Potential contribution of gut microbiota in the development of autoantibodies in T1D children carrying HLA-DRB1/DQB1 risk alleles: an experimental and in silico analysis.

This study aimed to investigate the prevalence of insulin autoantibody (IAA), glutamic acid decarboxylase antibody (GADA), and insulinoma-associated antigen-2 antibody (IA-2A) in type 1 diabetes (T1D) children based on the presence of predisposing HLA-II alleles. Additionally, to assess the sequence homology between autoantigens of islet cells and selected proteins derived from gut bacteria in terms of their binding capacities to HLA risk alleles, HLA-DRB1/DQB1 alleles were determined by PCR-SSOP in 111 T1D children (probands) along with 222 parents and 133 siblings. Autoantibodies were measured by ELISA, and in silico analysis was run as follows: protein extraction, homology and epitope prediction, peptide alignment, and HLA-peptide docking. Higher significant frequencies of DRB1*03:01, DQB1*02:01, and DQB1*03:02 alleles and DRB1*03:01 ~ DQB1*02:01 haplotype and lower frequencies of DRB1*11:01, DRB1*14:01, and DQB1*03:01 alleles were found in probands compared to parents and siblings. DRB1*11:01 ~ DQB1*03:01, DRB1*14:01 ~ DQB1*05:03, and DRB1*15:01-DQB1*06:02 haplotypes were significantly less frequent in the probands compared to parents. Out of 111 probands, 21 were seronegative, 90 tested positive for one autoantibody, and 15 showed the concurrent presence of three autoantibodies. Logistic regression analysis revealed that DRB1*04 ~ DQB1*03:02 haplotype was associated with the induction of GADA and IA-2A, while DRB1*11:01 ~ DQB1*03:01 was associated with seronegativity. Epitopes derived from GAD and gut bacteria showed strong binding capacities to HLA risk alleles. Due to the sequence similarities between gut bacteria-derived proteins and islet cell autoantigens and their potential for binding to HLA risk alleles, dysbiosis of gut microbiota can be considered another risk factor for the development of T1D, especially in genetically susceptible individuals.

New platinum (II) complexes based on schiff bases: synthesis, specification, X-ray structure, ADMET, DFT, molecular docking, and anticancer activity against breast cancer.

Acylpyrazolone-based Schiff base ligands (HLn) and their corresponding Pt(II) complexes with the general formula [Pt(Ln)(Cl)] (n = 1-3) were synthesized and characterized by different spectroscopic techniques including 1H-NMR, 195Pt-NMR, LC-Mass, FT-IR, and UV-Vis spectroscopy, as well as elemental analysis. The crystal structure of one of the Schiff base ligands was also obtained. Based on the ADMET comparative results and the bioavailability radar charts, the complexes are completely drug-like. The Schiff base complexes with a structural difference of one methyl group in ligand were used as anticancer agents against human breast cancer cell lines SKBR3 and MDA-MB-231. The IC50 values after treatment by [Pt(L1)Cl] and [Pt(L2)Cl] were obtained more than cisplatin and less than carboplatin on cancer cells MDA-MB-231 and SKBR3, while the IC50 value of [Pt(L3)Cl] was more than both other complexes and clinical Pt drugs. Molecular docking data showed that the groove binding is the main interaction with DNA double strands with a minor contribution from electrostatic interactions. To investigate the structure-activity relationship, DFT computational was done. All quantum chemical parameters display the drug approaching biomacromolecule and more biological activity of [Pt(L1)Cl] > [Pt(L2)Cl] > [Pt(L3)Cl]. So, three Schiff base platinum complexes can be suitable candidates as anticancer drugs. Schiff-base ligands (HLn) and their Pt(II) complexes ([Pt(Ln)(Cl)], n=1-3) were obtained. To investigate their biological property and main interactions with DNA, ADMET, and cytotoxicity against MDA-MB-231 and SKBR3, DFT, and Molecular docking were done.

Impact of interleukin-32α on T helper cell-related cytokines, transcription factors, and proliferation in patients with type 2 diabetes mellitus.

OBJECTIVE: The ability of interleukin (IL)-32α to induce T helper (Th) 1, Th17, and Treg cytokines (interferon gamma [IFN-γ], IL-17, and IL-10, respectively), and transcription factors ([signal transducer and activator of transcription (STAT) 1 and T-box (T-bet) for Th1, STAT3 and retinoid-related orphan receptor (ROR)-γt for Th17, and STAT5 and forkhead box P3 (Foxp3) for Treg]) were investigated in type 2 diabetes mellitus (T2DM). IL-32α effects on Th cell proliferation and related factors including IL-2 and NF-κB were also explored. METHODS: Serum levels of IL-32α in 31 patients and 31 healthy controls (HCs) were determined by ELISA assay. CD4+ T cells cultured with polyclonal activators in the presence and absence of recombinant IL-32α (rIL-32α). Gene expressions in cultured Th cells were assessed with real-time PCR. Cytokines in supernatants were measured with ELISA. Proliferation experiments were assessed by flow cytometry. RESULTS: The patients showed significant increase in IL-32α levels compared with HCs and its levels were positively correlated with fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). rIL-32α enhanced IL-17 and IL-2 production, increased ROR-γt and NF-κB expression, and enhanced Th proliferation in both patients and HCs. In patients, IL-17, ROR-γt, NF-κB, and proliferation levels were higher than those in HCs, in cultures with and without rIL-32α (rIL-32α+ and rIL-32α-). IL-2 levels in rIL-32α+cultures of patients were significantly higher than the HCs, and it was positively correlated with proliferation rate and NF-κB expression. CONCLUSIONS: Aberrant IL-32α levels are participated in T2DM pathogenesis. IL-32α potently induces Th17-related factors and amplifies the proliferative function of T cells.HighlightsEnhanced serum levels of IL-32α in T2DM patients was correlated with FPG and HbA1c.IL-32α increases ROR-γt expression and IL-17 production, and induces Th17 cells.IL-32α enhances NF-κB expression and IL-2 production, and promotes Th proliferation.IL-32α is more effective for inducing Th17 cells and proliferation in the patients.IL-32α axis could be mentioned as a future therapeutic goal for the T2DM.

Synthesis and crystal structures of new mixed-ligand schiff base complexes containing N-donor heterocyclic co-ligands: Molecular docking and pharmacophore modeling studies on the main proteases of SARS-CoV-2 virus (COVID-19 disease).

Three new mixed-ligand copper(II) complexes (1-3) with NN'O type unsymmetrical tridentate Schiff base ligands (SB) and N-donor heterocyclic co-ligands, with general formula [Cu(SB)(L)]ClO4, were synthesized and characterized using single crystal x-ray diffraction (SCXRD), FT-IR and UV-Vis spectroscopy and elemental analyses. The SB ligand is the half-unit form of the condensation of 1,3-propanediamine with 5-methoxysalicylaldehyde and the co-ligands (L) are pyridine (py in (1)), 2,2'-bipyridine (bpy in (2)) and 1,10-phenanthroline (phen in (3)). Crystal structures of (2) and (3) were obtained by SCXRD. Molecular docking and pharmacophore studies were performed to study the interactions between the synthesized complexes and SARS-CoV-2 virus main proteases (PDB IDs: 6LU7, 6WQF and 6W9C). Results revealed that complex (3) with phen co-ligand showed better docking scores with the three receptors, i.e. 6LU7 (-8.05 kcal.mol-1), 6W9C (-7.70 kcal.mol-1) and 6WQF (-7.75 kcal.mol-1). The order of the binding best energies for (3) was also as follows: 6LU7 > 6WQF > 6W9C. All of the studied complexes showed considerable performance, comparable to the standard drug, Favipiravir.

Investigating the anticancer properties of the two new platinum complexes with iso- and tert-pentylglycine by the DFT, molecular docking, and ADMET assessment and experimental confirmations.

In this study, two new anticancer platinum complexes formulated as [Pt(bpy)(L)]NO3 were synthesized using the iso and tert-pentylglycine ligands, two structural isomer ligands, to investigate side branches effect on the complex-DNA interaction. According to the comparative results of the ADMET assessment, these compounds can be considered as the drug-like molecules and oral medication. Mechanism of tumor inhibition and DNA binding parameters indicated the higher ability of the tert-isomer and also, both complexes acted through the disruption of the base pairs and stacks of helicity by the endothermic process. Fluorescence spectroscopy showed that the quenching mechanism is static for both drugs with large binding constant and high binding affinity towards the DNA. Also, the amount of binding constant of the tert -isomer was about 14 times of another structural isomerous complex. CD spectra indicated the conversion of the B-DNA into A-DNA form via electrostatic interaction for positively charged complexes. The cytotoxic data showed that both compounds have antiproliferative effects against the MCF-7 cell line and the inhibitory effect of the iso-derivative was better than the tert-one. Docking studies showed that the desolvation energy and hydrogen bond are more effective between the other interactions. The torsional free energy for both complexes mainly provided the groove binding along with partially electrostatic and intercalate binding. According to the density-functional theory data and because of positive electron density on the surface of complexes and facilitating of the metal drug to DNA phosphate groups approaching, both complexes may be good candidates for the anticancer drugs. Two new anticancer Pt(II) complexes were synthesized with glycine derivatives. In vitro cytotoxicity effects were tested against the human breast cancer cell line of MCF-7. Moreover, the modes of DNA binding with synthesized compounds were investigated using ADME prediction, DFT, molecular docking and spectroscopic methods.

Variable noninnocence of substituted azobis(phenylcyanamido)diruthenium complexes.

The synthetic chemistry of substituted 4,4'-azobis(phenylcyanamide) ligands was investigated, and the complexes [{Ru(tpy)(bpy)}2(µ-L)][PF6]2, where L = 2,2':5,5'-tetramethyl-4,4'-azobis(phenylcyanamido) (Me4adpc(2-)), 2,2'-dimethyl-4,4'-azobis(phenylcyanamido) (Me2adpc(2-)), unsubstituted (adpc(2-)), 3,3'-dichloro-4,4'-azobis(phenylcyanamido) (Cl2adpc(2-)), and 2,2':5,5'-tetrachloro-4,4'-azobis(phenylcyanamido) (Cl4adpc(2-)), were prepared and characterized by cyclic voltammetry and vis-near-IR (NIR) and IR spectroelectrochemistry. The room temperature electron paramagnetic resonance spectrum of [{Ru(tpy)(bpy)}2(µ-Me4adpc)](3+) showed an organic radical signal and is consistent with an oxidation-state description [Ru(II), Me4adpc(•-), Ru(II)](3+), while that of [{Ru(tpy)(bpy)}2(µ-Cl2adpc)](3+) at 10 K showed a low-symmetry Ru(III) signal, which is consistent with the description [Ru(III), Cl2adpc(2-), Ru(II)](3+). IR spectroelectrochemistry data suggest that [{Ru(tpy)(bpy)}2(µ-adpc)](3+) is delocalized and [{Ru(tpy)(bpy)}2(µ-Cl2adpc)](3+) and [{Ru(tpy)(bpy)}2(µ-Cl4adpc)](3+) are valence-trapped mixed-valence systems. A NIR absorption band that is unique to all [{Ru(tpy)(bpy)}2(µ-L)](3+) complexes is observed; however, its energy and intensity vary depending on the nature of the bridging ligand and, hence, the complexes' oxidation-state description.

Effect of sitagliptin therapy on IL-29 and its associated signaling molecules in patients with type 2 diabetes mellitus.

OBJECTIVE: The potential immunoregulatory capacity of sitagliptin on interleukin-29 (IL-29) and genes involved in its intracellular pathway were explored in type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: T2D patients treated with six months of sitagliptin (Sita+), patients not treated with sitagliptin (Sita-), and healthy controls (HCs) were included. IL-29 levels in the supernatant of stimulated mononuclear immune cells was determined with ELISA. The mRNA expression levels of IL-29, FOS, JUN, NF-AT2, NF-KB1, STAT1-2, IRF1, IRF3, IRF7, and IRF9 was assessed with real-time qPCR. RESULTS: Increased protein and gene levels of IL-29 were observed in Sita- group compared to HCs (p < 0.001 and p = 0.026), while those levels were diminished in Sita+ group in comparison with Sita- group (p < 0.001 and p = 0.008). Expression of FOS, NF-AT2 and NF-KB1 in Sita- patients was higher than HCs (p = 0.018, p = 0.021, and p = 0.001). A significant decrease in expression of FOS, NF-AT2, and NF-KB1 was found in Sita+ group versus Sita- parients (p = 0.027, p = 0.003, and p = 0.002). In Sita- patients, IL-29 levels were correlated to glucose metabolism parameters including FPG and HbA1c (p < 0.05 for all). CONCLUSION: Sitagliptin administration has a regulatory effect on the aggressive expression of IL-29 and its signaling molecules including FOS, NF-AT2 and NF-KB1 in T2D.

Metallosalen modified carbon nitride a versatile and reusable catalyst for environmentally friendly aldehyde oxidation.

The development of environmentally friendly catalysts for organic transformations is of great importance in the field of green chemistry. Aldehyde oxidation reactions play a crucial role in various industrial processes, including the synthesis of pharmaceuticals, agrochemicals, and fine chemicals. This paper presents the synthesis and evaluation of a new metallosalen carbon nitride catalyst named Co(salen)@g-C3N4. The catalyst was prepared by doping salicylaldehyde onto carbon nitride, and subsequently, incorporating cobalt through Schiff base chemistry. The Co(salen)@g-C3N4 catalyst was characterized using various spectroscopic techniques including Scanning Electron Microscopy (SEM), X-ray Diffraction (XRD), Infrared Spectroscopy (IR), and Thermogravimetric Analysis (TGA). Furthermore, after modification with salicylaldehyde, the carbon nitride component of the catalyst exhibited remarkable yields (74-98%) in oxidizing various aldehyde derivatives (20 examples) to benzoic acid. This oxidation reaction was carried out under mild conditions and resulted in short reaction times (120-300 min). Importantly, the catalyst demonstrated recyclability, as it could be reused for five consecutive runs without any loss of activity. The reusable nature of the catalyst, coupled with its excellent yields in oxidation reactions, makes it a promising and sustainable option for future applications.

Enhanced production of interleukin-29 and related genes are associated with T helper 1 cell parameters in patients with type 2 diabetes mellitus.

OBJECTIVE: The production of interleukin (IL)-29 andthe genes related to IL-29 signaling pathway (STAT1, NF-κB, and NFATc1), and T helper (Th) 1 cells (T-bet, IFN-γ, TNF-α, and IL-2) were evaluated in type 2 diabetes mellitus (T2DM). Correlations between IL-29 and diabetes parameters, and between gene expression in IL-29 pathway and Th1 cells were also examined. MATERIALS AND METHODS: 41 newly diagnosed patients with T2DM and 41 healthy controls were recruited. CD4+ T cells were purifed and the production of IL-29 in the supernatant of anti- CD3 and anti- CD28 activated Th cells was detected using ELISA. The expression of IL-29- and Th1- related genes was determined with real-time PCR. RESULTS: The secretion of IL-29 and the expression levels of NF-κB, NFATc1, IFN-γ, and TNF-α in Th cells were seen to be increased in diabetes persons compared to controls. Positive connections between IL-29 with hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) were found in diabetes persons. IL-29 was positively correlated with NFATc1 and TNF-α. NFATc1 was positively related to TNF-α. CONCLUSION: Abnormal expression levels of IL-29- and Th1- related genes are linked with T2DM pathogenesis. IL-29 may amplify the expression of Th1-specific genes especially TNF-α by upregulating NFATc1 expression.

Effect of 50-Hz magnetic fields on the expression of activation-induced deaminase, B-cell lymphoma 6 and serum levels of interleukin-6, interleukin-21.

BACKGROUND: Investigations showed different effects of magnetic fields (MFs) on the immune system. During humoral immune responses, genes of activation-induced deaminase (AID) and B-cell lymphoma-6 (Bcl-6) are expressed and interleukin (IL)-6 and IL-21 are produced. These factors play significant roles in class switching, affinity maturation of antibodies and activations of B cells germinal centers (GCs). Therefore, this study investigated the effect of 50-Hz MFs exposure with different densities on these factors. MATERIALS AND METHODS: Eighty rats were divided into four exposures and control groups. The treatment groups were exposed to magnetic flux densities of 1, 100, 500, and 2000 µT (50 Hz, 2 h/d for 60 d). To activation of the immune system, all the animals were immunized with human serum albumin on days 31, 44, and 58 of exposure. Reverse transcription-quantitative polymerase chain reaction was used to assay the expression levels of AID and Bcl-6 genes in the spleen. The serum levels of IL-6 and IL-21 were also detected by enzyme-linked immunosorbent assay at the pre-and post-immunization phases. RESULTS: AID expression was significantly declined at 1µT magnetic flux density, while no change was observed in the expression of Bcl-6. Serum IL-6 was increased only in the 500 µT group at the post-immunization phase. CONCLUSIONS: It seems exposure to 50-Hz MFs at 1 µT density, suppresses AID and may cause a decline in class switching and affinity maturation of Abs. On the other hand, exposure to 500 µT, may activate them. These findings demonstrate the various potential effects of MFs on the humoral immune system.

Maternal high-intensity interval training as a suitable approach for offspring's heart protection in rat: evidence from oxidative stress and mitochondrial genes.

Considerable scientific evidence suggests that the intrauterine environment plays a crucial role in determining the long-term health of offspring. The present study aims to investigate the effects of high-intensity interval training in maternal rats before and during pregnancy on the antioxidant status, mitochondrial gene expression, and anxiety-like behavior of their offspring. A total of thirty-two female rats were assigned to four maternal groups based on the timing of exercise: before pregnancy, before and during pregnancy, during pregnancy, and sedentary. The female and male offspring were allocated to groups that matched their mothers' exercise regimen. Anxiety-like behavior in the offspring was evaluated using the open-field and elevated plus-maze tests. Our findings indicate that maternal HIIT does not have any detrimental effect on the anxiety-related behavior of offspring. Also, maternal exercise before and during pregnancy could improve the general activity of the offspring. Furthermore, our results demonstrate that female offspring exhibit more locomotion activity than males. Besides, maternal HIIT leads to a reduction in the levels of TOS and MDA, while TAC levels increase, and significantly upregulate the gene expression of PGC1-α, NFR1, and NRF2 in both sexes in the heart. Therefore, our study suggests that maternal HIIT is a beneficial maternal behavior and serves as a cardioprotective agent to enhance the health of the next generations.

Synthesis and characterization of two new mixed-ligand Cu(II) complexes of a tridentate NN'O type Schiff base ligand and N-donor heterocyclic co-ligands: In vitro anticancer assay, DNA/human leukemia/COVID-19 molecular docking studies, and pharmacophore modeling.

Two new mixed-ligand complexes with general formula [Cu(SB)(L')]ClO4 (1 and 2) were synthesized and characterized by different spectroscopic and analytical techniques including Fourier transform infrared (FT-IR) and UV-Vis spectroscopy and elemental analyses. The SB ligand is an unsymmetrical tridentate NN'O type Schiff base ligand that was derived from the condensation of 1,2-ethylenediamine and 5-bromo-2-hydroxy-3-nitrobenzaldehyde. The L' ligand is pyridine in (1) and 2,2'-dimethyl-4,4'-bithiazole (BTZ) in (2). Crystal structure of (2) was also obtained. The two complexes were used as anticancer agents against leukemia cancer cell line HL-60 and showed considerable anticancer activity. The anticancer activity of these complexes was comparable with the standard drug 5-fluorouracil (5-FU). Molecular docking and pharmacophore studies were also performed on DNA (PDB:1BNA) and leukemia inhibitor factor (LIF) (PDB:1EMR) to further investigate the anticancer and anti-COVID activity of these complexes. The molecular docking results against DNA revealed that (1) preferentially binds to the major groove of DNA receptor whereas (2) binds to the minor groove. Complex (2) performed better with 1EMR. The experimental and theoretical results showed good correlation. Molecular docking and pharmacophore studies were also applied to study the interactions between the synthesized complexes and SARS-CoV-2 virus receptor protein (PDB ID:6LU7). The results revealed that complex (2) had better interaction than (1), the free ligands (SB and BTZ), and the standard drug favipiravir.

Peripheral distributions of IL-4-producing CD4 + T cells and CD4 + CD25 + FoxP3 + T cells (Tregs) in rheumatoid arthritis patients with poor response to therapy are associated with HLA shared epitope alleles and ACPA status.

Specific profiling of CD4 + T cell subsets in the circulation and inflamed joints of rheumatoid arthritis (RA) patients may have therapeutic implications. This study aimed to evaluate the peripheral distributions of Th2 and Treg cells in relation to HLA-shared epitope (SE) alleles and anti-cyclic citrullinated peptide antibody (ACPAs) status in patients with good response (GR) and poor response (PR) to treatment. The frequencies of IL-4-producing CD4 + T cells (Th2) and CD4 + CD25 + Foxp3 + T cells (Tregs) were determined by flow cytometry in 167 RA patients including 114 GR and 53 PR cases. CD4 + T cell subsets were also analyzed based on HLA-SE and ACPAs statuses. One hundred nine of 167 patients were positives for HLA-SE, 63.4% for ACPAs, 43.7% for SE/ACPAs and 14.9% were negatives for SE/ACPAs. Higher frequencies of Th2 (P = 0.001) and Treg cells (P = 0.03) were found in the patients versus controls. Increased and decreased frequencies of Th2 and Tregs cells were observed in the PR versus GR patients respectively (P = 0.003 and P = 0.004). Higher proportions of Th2 cells were observed in the SE+RA versus SE-RA (P = 0.001), in ACPA+RA versus ACPA-RA (P = 0.005) and in the SE+ACPA+RA versus SE-ACPA-RA patients (P = 0.002). Treg cells frequencies decreased in the SE+RA versus SE-RA (P = 0.03) and in SE+ACPA+RA versus SE-ACPA-RA (P = 0.02). ACPA+GR and SE+PR patients showed higher proportions of Th2 cells than ACPA-GR and SE-PR patients respectively (P = 0.02 and P = 0.01). Analysis of the CD4 + T cell subsets profiles in conjunction with genetic background and autoantibodies patterns can be useful for precise therapeutic response monitoring in the RA patients.

Changes in T helper cell-related factors in patients with type 2 diabetes mellitus after empagliflozin therapy.

The immune factors related to T helper (Th) 1 (T-bet, STAT1, and IFN-γ), Th17 (ROR-γt, STAT3, and IL-17), and Treg (FOXP3, STAT5, and IL-10) cells, and SOCS1/3 and the proliferation of Th cells were investigated in type 2 diabetes mellitus patients before (baseline) and after empagliflozin therapy. A total of 56 patients on metformin and gliclazide were separated into two groups: Group 1 did not receive empagliflozin (EMPA-) and the Group 2 received 10 mg/day of empagliflozin for 6 months (EMPA+). The expressions of T-bet, ROR-γt, FOXP3, STAT1/3/5 and SOCS1/3 were evaluated in CD4+ T cells with real-time PCR. The production of IFN-γ, IL-17, and IL-10 from CD4+ T cells was measured using ELISA. The proliferation of Th cells was assessed with flow cytometry. Six months of empagliflozin therapy significantly reduced the expression of ROR-γt and increased FOXP3 and STAT5 expression, compared to baseline. Production of IL-17 decreased after empagliflozin treatment, while IL-10 was enhanced in the EMPA+ group. Oral administration of empagliflozin or the addition of empagliflozin to the cell cultures diminished the proliferation of Th cells. Empagliflozin showed anti-inflammatory effects on Th cells by decreasing Th17-related factors, reducing proliferation capacity, and increasing Treg cell properties.

Reduced frequency and functional potency of CD49d- T regulatory cells in patients with newly diagnosed type 2 diabetes mellitus.

This study set out to check the quantitative and qualitative properties of peripheral CD4+CD25+CD49d- T regulatory (CD49d- Treg) cells in type 2 diabetes mellitus (T2DM) patients. This work comprised 35 newly diagnosed patients and 35 healthy controls (HCs). The frequency of FoxP3 expressing CD49d- Treg cells was determined by flow cytometry. The gene expression of FoxP3 and CD49d was assessed by real-time PCR. Suppression assays with purified CD49d- Treg cells and CD4+CD25- T conventional (Tconv) cells were done by flow cytometry. The supernatants of Tconv/CD49d- Treg co-cultures were tested for IFN-γ, IL-4, IL-17, and IL-10 using ELISA. The frequency of CD49d- Treg cells (by both CD4+CD25+CD49d- and CD4+CD25++CD49d- phenotypes) observed to be reduced in patients versus HCs. In the patients, decreased protein and gene expression of FoxP3 was seen in CD49d- Treg cells. Suppressive potency of CD49d- Treg cells to inhibit Tconv cells proliferation was diminished, and inversely related to fasting plasma glucose and hemoglobin A1c in the patients. Tconv cells from T2DM patients released higher amount of IL-17 and lower concentration of IL-10 versus HCs. In Tconv/CD49d- Tregs co-cultures, decreased IL-17 and increased IL-10 levels were seen in HCs, but not T2DM patients. CD49d- Treg cells from the patients have a fundamental defect and Treg cells fail to inhibit the aggressive inflammatory responses.

Two new oral candidates as anticancer platinum complexes of 1,3-dimethyl pentyl glycine ligand as doping agents against breast cancer.

1,3-Dimethylpentylamine (Geranamine) with a similar structure to amphetamine has been used as an athletic performance promoter (doping agent) and also as an indirect sympathomimetic drug to synthesize of 1,3-dimethyl pentyl glycine (13DMPG). Thereafter, two new anticancer platinum complexes as [Pt(DACH)(13DMPG)]NO3 and [Pt(bpy)(13DMPG)]NO3 were synthesized using this ligand and then characterized by spectroscopic methods. ADMET comparative results indicated that they are entirely in the pink area of the Bioavailability Radar, so they can be considered as drug-like and oral medications. Mechanism of tumor inhibition and DNA binding parameters were investigated and the results indicated the higher ability of [Pt(bpy)(13DMPG)]NO3 with the endothermic process for both systems compared with [Pt(DACH)(13DMPG)]NO3. Fluorescence study showed that the quenching mechanism is static for both drugs with large binding constant and high binding (Kb ≈ 8000 M-1 and kq ≈ 5.3 × 1011 M-1 s-1) affinity towards DNA. CD spectra showed the increased intensity of the positive band and the decreased negative band, meaning B-DNA converting to A-DNA form via electrostatic interaction for positively charged complexes. The cytotoxic effect analyzed by MTT assay showed that both compounds have effective antiproliferative on MCF-7 cell line. In addition, the inhibition effect of [Pt(DACH)(13DMPG)]NO3 (IC50 = 17 µM) was shown to be better than [Pt(bpy)(13DMPG)]NO3 (IC50 = 45 µM). According to DFT results, anticancer properties of [Pt(bpy)(13DMPG)]NO3 mainly is more than cisplatin and [Pt(DACH)(13DMPG)]NO3. Docking studies showed that the desolvation energy and hydrogen bond are more effective compared to the other interactions. The torsional free energy, about +1.19 kcal/mol, for both complexes mainly provides groove binding with partially electrostatic and intercalate bindings.

Clinical Relevance of HLA-DRB1 and -DQB1 Alleles in Iranian Systemic Lupus Erythematosus Patients.

Given the potential link between genetic risk factors and clinical features of systemic lupus erythematosus (SLE), this study aimed to explore the relationship between human leukocyte antigen (HLA)-DRB1/DQB1 alleles and haplotypes and clinical sub-phenotypes of the disease in a group of Iranian SLE patients. HLA-DRB1 and HLA-DQB1 alleles were determined by PCR-SSP in 127 SLE patients and 153 ethnically-matched healthy controls. The relationships between various clinical manifestations and HLA alleles/haplotypes were analyzed in the patients. We observed the positive associations of DRB1*07 and DRB1*07-DQB1*02 haplotypes with articular and pulmonary involvement (p=0.006 and p<0.001 respectively), DRB1*03 and DQB1*02 alleles, and DRB1*03-DQB1*02 haplotypes with cutaneous (p=0.03, p=0.004 and p=0.02 respectively) and renal involvement, and DRB1*13 as well as DRB1*13-DQB1*06 haplotypes with renal involvement. Conversely, negative associations of DRB1*13 with cutaneous and gastrointestinal disorders (p=0.004 and p=0.02 respectively) and DRB1*01 with renal involvement (p=0.03) were found in our patients. Patients carrying susceptible HLA-DRB1 alleles had a higher risk for expression of cutaneous involvement (p=0.03), anti-coagulant antibody development (p=0.01), and a lower risk for pulmonary disorders compared to patients' negatives for susceptible alleles (p=0.04). Our findings on associations between HLA risk allele (DRB1*03) as well as non-risk alleles with particular clinical manifestations and between the potentially protective allele (DRB1*01) and protection against renal involvement indicate the important role of HLA class II genes in predisposing of specific serological and clinical features of SLE disease which could be implicative for therapeutic applications and better management of SLE patients.

Diminished functional properties of T regulatory cells in major depressive disorder: The influence of selective serotonin reuptake inhibitor.

The properties of CD4+CD25hi T regulatory cells (Tregs), and interleukin (IL)-2 pathway were investigated in major depressive disorder (MDD) patients treated with or without selective serotonin reuptake inhibitor (SSRI). The frequencies of FOXP3 and pSTAT5 in peripheral Tregs were found to be diminished in untreated patients (SSRI-) versus HCs (p < .001 for both), while their percentages were increased in treated patients (SSRI+) versus untreated patients (p < .001 and p = .04). The proliferation of CD4+ T cells was higher in SSRI-MDD patients versus HCs (p = .03). The SSRI-MDD patients showed a lower concentration of supernatant TGF-ß than HCs (p = .001), while the production of TGF-ß was enhanced in SSRI+MDD versus SSRI-MDD patients (p = .003). The number of CD45RA-expressing Tregs, the expression of JAK1 and JAK3, and the levels of IL-2 and IL-10 were similar between the patients and HCs. The study results showed that untreated patients have an impaired IL-2 signaling pathway and defective Tregs, and SSRI treatment may improve the Tregs function.

Evaluation of Interleukin-23 and JAKs/STATs/SOCSs/ROR-γt Expression in Type 2 Diabetes Mellitus Patients Treated With or Without Sitagliptin.

The production of interleukin-23 (IL-23) and the expression levels of related genes were evaluated in type 2 diabetes mellitus patients. The correlations between them were also determined. Thirty patients without sitagliptin (sitagliptin negative; SN), 30 patients with sitagliptin (sitagliptin positive; SP), and 30 healthy controls (HCs) were recruited. The level of IL-23 in the supernatant of anti CD3-activated peripheral blood mononuclear cells (PBMCs) was assessed using enzyme-linked immunosorbent assay. The expressions of IL-23, JAK1/JAK2/TYK2, STAT1/STAT3, ROR-γt, and SOCS1/SOCS3 in PBMCs were evaluated by real-time polymerase chain reaction. The production of IL-23 and the expressions of IL-23, JAK2, STAT3, and ROR-γt were observed to be enhanced in SN patients versus HCs, while the levels were decreased in SP patients versus SN patients (P < 0.05). SOCS1 and SOCS3 expressions were lower in SN patients than HCs, and their expressions were elevated in SP patients versus SN patients (P < 0.05). In SN patients, positive correlations between the IL-23 with fasting plasma glucose and HbA1c were observed, and JAK2/STAT3/ROR-γt were positively correlated with IL-23. JAK2, STAT3, and ROR-γt were positively related to each other and were negatively related to SOCS3. Enhanced IL-23/JAK2/STAT3/ROR-γt and reduced SOCS1/SOCS3 were found in SN patients. Sitagliptin may regulate the IL-23 and related gene expression.

Induction of Cell Cycle Arrest in MKN45 Cells after Schiff Base Oxovanadium Complex Treatment Using Changes in Gene Expression of CdC25 and P53.

Compounds containing heavy metals such as vanadium, nickel, and cobalt may be useful for the treatment of various diseases. Multiple studies have been carried out on the anticancer effects of vanadium-contained compounds on different cell types. This study aimed to evaluate the role of schiff base oxovanadium complex ([N,N'-bis(3-methoxy-salicylidene)-1,2-phenylenediamine]Vanadium(IV) Oxide Complex) on cell cycle arrest and different cell cycle phases in MKN45 cell of gastric cancer. Schiff base oxovanadium complex was used to assessthe amount of cytotoxicity via cell viability test. PI color and flow cytometry technique were applied to evaluate the effects of vanadium synthetic compounds on cell cycle phases; subsequently, we analyzed the change rates of gene expression in P53, GADD45, and CDC25 genes, which are involved in cell division phases. The findings indicated that the vital activities of time-dependent and concentration-dependent MKN45 cells with schiff base oxovanadium complex were significantly reduced; therefore, this complex is able to inhibit the migration of cancer cells and metastatic activities in a time-dependent mode. Cell cycle arrest was obtained after 48 h of treatment in phase G2/M at 1 microgram/milliliter (µg/ml) concentration. This is probably attributed to the increased gene expression of P53 and GADD45 genes and reduced gene expression of CDC25 gene. Compounds containing such heavy metals as vanadium decrease the growth, proliferation, and migration of MKN45 cells. They arrest cell cycle in phase G2/M via changing the controllers of cell division phases activated due to DNA damage.