Aldose reductase inhibitory and antiglycation properties of phytoconstituents of Cichorium intybus: Potential therapeutic role in diabetic retinopathy.

Diabetic vascular complication including diabetic retinopathy is a major morbidity in Saudia Arabia. The polyol pathway aka aldose reductase (AR) pathway has gained significant association with diabetic retinopathy with regard to chronically enhanced glucose metabolism. Considerable research has been put forth to develop more effective therapeutic strategies to overcome the overwhelming challenges of vascular complications associated with diabetes. In this regard, constituents of Cichorium intybus can offer strong AR inhibitory potential because of their strong antidiabetic properties. Therefore, aim of this study was to investigate the AR inhibitory as well as antiglycation potential of C. intybus extract/compounds. The preliminary in vitro results showed that methanolic extract of C. intybus could significantly inhibit AR enzyme and advanced glycation end product formation. Eventually, based on previous studies and reviews, we selected one hundred fifteen C. intybus root constituents and screened them through Lipinski's rule of five and ADMET analysis. Later, after molecular docking analysis of eight compounds, five best were selected for molecular dynamics simulation to deduce their binding affinity with the AR enzyme. Finally, three out of five compounds were further tested in vitro for their AR inhibitory potential and antiglycation properties. Enzyme assay and kinetic studies showed that all the three tested compounds were having potent AR inhibitory properties, although to a lesser extent than ellagic acid and tolrestat. Similarly, kaempferol showed strong antiglycation property equivalent to ellagic acid, but greater than aminoguanidine. Intriguingly, significant reduction in sorbitol accumulation in RBCs by the tested compounds substantiated strong AR inhibition by these compounds. Moreover, decrease in sorbitol accumulation under high glucose environment also signifies the potential application of these compounds in diabetic retinopathy and other vascular complications. Thus, in sum, the in silico and in vitro studies combinedly showed that C. intybus root is a treasure for therapeutic compounds and can be explored further for drug development against diabetic retinopathy.

Synthesis, Characterization, Antiglycation Evaluation, Molecular Docking, and ADMET Studies of 4-Thiazolidinone Derivatives.

The design and development of new small-molecule glycation inhibitors are essential for preventing various chronic diseases, including diabetes mellitus, immunoinflammation, cardiovascular, and neurodegenerative diseases. 4-Thiazolidinone or thiazolidine-4-one is a well-known heterocyclic compound with the potential to inhibit the formation of advanced glycation end products. In the present work, we report the synthesis and characterization of four new 5-arylidene 3-cyclopropyl-2-(phenylimino)thiazolidin-4-one (1-4) compounds and their human serum albumin glycation inhibitory activity. One of the compounds 5-(2H-1,3-benzodioxol-5-ylmethylidene)-3-cyclopropyl-2-(phenylimino)-1,3-thiazolidin-4-one (3) showed potent inhibition in the synthesis of initial, intermediary, and final products of glycation reactions. Besides, conformational changes in the α-helix and ß-sheet (due to hyperglycemia) were also found to be reversed upon the addition of (3). Experimental findings were complemented by computational [molecular docking, ADME/Tox, and density functional theory (DFT)] studies. The docking scores of the compounds were in order 1 > 3 > 2 > 4, indicating the importance of the polar group at the 5-arylidene moiety. The results of ADME/Tox and DFT calculations revealed the safe nature of the compounds with high drug-likeness and stability. Overall, we speculate that the results of this study could provide valuable insights into the biological activity of 4-thiazolidinones.

Directional preference for glioblastoma cancer cell membrane encapsulated nanoparticle population: A probabilistic approach for cancer therapeutics.

Background: Selective cancer cell recognition is the most challenging objective in the targeted delivery of anti-cancer agents. Extruded specific cancer cell membrane coated nanoparticles, exploiting the potential of homotypic binding along with certain protein-receptor interactions, have recently proven to be the method of choice for targeted delivery of anti-cancer drugs. Prediction of the selective targeting efficiency of the cancer cell membrane encapsulated nanoparticles (CCMEN) is the most critical aspect in selecting this strategy as a method of delivery. Materials and methods: A probabilistic model based on binding scores and differential expression levels of Glioblastoma cancer cells (GCC) membrane proteins (factors and receptors) was implemented on python 3.9.1. Conditional binding efficiency (CBE) was derived for each combination of protein involved in the interactions. Selective propensities and Odds ratios in favour of cancer cells interactions were determined for all the possible combination of surface proteins for 'k' degree of interaction. The model was experimentally validated by two types of Test cultures. Results: Several Glioblastoma cell surface antigens were identified from literature and databases. Those were screened based on the relevance, availability of expression levels and crystal structure in public databases. High priority eleven surface antigens were selected for probabilistic modelling. A new term, Break-even point (BEP) was defined as a characteristic of the typical cancer cell membrane encapsulated delivery agents. The model predictions lie within ±7% of the experimentally observed values for both experimental test culture types. Conclusion: The implemented probabilistic model efficiently predicted the directional preference of the exposed nanoparticle coated with cancer cell membrane (in this case GCC membrane). This model, however, is developed and validated for glioblastoma, can be easily tailored for any type of cancer involving CCMEN as delivery agents for potential cancer immunotherapy. This probabilistic model would help in the development of future cancer immunotherapeutic with greater specificity.

Increased Levels of Autoantibodies against ROS-Modified Proteins in Depressed Individuals with Decrease in Antibodies against SARS-CoV-2 Antigen (S1-RBD).

Coronavirus 2019 (COVID-19) disease management is highly dependent on the immune status of the infected individual. An increase in the incidence of depression has been observed during the ongoing COVID-19 pandemic. Autoantibodies against in vitro reactive oxygen species (ROS) modified BSA and Lys as well as antibodies against receptor binding domain subunit S1 (S1-RBD) (S1-RBD-Abs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were estimated using direct binding and competition ELISA. Serum samples were also tested for fasting blood glucose (FBG), malondialdehyde (MDA), carbonyl content (CC), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Significant structural changes were observed in ROS modified BSA and Lys. Female depressed subjects who were also smokers (F-D-S) showed the highest levels of oxidative stress (MDA and CC levels). Similarly, increased levels of autoantibodies against ROS modified proteins were detected in F-D-S subjects, in males who were depressed and in smokers (M-D-S) compared to the other subjects from the rest of the groups. However, contrary to this observation, levels of S1-RBD-Abs were found to be lowest in the F-D-S and M-D-S groups. During the pandemic, large numbers of individuals have experienced depression, which may induce excessive oxidative stress, causing modifications in circulatory proteins. Thus, the formation of neo-antigens is induced, which lead to the generation of autoantibodies. The concomitant effect of increased autoantibodies with elevated levels of IFN-γ and TNF-α possibly tilt the immune balance toward autoantibody generation rather than the formation of S1-RBD-Abs. Thus, it is important to identify individuals who are at risk of depression to determine immune status and facilitate the better management of COVID-19.

Presence of Circulatory Autoantibodies Against ROS-Modified Histone H1 Protein in Lymphoma Patients.

Lymphoma is a chronic inflammatory disease in which the immune system is highly affected. Increased oxidative stress is one of the common conditions of cancer and affects macromolecules. Histone modifications affect the chromatin structure and functions. In this study, histone H1 (His-H1) protein was modified by reactive oxygen species (ROS), and structural and chemical changes were studied. Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients were selected, and oxidative stress markers, inflammatory cytokines, and serum autoantibodies were analyzed using biochemical and immunological assays. Furthermore, the formation of antigen-antibody immune complexes was assessed by the Langmuir plot. ROS-modified His-H1 (ROS-His-H1) showed substantial structural perturbation in protein (UV-hyperchromicity and increased intrinsic fluorescence) compared to the native His-H1 protein. A possible explanation for the changes is suggested by the exposure of the aromatic chromophore to the solvent. In-depth structural analysis by circular dichroism (CD) exhibited major changes in α-helix (-21.43%) and turns (+33%), reflecting changes in the secondary structure of histone H1 protein after ROS exposure. ELISA and competitive ELISA findings revealed high recognitions of serum autoantibodies to ROS-His-H1 from NHL, followed by HL subjects. Healthy controls showed negligible binding. Non-modified His-H1 did not show any binding with serum samples from either cohort. High apparent association constants (ACCs) were calculated for ROS-His-H1 using purified IgGs from NHL (1.46 × 10-6 M) compared to HL (1.33 × 10-6 M) patients. Non-modified His-H1 exhibited a hundred times less ACC for NHL (2.38 × 10-8 M) and HL (2.46 × 10-8 M) patients. Thus, ROS modifications of histone H1 cause structural changes and expose cryptic neo-epitopes on the protein against which autoantibodies were generated. These perturbations might affect the histone DNA interaction dynamics and potentially be correlated with gene dysregulation. These subtle molecular changes with an immune imbalance might further aggravate the disease.

Seroprevalence of Anti-S1-RBD Antibodies in Pre-pandemic and Pandemic Subjects From Hail Region, KSA.

Background: Two years into the pandemic, yet the threat of new SARS-CoV-2 variants continues to loom large. Sustained efforts are required to fully understand the infection in asymptomatic individuals and those with complications. Identification, containment, care, and preventative strategies rely on understanding the varied humoral immune responses. Methods: An in-house ELISA was developed and standardized to screen for serum IgG antibodies against the SARS-CoV-2 S1-RBD protein as an antigen. This study aims to investigate the seroprevalence of serum antibodies against S1-RBD antigen in pre-pandemic (n = 120) and during the early pandemic period (n = 120) in subjects from the Hail region, KSA and to correlate it with clinical and demographic factors. Results: Samples collected from both male (n = 60) and female (n = 60) subjects during the pandemic in the age groups of 20-40 (0.31 ± 0.029 and 0.29 ± 0.024, respectively) and 41-60 years (0.35 ± 0.026 and 0.30 ± 0.025, respectively) showed significantly higher levels of serum antibodies against S-RBD antigen than the age-matched pre-pandemic samples [male (n = 60) and female (n = 60)]. Pandemic subjects exhibited significantly (p < 0.01) higher inhibition (80-88%) than age-matched pre-pandemic subjects (32-39%). Antibodies against S1-RBD antigen were detected in approximately 10% of the total pre-pandemic population (males and females). However, subjects > 60 years did not show antibodies. Conclusion: Antibody levels increased in samples collected during the pandemic, even though these subjects were not clinically COVID-19 positive. A small number of pre-pandemic subjects showed serum antibodies, suggesting prior exposure to other coronaviruses in the region. With dwindling neutralizing antibody levels and reduced vaccine efficacy against newer variants, it remains crucial to develop better assays for surveillance, management, and future research.

CRISPR/Cas9 and next generation sequencing in the personalized treatment of Cancer.

BACKGROUND: Cancer is caused by a combination of genetic and epigenetic abnormalities. Current cancer therapies are limited due to the complexity of their mechanism, underlining the need for alternative therapeutic approaches. Interestingly, combining the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9) system with next-generation sequencing (NGS) has the potential to speed up the identification, validation, and targeting of high-value targets. MAIN TEXT: Personalized or precision medicine combines genetic information with phenotypic and environmental characteristics to produce healthcare tailored to the individual and eliminates the constraints of "one-size-fits-all" therapy. Precision medicine is now possible thanks to cancer genome sequencing. Having advantages over limited sample requirements and the recent development of biomarkers have made the use of NGS a major leap in personalized medicine. Tumor and cell-free DNA profiling using NGS, proteome and RNA analyses, and a better understanding of immunological systems, are all helping to improve cancer treatment choices. Finally, direct targeting of tumor genes in cancer cells with CRISPR/Cas9 may be achievable, allowing for eliminating genetic changes that lead to tumor growth and metastatic capability. CONCLUSION: With NGS and CRISPR/Cas9, the goal is no longer to match the treatment for the diagnosed tumor but rather to build a treatment method that fits the tumor exactly. Hence, in this review, we have discussed the potential role of CRISPR/Cas9 and NGS in advancing personalized medicine.

Biologically Active α-Amino Amide Analogs and γδ T Cells-A Unique Anticancer Approach for Leukemia.

Advanced stage cancers are aggressive and difficult to treat with mono-therapeutics, substantially decreasing patient survival rates. Hence, there is an urgent need to develop unique therapeutic approaches to treat cancer with superior potency and efficacy. This study investigates a new approach to develop a potent combinational therapy to treat advanced stage leukemia. Biologically active α-amino amide analogs (RS)-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenylpropiolamide (α-AAA-A) and (RS)-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenylbut2-enamide (α-AAA-B) were synthesized using linear Ugi multicomponent reaction. Cytotoxicities and IC50 values of α-AAA-A and α-AAA-B against leukemia cancer cell lines (HL-60 and K562) were analyzed though MTT assay. Cytotoxic assay analyzed percent killing of leukemia cell lines due to the effect of γδ T cells alone or in combination with α-AAA-A or α-AAA-B. Synthesized biologically active molecule α-AAA-A exhibited increased cytotoxicity of HL-60 (54%) and K562 (44%) compared with α-AAA-B (44% and 36% respectively). Similarly, α-AAA-A showed low IC50 values for HL-60 (1.61 ± 0.11 µM) and K562 (3.01 ± 0.14 µM) compared to α-AAA-B (3.12 ± 0.15 µM and 6.21 ± 0.17 µM respectively). Additive effect of amide analogs and γδ T cells showed significantly high leukemia cancer cell killing as compared to γδ T cells alone. A unique combinational therapy with γδ T cells and biologically active anti-cancer molecules (α-AAA-A/B), concomitantly may be a promising cancer therapy.

Optimization of methods for peripheral blood mononuclear cells isolation and expansion of human gamma delta T cells.

Human Vg9/Vδ2 T cells (γδ T cells) are immune surveillance cells both in innate and adaptive immunity and are a possible target for anticancer therapies, which can induce immune responses in a variety of cancers. Small non-peptide antigens such as zoledronate can do activation and expansion of T cells in vitro. It is evident that for adoptive cancer therapies, large numbers of functional cells are needed into cancer patients. Hence, optimization of methods needs to be carried out for the efficient expansion of these T cells. Standardization of peripheral blood mononuclear cells (PBMCs) isolation was devised. Cytokines (interleukin 2 (IL-2) and interleukin 15 (IL-15)) and zoledronate were also standardized for different concentrations. It was found that an increased number of PBMCs were recovered when washing was done at 1100 revolution per minute (rpm). Significantly high expansion fold was (2524 ± 787 expansion fold) achieved when stimulation of PBMCs was done with 1 µM of zoledronate and both cytokines IL-2 and IL-15 supported the expansion and survival of cells at the concentrations of 100 IU/ml and 10 ng/ml respectively. 14-day cultures showed highly pure (91.6 ± 5.1%) and live (96.5 ± 2.5%) expanded γδ T cells. This study aimed to standardize an easy to manipulate technique for the expansion of γδ T cells, giving a higher yield.

Combinational therapeutics to combat cancer.

Mono-therapeutics is rarely effective as a treatment option, which limits the survival of patients in advanced grade aggressive cancers. Combinational therapeutics (multiple drugs for multiple targets) to combat cancer is gaining momentum in recent years. Hence, it is of interest to document known data for combinational therapeutics in cancer treatment. An amalgamation of therapeutic agents enhances the efficacy and potency of the therapy. Combinational therapy can potentially target multiple pathways that are necessary for the cancer cells to proliferate, and/or target molecules, which may help cancer to become more aggressive and metastasize. In this review, we discuss combinational therapeutics, which include human γδ T cells in combinations with biologically active anti-cancer molecules, which synergistically may produce promising combinational therapeutics.

Cytokine Response in SARS-CoV-2 Infection in the Elderly.

The last few months of 2019 witnessed the emergence, rise and rapid spread of a novel coronavirus known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing an acute respiratory disease called coronavirus disease 2019 or Covid-19. Severe pathological manifestations of the disease in the infected population with comorbidities are linked to acute respiratory distress syndrome (ARDS), associated with an exaggerated synthesis and expression of cytokines, leading to a systemic inflammatory response also known as a cytokine storm (CS). Elderly patients (>60 years of age) showed more deaths in Covid-19 infection. Age-related immune imbalance increases patient susceptibility to CS. In acute Covid-19 infection, it is difficult to minimize or control the overproduction of cytokines; hence, limited medical treatments are effective. This review aims to provide an overview of the current knowledge of involvement of cytokines in SARS-CoV-2 infection, susceptibility factors for the accompanying cytokine storm in severe Covid-19 cases and possible treatment strategies.

Endometrial cancer patients have high affinity antibodies for estrogen metabolite-receptor aggregate: A potential biomarker for EC.

AIM: Elevated levels of 16α-hydroxyestrone (16α-OHE1 ) have been described in endometrial cancer (EC) and estrogen receptors (ER) expressed in endometrial tissue, but research on their combined role is lacking. We aimed to investigate the affinity and binding specificity of EC antibodies against the 16α-OHE1 -ERα aggregate in the serum of EC patients. Specificities of EC antibodies were also evaluated according to various clinical characteristics found in these cancer patients. METHODS: The binding specificity and affinity of EC antibodies against 16α-OHE1 -ERα in the serum of 120 EC patients were evaluated by direct binding and competition ELISA and quantitative precipitation titration. Binding of EC antibodies was also determined according to various clinical characteristics in EC patients through competition ELISA. RESULTS: Antibodies from EC patients demonstrated high recognition of 16α-OHE1 -ERα compared to ERα (P < 0.05) or 16α-OHE1 (P < 0.001). The relative affinity of EC IgG was 1.49 × 10-7 M, 1.34 × 10-6 M and 1.13 × 10-6 M for 16α-OHE1 -ERα, ERα and 16α-OHE1 , respectively. Several factors, such as obesity, postmenopausal status, use of hormonal therapy, ER and progesterone receptor (PR) status, low 2-OHE1 /16α-OHE1 ratio, chemotherapy and hypertension, augment the production of antibodies against 16α-OHE1 -ERα in EC patients. CONCLUSION: 16α-OHE1 -ERα is a high-affinity antigen for EC antibodies in the serum of EC patients and might function as a biomarker for this disease. Furthermore, several factors enhanced the production of antibodies against 16α-OHE1 -ERα in the sera of these EC patients.

Estrogenization of insulin by catecholestrogen produced high affinity autoantibodies and altered the normal function of insulin in type 1 diabetes.

AIMS: Insulin (Ins) covalently modified by catecholestrogens (CEs) was commonly found in diabetic patients who have developed insulin resistance. Estrogenization of insulin altered its molecular function and effect carbohydrates metabolisms in these patients. Insulin resistance is a common phenomenon in diabetes but the exact mechanism remains unknown. In this study, binding specificity and affinity of autoantibodies against estrogenized insulin (4-hydroxyestradiol-insulin; 4-OHE2-Ins) were assayed in the serum of type 1 diabetes (T1D) patients in order to explain the phenomena behind insulin resistance. MATERIALS AND METHODS: Specificity and affinity of autoantibodies from the sera of 66 T1D patients and 41 controls were analyzed by direct binding, competition ELISA and quantitative precipitin titration. Insulin was also estimated in the serum of T1D patients by ELISA. KEY FINDING: Estrogenized insulin (4-OHE2-Ins) exhibited high affinity and specificity to T1D autoantibodies in comparison to Ins (p < .05) or 4-OHE2 (p < .001). Estrogenization of insulin alters its interaction with the insulin receptor (IR). The affinity constant of 4-OHE2-Ins with the T1D autoantibodies was found to be 1.41 × 10-7 M. SIGNIFICANCE: Estrogenization of insulin by catecholestrogen makes these molecules highly antigenic and produced high-affinity autoantibodies in T1D patients. As a result, patients develop insulin resistance and presented this molecule as a potential biomarker for T1D.

Depression linked to higher antibodies production against estrogenized insulin in type 1 diabetes.

Depression has been commonly associated with type 1 diabetes (T1D) and insulin covalently modified with catecholestrogens (CEs) was found in serum of these T1D patients. This study aimed to know whether depression link to higher antibodies against estrogenized insulin in T1D. ELISA (direct binding and competition) and quantitative precipitin titration were used to detect antibodies and their affinities against estrogenized insulin in the serum of 66 depressed T1D (DT1D) patients (out of 110 T1D) and 41 control subjects. Antibodies from DT1D patients showed high binding specificity to estrogenized insulin (2-hydroestradiol-insulin; 2-OHE2-Ins) in comparison to overall T1D patients (p < 0.05) or control subjects (p < 0.001). However, T1D sera demonstrate high recognition to 2-OHE2-Ins as compared to Ins (p < 0.05) or 2-OHE2 (p < 0.001). The affinity of antibodies from DT1D and T1D patients was 1.32 × 10-7 M and 1.43 × 10-7 M, respectively. Depression linked to higher antibodies production against estrogenized insulin in T1D. Furthermore, depression in T1D generates inflammatory conditions that further increased antibodies production in T1D patients.

Correlations between Direct and Calculated Low-Density Lipoprotein Cholesterol Measurements in Children and Adolescents.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C), as a modifiable risk factor for atherosclerotic cardiovascular disease, should be assessed and monitored. This study compared directly measured and Friedewald-estimated LDL-C values in children and adolescents. METHODS: Blood samples were collected from 464 children and adolescents. Calculated LDL-C (CLDL-C) levels were estimated using the Friedewald formula for any triglyceride value below 4.6 mmol/L. Direct LDL-C (DLDL-C) levels were measured on an ARCHITECT c8000 Abbott Clinical Chemistry Analyzer. The differences in LDL-C were then calculated. RESULTS: The correlation coefficients (R) between DLDL-C and CLDL-C were 0.978 (P = .148) and R = 0.970 (P = .052) for children and adolescents, respectively. Children with LDL-C values above 4.92 mmol/L had a correlation value of 0.971 (P = .419). The correlation and agreement between DLDL-C and CLDL-C in adolescents were moderate for LDL-C below 2.85 mmol/L (R = 0.806; 84.1%) and improved above 2.85 mmol/L (R = 0.978; 91.5%). In children, good correlations between DLDL-C and CLDL-C were observed for normal (<0.85 mmol/L), borderline (0.85-1.12 mmol/L), and abnormal (≥1.13 mmol/L) triglyceride levels (R = 0.9782, 0.990, and 0.951, respectively). The rates of agreement were better for normal (80.5%) and borderline (82.9%) but not abnormal (68.2%) triglyceride levels. CONCLUSION: We observed good agreement between DLDL-C and CLDL-C in both children and adolescents. The Friedewald formula provided an adequate estimate of LDL-C for most fasting specimens. LDL-C difference percentage can also be used as a quality indicator to check laboratory analyzer performance in healthy subjects.

Dicarbonyls Generation, Toxicities, Detoxifications and Potential Roles in Diabetes Complications.

It has been well established that advanced glycation end-products (AGEs) have a strong correlation with diabetes and its secondary complications. Moreover, dicarbonyls, especially, methylglyoxal (MG) and glyoxal, accelerate AGEs formation and hence, have potential roles in the pathogenesis of diabetes. They can also induce oxidative stress and concomitantly decrease the efficiency of antioxidant enzymes. Increased proinflammatory cytokines (tumor necrosis factor-α and interleukin- 1ß) are secreted by monocytes due to the dicarbonyl-modified proteins. High levels of blood dicarbonyls have been identified in diabetes and its associated complications (retinopathy, nephropathy and neuropathy). This review aims to provide a better understanding by including in-depth information about the formation of MG and glyoxal through multiple pathways with a focus on their biological functions and detoxifications. The potential role of these dicarbonyls in secondary diabetic complications is also discussed.

Depression and its related parameters increased the production of autoantibodies against 16α-hydroxyestrone-albumin complex in systemic lupus erythematosus.

Depression is the common and early symptoms associated with early onset of SLE, 16α-hydroxyestrone (16α-OHE1) levels were found to be significantly higher in serum and urine in patients with SLE. This study was carried out in order to know whether depression and its related parameters in the SLE patients enhanced the production of autoantibodies against 16α-OHE1-albumin (A) complexes. The autoantibodies in the serum of 100 SLE [including 65 depressed SLE (DSLE)] patients and 37 control subjects were detected by using direct binding, inhibition ELISA and quantitative precipitin titration. Autoantibodies from DSLE patients (and also the patients who were taken anti-depressant and with neurological symptoms) showed high binding to 16α-OHE1-A in contrast to SLE (p < 0.05) and control subjects (p < 0.001). Although, SLE sera showed high recognition to 16α-OHE1-A in comparison to A (p < 0.05) or 16α-OHE1 (p < 0.001). The affinity of autoantibodies for 16α-OHE1-A was found to be high for DSLE (1.16 × 10-7 M) and SLE (1.24 × 10-7 M) patients as detected by Langmuir plot. The concentration of 16α-OHE1 (p < 0.05) and inflammatory cytokines (IL-6, p < 0.05 and IL-17, p < 0.001) in the serum of SLE patients was found to be significantly higher than controls. Depression and its related parameters in SLE enhanced the production of autoantibodies against 16α-OHE1-A through the generation of inflammatory conditions. Depression in SLE patients increased the release of pro-inflammatory cytokine (IL-6 and IL-17) that in turn generating more autoantibodies and showed strong recognition to 16α-OHE1-A.

Depression enhanced the production of autoantibodies against 16α­hydroxyestrone-estrogen receptor adduct in breast cancer.

Mentally depressed breast cancer (MDBC) patients expressed estrogen receptor (ER) and 16α­hydroxyestrone (16α­OHE1) is directly responsible for causing breast cancer (BC). This study aimed to identify whether depression in breast cancer patients enhanced the production of autoantibodies against 16α­OHE1-ER adduct in breast cancer patients. The antibodies in the serum of 65 breast cancer patients (including 35 MDBC) and 40 control subjects were screened by direct binding, inhibition enzyme-linked immunosorbent assay (ELISA), and quantitative precipitin titration. Competition ELISA was also utilized for the estimation of 16α­OHE1 in the serum of 30 cancer patients. Autoantibodies from MDBC showed strong recognition to 16α­OHE1-ER in comparison to overall breast cancer patients (p < 0.05) and control subjects (p < 0.001). Although breast cancer sera showed high binding to 16α­OHE1-ER in comparison to ER (p < 0.05) or 16α­OHE1 (p < 0.001), the relative affinities of autoantibodies for 16α­OHE1-ER were found to be 1.38 × 10-7 and 1.23 × 10-7 for breast cancer and MDBC patients respectively. No significant difference, either in the level of 16α­OHE1 or 2­hydroxyestrone/16α­OHE1 ratio, was observed in the serum of cancer patients compared with controls, although inflammatory cytokines (IL-6, TNF-α) were significantly high in these patients. Depression in breast cancer patients augments the production of autoantibodies against 16α­OHE1-ER through the generation of inflammatory conditions. Depression in these patients increased the release of pro-inflammatory cytokines that generate more autoantibodies and show strong binding with 16α­OHE1-ER.

Cancer morbidity in rheumatoid arthritis: role of estrogen metabolites.

Estrogen metabolites have been implicated in rheumatoid arthritis (RA) and cancer, although the mechanism remains unestablished. Some estrogen metabolites, which are used for the assessment of cancer risk, play an important role in RA. The pathways by which malignancies associated with RA remain elusive. Possible mechanism involves enzymatic or nonenzymatic oxidation of estrogen into catecholestrogen metabolites through semiquinone and quinone redox cycle to produce free radicals that can cause DNA modifications. Modifications of DNA alter its immunogenicity and trigger various immune responses leading to elevated levels of cancer and RA antibodies. However, the role of different estrogen metabolites as a mediator of immune response cannot be ruled out in various immune-related diseases.