32 allele among Turkmens may be attributed to the admixture with European descent people. We conclude that the CCR5Δ32 polymorphism may be absent in the Iranian Turkmen population, and further studies with a large population are needed.

BACKGROUND: Human life quality and expectancy have increased dramatically over the past 5 decades because of improvements in nutrition and antibiotic's usage fighting against infectious diseases. Yet, it was soon revealed that the microbes adapted to develop resistance to any of the drugs that were used. Recently, there is great concern that commensal bacteria from food and the gastrointestinal tract of humans and animals could act as a reservoir for antibiotic resistance genes. Methodology. This study was intended for evaluating the phenotypic antibiotic resistance/sensitivity profiles of probiotic bacteria from human breast milk and evaluating the inhibitory effect of the probiotic bacteria against both Gram-negative and Gram-positive bacteria. RESULTS: The results point out that some of the isolated bacteria were resistant to diverse antibiotics including gentamycin, imipenem, trimethoprim sulfamethoxazole, and nalidixic acid. Susceptibility profile to certain antibiotics like vancomycin, tetracycline, ofloxacin, chloramphenicol, streptomycin, rifampicin, and bacitracin was also observed. The antimicrobial qualities of cell-free supernatants of some probiotic bacteria inhibited the growth of indicator bacteria. Also, antimicrobial properties of the probiotic bacteria from the present study attributed to the production of organic acid, bacterial adhesion to hydrocarbons (BATH), salt aggregation, coaggregation with pathogens, and bacteriocin production. Some isolated bacteria from human milk displayed higher hydrophobicity in addition to intrinsic probiotic properties like Gram-positive classification, catalase-negative activity, resistance to gastric juice (pH 2), and bile salt (0.3%) concentration. CONCLUSION: This study has added to the data of the antibiotic and antimicrobial activity of some probiotic bacteria from some samples of Pakistani women breast milk. Probiotic bacteria are usually considered to decrease gastrointestinal tract diseases by adhering to the gut epithelial and reducing population of pathogens and in the case of Streptococcus lactarius MB622 and Streptococcus salivarius MB620 in terms of hydrophobicity and exclusion of indicator pathogenic strains.

Acute myeloid leukemia (AML) is a blood cancer caused by the abnormal proliferation and differentiation of hematopoietic stem cells in the bone marrow. The actual genetic markers and molecular mechanisms of AML prognosis are unclear till today. This study used bioinformatics approaches for identifying hub genes and pathways associated with AML development to uncover potential molecular mechanisms. The expression profiles of RNA-Seq datasets, GSE68925 and GSE183817, were retrieved from the Gene Expression Omnibus (GEO) database. These two datasets were analyzed by GREIN to obtain differentially expressed genes (DEGs), which were used for performing the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, protein-protein interaction (PPI), and survival analysis. The molecular docking and dynamic simulation were performed to identify the most effective drug/s for AML from the drug list approved by the Food and Drug Administration (FDA). By integrating the two datasets, 238 DEGs were identified as likely to be affected by AML progression. GO enrichment analyses exhibited that the upregulated genes were mainly associated with inflammatory response (BP) and extracellular region (CC). The downregulated DEGs were involved in the T-cell receptor signalling pathway (BP), an integral component of the lumenal side of the endoplasmic reticulum membrane (CC) and peptide antigen binding (MF). The pathway enrichment analysis showed that the upregulated DEGs were mainly associated with the T-cell receptor signalling pathway. Among the top 15 hub genes, the expression levels of ALDH1A1 and CFD were associated with the prognosis of AML. Four FDA-approved drugs were selected, and a top-ranked drug was identified for each biomarker through molecular docking studies. The top-ranked drugs were further confirmed by molecular dynamic simulation that revealed their binding stability and confirmed their stable performance. Therefore, the drug compounds, enasidenib and gilteritinib, can be recommended as the most effective drugs against the ALDH1A1 and CFD proteins, respectively.

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPKT) is a complex and demanding procedure with a considerable risk of morbidity and mortality. Advances in surgical techniques and organ preservation have introduced changes in care protocols. Two cohorts of patients receiving SPKT with two different protocols were compared to determine overall survival and pancreatic and renal graft failure-free survival. METHODS: This retrospective observational study was conducted in two cohorts of SPKT recipient patients that underwent surgery between 2001 and 2021. Outcomes were compared in transplant patients between 2001 and 2011 (cohort 1; initial protocol) and 2012-2021 (cohort 2; improved protocol). In addition to the temporality, the cohorts were defined by a protocolization of technical aspects and medical management in cohort 2 (improved protocol), compared to a wide variability in the procedures carried out in cohort 1 (initial protocol). Overall survival and pancreatic and renal graft failure-free survival were the primary outcomes. These outcomes were determined using Kaplan-Meier survival analysis and the log-rank test. RESULTS: Fifty-five SPKT were performed during the study period: 32 in cohort 1 and 23 in cohort 2. In the survival analysis, an average of 2546 days (95% CI: 1902-3190) was found in cohort 1, while in cohort 2, it was 2540 days (95% CI: 2100-3204) (p > 0.05). Pancreatic graft failure-free survival had an average of 1705 days (95% CI: 1037-2373) in cohort 1, lower than the average in cohort 2 (2337 days; 95% CI: 1887-2788) (p = 0.016). Similarly, renal graft failure-free survival had an average of 2167 days (95% CI: 1485-2849) in cohort 1, lower than the average in cohort 2 (2583 days; 95% CI: 2159-3006) (p = 0.017). CONCLUSIONS: This analysis indicates that pancreatic and renal graft failure-free survival associated with SPKT decreased significantly in cohort 2, with results related to improvements in the treatment protocol implemented in that cohort.