Cholesterol and Cytokines: Molecular Links to Atherosclerosis and Carcinogenesis.

An increase of cholesterol concentration within the artery obstructs arterial blood flow once it deposits alongside the arterial wall. This results in atherosclerosis. Carcinogenesis causes a quicker clearance of vascular cholesterol to meet the demands of tumour cell development. Both illnesses have an increased concentration of pro-inflammatory cytokines in the blood. To search the comparative characteristics of cholesterol and pro-inflammatory cytokines in the pathogenesis of atherosclerosis and carcinogenesis, a comprehensive online survey using MEDLINE, Scopus, PubMed, and Google Scholar was conducted for relevant journals with key search term cholesterol and cytokines in atherosclerotic and cancerous patients. According to reports, hypercholesterolaemia related dyslipidemia causes atherosclerosis in blood arteries and hypercholesterolaemia in cell nucleus is a reason for developing carcinogenesis. It is also noted that pro-inflammatory cytokines are involved in both of the aforementioned pathogenesis. Changes in anti-inflammatory cytokines are only the characteristic features of each kind. Thus, Cholesterol and pro-inflammatory cytokines are intensely interlinked in the genesis of atherosclerotic and carcinogenic consequences.

Obesity: An Impact with Cardiovascular and Cerebrovascular Diseases.

The authors sought to correlate the complex sequel of obesity with various parameters known to develop metabolic syndrome viz. insulin resistance, dyslipidemia, hypertension etc., as these anomalies are linked to vascular atherosclerosis and outbreak of cardiovascular and cerebrovascular diseases.  A comprehensive online survey using MEDLINE, Scopus, PubMed and Google Scholar was conducted for relevant journals from 1970 till present time (2023) with key search terms like: 'obesity', 'leptin', type-2 diabetes', 'atherosclerosis', 'cardiovascular and cerebrovascular diseases'. The findings of the reports were compared and correlated. The information was then collated for developing this review. Reports showed that in human obesity, hyper-leptinemia could induce hyperglycemia, which in turn templates hypercholesterolemia. Persisting hypercholesterolemia over a period of time may en-route atherosclerosis in blood vessels. Thus obesity has been considered as a template for originating hyperglycemia, hypercholesterolemia and outbreak of vascular atherogenesis or in other words, obesity in long run can trigger atherosclerosis and its related disorders e.g. heart attack and stroke. Literature survey shows that primarily, co-morbidities of human obesity start with leptin and insulin resistance and then multiplies with metabolic irregularities to an extreme that results in pathogenesis of heart attack and stroke. Atherosclerosis associated cardiovascular and cerebrovascular events are independent risks of obese subjects and particularly in the cases of persisting obesity.

A Pilot Study on Blood Components in COVID-19 Affected Subjects: A Correlation to UPR Signalling and ER-Stress.

Abstract: The endoplasmic reticulum (ER) is the site for protein synthesis, its folding and secretion. An intricate set of signalling pathways, called UPR pathways, have been evolved by ER in mammalian cells, to allow the cell to respond the presence of misfolded proteins within the ER. Breaching of these signalling systems by disease oriented accumulation of unfolded proteins may develop cellular stress. The aim of this study is to explore whether COVID-19 infection is responsible for developing this kind of endoplasmic reticulum related stress (ER-stress). ER-stress was evaluated by checking the expression of ER-stress markers e.g. PERK (adapting) and TRAF2 (alarming). ER-stress was correlated to several blood parameters viz. IgG, pro- and anti-inflammatory cytokines, leukocytes, lymphocytes, RBC, haemoglobin and PaO2/FiO2 ratio (ratio of arterial oxygen partial pressure to fractional inspired oxygen) in COVID-19 affected subjects. COVID-19 infection was found to be a state of protein homeostasis (proteostasis) collapse. Changes in IgG levels showed very poor immune response by the infected subjects. At the initial phase of the disease, pro-inflammatory cytokine levels were high and anti-inflammatory cytokines levels were low; though they were partly compromised at later phase of the disease. Total leukocyte concentration increased over the period of time; while percentage of lymphocytes were dropped. No significant changes were observed in cases of RBC counts and haemoglobin (Hb) levels. Both RBC and Hb were maintained at their normal range. In mildly stressed group, PaO2/FiO2 ratio (oxygenation status) was in the higher side of normal range; whereas in other two groups the ratio was in respiratory distress syndrome mode. Virus could induce mild to severe ER-stress, which could be the cause of cellular death and systemic dysfunction introducing fatal consequences. Graphical Abstract: Schematic representation of SARS-CoV-2 infection and related consequences.

A Pilot Study on COVID-19 Positive Subjects: An Excerpt of Post-Infection-Pro-Diabetic Disposition & Related Consequences in Correlation to Hepato-Pancreatic Bio-Markers, Pro-Inflammatory Cytokines and Other Risk Factors.

COVID-19, a global pandemic that led to increased morbidity and mortality worldwide since its outcome at the end of the year 2019. A newly discovered variant of severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) was the arbitrator for spreading the syndrome by droplet transmission causing multi-organ failure in many occasions. A post-infection-pro-diabetic disposition was found evident in this study with the persistence of hepato-pancreatic aberrations in respect of reference range of tissue specific bio-markers in hospital admitted COVID-19 cases. The results of this study show that hyperglycemia is a risk factor in precipitating disease oriented complications to the patients with COVID-19 disease. A post-infection follow- up on glycemic-index and related complexities is a vital need to the COVID-19 infected convalescent subjects. Implementation of guidelines on social measure and awareness of anti-viral interventions may be the only way to prevent COVID-19 transmission.

Withdrawal Notice: Obesity: A template to trigger metabolic syndromes and carcinoma. Metformin: A drug target

The article has been withdrawn at the request of the authors and editor of the journal "Current Drug Targets" due to incoherent content.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php. BENTHAM SCIENCE DISCLAIMER: It is a condition of publishers that manuscripts submitted to this journal should not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and while submit- ting the article for publication, the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is trans-ferred to the publishers, if and when the article is accepted for publication.

Cholesterol: A Prelate in Cell Nucleus and its Serendipity.

Cholesterol is a chameleon bio-molecule in cellular multiplex. It acts as a prelate in almost every cellular compartment with its site specific characteristics viz. regulation of structural veracity and scaffold fluidity of bio-membranes, insulation of electrical transmission in nerves, controlling of genes by making steroid endocrines, acting as precursors of metabolic regulators and many more with its emerging prophecy in the cell nucleus to drive new cell formation. Besides the crucial legacy in cellular functionality, cholesterol is ostracized as a member of LDL particle, which has been proved responsible to clog blood vessels. LDL particles get deposited in the blood vessels because of their poor clearance owing to the non-functioning LDL receptor on the vessel wall and surrounding tissues. Blocking of blood vessel promotes heart attack and stroke. On the other hand, cholesterol has been targeted as pro-cancerous molecule. At this phase again cholesterol is biphasic. Although cholesterol is essential to construct nuclear membrane and its lipid-rafts; in cancer tumour cells, cholesterol is not under the control of intracellular feedback regulation and gets accumulated within cell nucleus by crossing nuclear membrane and promoting cell proliferation. In precancerous stage, the immune cells also die because of the lack of requisite concentration of intracellular and intranuclear cholesterol pool. The existence of cholesterol within the cell nucleus has been found in the nuclear membrane, epichromosomal location and nucleoplasm. The existence of cholesterol in the microdomain of nuclear raft has been reported to be linked with gene transcription, cell proliferation and apoptosis. Hydrolysis of cholesterol esters in chromosomal domain is linked with new cell generation. Apparently, Cholesterol is now a prelate in cell nucleus too ------ A serendipity in cellular haven.

Differential Response of B Cells to an Immunogen, a Mitogen and a Chemical Carcinogen in a Mouse Model System

Background: B cells are specific antibody generating cells which respond to foreign intruders in the circulation. The purpose of this study was to compare the relative immunogenic potentials of three well established agent types viz. an immunogen, a mitogen and a carcinogen, by following B cell responses to their presence in a mouse model system. Methods: Mice were treated with tetanus toxoid (immunogen), poke weed mitogen (typical mitogen), and benzo-α- pyrene (carcinogen) and generated B cell populations were determined in isolated splenic lymphocytes (splenocytes) by flow cytometry using specific anti-B cell marker antibodies. Flow cytometric estimation of LDL receptor (LDLR) expression, along with associated B cell markers, was also conducted. Kit based estimation of serum IgG, western blotting for LDLR estimation on total splenocytes and spectrometry for cholesterol and serum protein estimation were further undertaken. Student's T-tests and one way ANOVA followed by the Bonferroni method were employed for statistical analysis. Results: The mitogen was found to better stimulate B cell marker expression than the immunogen, although the latter was more effective at inducing antibody production. The chemical carcinogen benzo-α-pyrene at low concentration acted potentially like a mitogen but almost zero immunity was apparent at a carcinogenic dose, with a low profile for LDLR expression and intracellular cholesterol. Conclusion: The findings in our study demonstrate an impact of concentration of BaP on generation of humoral immunity. Probably by immunosuppression through restriction of B-cell populations and associated antibodies, benzo-α-pyrene may exerts carcinogenicity. The level of cholesterol was found to be a pivotal target.

Cholesterol Homeostasis in Isolated Lymphocytes: a Differential Correlation Between Male Control and Chronic Lymphocytic Leukemia Subjects

Background: This study was performed to investigate any association between cellular cholesterol homeostasis and chronic lymphocytic leukemia (CLL). CLL is characterized primarily by an abnormal accumulation of neoplastic B cells in the blood, bone marrow, lymph nodes and spleen. Methods: Men aged >50 years participated in this study. Enzyme-based plasma lipid profile estimations, peripheral blood lymphocyte isolation, lysate preparations, SDS-PAGE, western blotting, dil-LDL uptake and ultracentrifugation were employed. Results: Our study demonstrated hypocholesterolemia in lymphocytic leukemia in addition to hyper-expression of LDLRs in leukemic lymphocytes. Breakdown of intracellular cholesterol homeostasis and failure to maintain the feedback mechanism normally processed by the transcription factor SREBP-2 in the cytoplasm was apparent. The presence of cholesterol in the nucleus was noted in leukemic lymphocytes. A comparison of cholesterol homeostasis between healthy controls and CLL subjects showed that cholesterol may contribute to lymphocytic leukemia. While plasma cholesterol levels decreased (p < 0.0005), hyper-expression of LDLR (p=0.0001), SREBP-2 (transcription factor of LDLR) (p=0.0001) and PBR (nuclear cholesterol channel protein) (p=0.016) was observed in lymphocytes isolated from CLL subjects in association with a significant increase in intracellular cholesterol in the nuclear (p=0.036) and cytoplasmic (p=0.004) compartments. Conclusion: This study provided insights into cholesterol homeostasis in CLL subjects regarding LDLR, SREBP-2 and PBR. Cholesterol may enter the nucleus through highly expressed PBR and may be involved in development of leukemia by influencing cell cycle mechanisms in the lymphocytes of CLL subjects.

Interlink between cholesterol & cell cycle in prostate carcinoma.

Background & objectives: Earlier reports have shown hypocholesterolaemia in cancer patients and high number of lipid rafts in cancer cells. The primary objective of this study was to compare the intracellular cholesterol turnover in non-cancerous (benign) prostatic hyperplasia (BPH) and carcinoma prostate (CAP) with normal prostate cells obtained from patients undergoing radical cystectomy for carcinoma bladder (sham control). Methods: ELISA-based estimation of prostate-specific antigen (PSA), evaluation of expression of low-density lipoprotein receptor (LDLR), peripheral-type benzodiazepine receptor (PBR) and cyclin E, immunohistochemistry and confocal microscopy, measurement of integrated optical density of the diaminobenzidine (DAB)-stained immunohistograms, isolation of nucleus and cell cytoplasm from prostate tissue by ultracentrifugation followed by estimation of cholesterol spectrophotometrically in isolated nuclear and cytoplasmic fractions were performed. Results: Seventy five individuals, 25 for each group (BPH n=25; CAP n=25 and sham control n=25), were included in the study. Cholesterol was increased in the cytoplasm and nucleus of the prostate cancer cells along with elevated expression of LDLR. Increased cholesterol concentration in the cell nucleus was found comparable with the increased expression of cholesterol transporter viz. PBR in the prostate tumour tissues as compared to its expression in normal prostate cells obtained from individuals undergoing radical cystectomy for carcinoma bladder. Cell cycle protein cyclin E was also highly expressed in cancer tissues. Interpretation & conclusions: The present findings along with increased expression of cell cycle protein cyclin E in the cell nucleus of the tumour tissue suggested the possibility of an intriguing role of cholesterol in the mechanism of cell cycle process of prostate cell proliferation.

Lectin-like Oxidized Low-Density Lipoprotein (LDL) Receptor (LOX-1): A Chameleon Receptor for Oxidized LDL.

LOX-1, one of the main receptors for oxLDL, is found mainly on the surface of endothelial cells. It is a multifacet 52 kDa type II transmembrane protein that structurally belongs to the C-type lectin family. It exists with short intracellular N-terminal and long extracellular C-terminal hydrophilic domains separated by a hydrophobic domain of 26 amino acids. LOX-1 acts like a bifunctional receptor either showing pro-atherogenicity by activating the NFκB-mediated down signaling cascade for gene activation of pro-inflammatory molecules or playing an atheroprotective agent by receptor-mediated uptake of oxLDL in the presence of an anti-inflammatory molecule like IL-10. Mildly, moderately, and highly oxidized LDL show their characteristic features upon LOX-1 activation and its ligand binding indenture. The polymorphic LOX-1 genes are intensively associated with increased susceptibility to myocardial diseases. The splicing variant LOX IN dimerizes with the native form of LOX-1 and protects cells from damage by oxidized LDL. In the developing field of regenerating medicine, LOX-1 is a potential target for therapeutic intervention.

Reciprocal coordination of a combination oral contraceptive containing desogestrel+ethinyl estradiol on the expression of LOX-1 and LDLR in placental trophoblast cells.

BACKGROUND: The aim of this study was to assess the consistency of antiatherosclerotic potential of a combination oral contraceptive steroid (ethinyl estradiol+desogestrel) by rating its effect on the differential expression of the low-density lipoprotein receptor (LDLR) and lectin-like oxidized LDL (LOX-1) receptor. STUDY DESIGN: Cells from placental trophoblast cell line (JAR) and differentiated primary placental trophoblast cells isolated from term human placentae were used for this study. Expressions of LOX-1 and LDLR were assessed by immunoblot and immunocytochemistry assays. Differential effects of the constituent steroids in the combination of ethinyl estradiol and desogestrel were verified on the expression profile of the receptors. RESULTS: Desogestrel opposed the effect of ethinyl estradiol on LOX-1 expression, and when used in combination, the combination oral contraceptive reduced the expression of LOX-1 in contrast to LDLR. The characteristic change in the expressions of LOX-1 and LDLR showed an antiatherosclerotic improvisation at the unique combination of ethinyl estradiol (10 ng/mL) and desogestrel (20 ng/mL). CONCLUSION: The aforesaid combination of ethinyl estradiol and desogestrel keeps LOX-1 and LDLR reciprocally expressed in antiatherosclerotic mode.

Effect of a combination oral contraceptive (desogestrel+ethinyl estradiol) on the expression of low-density lipoprotein receptor and its transcription factor (SREBP2) in placental trophoblast cells.

BACKGROUND: This in vitro study deals with the effect of a combination oral contraceptive steroid - desogestrel and ethinyl estradiol - on the expression of low-density lipoprotein receptor (LDLR) and its transcription factor (SREBP2) in assessing the functional effectiveness of the LDLR. STUDY DESIGN: Differentiated primary placental trophoblast cells isolated from term human placentae and cells from Jar cell line were used for the study. Low-density lipoprotein receptor and SREBP2 expressions were assessed by immunocytochemistry and immunoblot assays with and without combination contraceptive steroid challenge. Functional activity of LDLR was studied by rating the profile of cellular uptake of fluorescent Dil-LDL (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanin perchlorate-LDL). Quantitation of Dil-LDL was done spectrofluorometrically. RESULTS: Variation of concentration(s) of either of the components of a combination preparation (desogestrel and ethinyl estradiol) showed a comparable change in the expressions of LDLR and SREBP2 to attain their optimal levels. Maximum expression and a significant functional effectiveness were observed at a unique combination of desogestrel (20 ng/mL) and ethinyl estradiol (10 ng/mL). CONCLUSION: The stimulatory effect of a combination contraceptive steroid on LDLR expression is an associated phenomenon of the contraceptive-mediated stimulation of SREBP2 expression.

Study of low-density lipoprotein receptor regulation by oral (steroid) contraceptives: desogestrel, levonorgestrel and ethinyl estradiol in JEG-3 cell line and placental tissue.

BACKGROUND: The aim of this study was to compare in vitro the role of two oral contraceptives, desogestrel (a less androgenic derivative of levonorgestrel) and levonorgestrel--alone and in combination with ethinyl estradiol--on low-density lipoprotein (LDL) receptor regulation by assessing receptor protein expression and functional effectiveness. STUDY DESIGN: Placental tissue and cultured placental cells (JEG-3) were used to study the expression and endocytotic activity of LDL receptor protein. The expression of the receptor was assessed by immunocytochemistry and immunoblot assays with and without contraceptive challenge. Functioning activity of LDL receptor was studied by measuring the rate of uptake of LDL by placental cells. Quantification of LDL was based on the total cholesterol content of the lipoprotein. RESULTS: A combination of desogestrel (20 ng/mL of incubation medium) and ethinyl estradiol (10 ng/mL of incubation medium) maintained the LDL receptor at high level of expression and functioning mode. In contrast, the double-blind preparation of levonorgestrel (20 ng/mL) and ethinyl estradiol (10 ng/mL) had shown much lower expression as well as receptor-mediated LDL uptake. The concentration of contraceptives used in this study was similar to the prevailing concentration of oral contraceptives in clinical use. CONCLUSION: Higher expression of LDL receptor and enhanced rate of LDL uptake by the receptor protein projects the possibility that there might be less atherosclerosis-related disorders from the combination of desogestrol and ethinyl estradiol.

Familial homozygous hypercholesterolemia: report of two patients and review of the literature.

Familial homozygous hypercholesterolemia is a rare autosomal dominant, metabolic disorder caused by mutation in the gene, which encodes the synthesis of low-density lipoprotein receptors and is characterized by increased serum low-density lipoprotein cholesterol. Multiple types of xanthomas occur, such as tendinous, tuberous, xanthelasma, and sub-periosteal. Intertriginous xanthomas are rare but if present are pathognomonic of this disorder. We report two children with familial homozygous hypercholesterolemia who had multiple xanthomas including the intertriginous variety.