The role of inflammation in the development of type 2 diabetes mellitus (T2DM) related skin complications necessitates further investigation. This study aims to explore the correlation between inflammation and cutaneous alterations in T2DM, enhancing comprehension of underlying mechanism involved.

Utilizing bioinformatics, the GSE38396 and GSE92724 datasets were employed to identify differentially expressed genes (DEGs) and potential hub genes in T2DM-related skin inflammation. Subsequently, gene functional enrichment analysis was employed for functional annotation. Finally, we validated the regulatory impact of hub gene on inflammation during high glucose incubation using the in vitro model.

A comprehensive analysis identified 742 DEGs, including 9 hub genes and 4 potential biomarkers. Compared to the CON group, the expression of M2 macrophages was significantly upregulated in the T2DM group, while resting dendritic cells and eosinophils showed notable decreases, indicating a significant correlation with CEBPA. Furthermore, functional enrichment analysis revealed significant enrichment of DEGs in pathways linked to immunity and diabetes pathogenesis. Interestingly, overexpression of CEBPA demonstrated anti-inflammatory effects under hyperglycemic conditions, while silencing CEBPA expression appeared to worsen inflammation.

CEBPA emerges as a potential hub gene for skin inflammation in T2DM, shedding light on the underlying mechanisms of this condition.

Humans are perhaps evolutionarily engineered to get deeply addicted to sugar, as it not only provides energy but also helps in storing fats, which helps in survival during starvation. Additionally, sugars (glucose and fructose) stimulate the feel-good factor, as they trigger the secretion of serotonin and dopamine in the brain, associated with the reward sensation, uplifting the mood in general. However, when consumed in excess, it contributes to energy imbalance, weight gain, and obesity, leading to the onset of a complex metabolic disorder, generally referred to as diabetes. Type 2 diabetes mellitus (T2DM) is one of the most prevalent forms of diabetes, nearly affecting all age groups. T2DM is clinically diagnosed with a cardinal sign of chronic hyperglycemia (excessive sugar in the blood). Chronic hyperglycemia, coupled with dysfunctions of pancreatic β-cells, insulin resistance, and immune inflammation, further exacerbate the pathology of T2DM. Uncontrolled T2DM, a major public health concern, also contributes significantly toward the onset and progression of several micro- and macrovascular diseases, such as diabetic retinopathy, nephropathy, neuropathy, atherosclerosis, and cardiovascular diseases, including cancer. The current review discusses the epidemiology, causative factors, pathophysiology, and associated comorbidities, including the existing and emerging therapies related to T2DM. It also provides a future roadmap for alternative drug discovery for the management of T2DM.

Type 2 diabetes mellitus is a complex metabolic disorder characterized by insulin resistance and, subsequently, decreased insulin secretion. This condition is closely linked to obesity, a major risk factor that boosts the development of chronic systemic inflammation, which, in turn, is recognized for its crucial role in the onset of insulin resistance. Under conditions of obesity, adipose tissue, particularly visceral fat, becomes an active endocrine organ that releases a wide range of pro-inflammatory mediators, including cytokines, chemokines, and adipokines. These mediators, along with cluster of differentiation (CD) markers, contribute to the maintenance of systemic low-grade inflammation, promote cellular signaling and facilitate the infiltration of inflammatory cells into tissues. Emerging studies have indicated the accumulation of a new cell population in the adipose tissue in these conditions, known as myeloid-derived suppressor cells (MDSCs). These cells possess the ability to suppress the immune system, impacting obesity-related chronic inflammation. Given the limited literature addressing the role of MDSCs in the context of type 2 diabetes, this article aims to explore the complex interaction between inflammation, obesity, and MDSC activity. Identifying and understanding the role of these immature cells is essential not only for improving the management of type 2 diabetes but also for the potential development of targeted therapeutic strategies aimed at both glycemic control and the reduction in associated inflammation.

Autoimmune diseases are characterized by dysregulated immunity against self-antigens. Current treatment of autoimmune diseases largely relies on suppressing host immunity to prevent excessive inflammation. Other immunotherapy options, such as cytokine or cell-targeted therapies, have also been used. However, most patients do not benefit from these therapies as recurrence of the disease usually occurs. Therefore, more effort is needed to find alternative immune therapeutics. Schistosoma infection has been a significant public health problem in most developing countries. Schistosoma parasites produce eggs that continuously secrete soluble egg antigen (SEA), which is a known modulator of host immune responses by enhancing Th2 immunity and alleviating outcomes of Th1 and Th17 responses. Recently, SEA has shown promise in treating autoimmune disorders due to their substantial immune-regulatory effects. Despite this interest, how these antigens modulate human immunity demonstrates only limited pieces of evidence, and whether there is potential for Schistosoma antigens in other diseases in the future remains an unsolved question. This review discusses how SEA modulates human immune responses and its potential for development as a novel immunotherapeutic for autoimmune diseases. We also discuss the immune modulatory effects of other non-SEA schistosome antigens at different stages of the parasite's life cycle.

The aim of this study is to look into the clinical and biochemical outcomes of D3K2 supplementation in addition to nonsurgical periodontal treatment (NSPT) for patients suffering from diabetes mellitus (DM) and periodontitis.

Thirty-eight participants with DM and periodontitis were randomized into two different groups. The test group provided NSPT with D3K2 whereas the control group received NSPT with placebo. Clinical periodontal parameters were recorded and serum and gingival crevicular fluid (GCF) were sampled at baseline and at the third and the sixth months after treatment. Glycated hemoglobin A1c (HbA1c), fasting blood glucose (FBG), 25(OH)D3, parathyroid hormone (PTH), calcium (Ca) and magnesium (Mg) values were determined in blood samples. GCF and serum interleukin (IL)-1β and IL-10 levels were analyzed using enzyme-linked immunosorbent assay.

All clinical periodontal parameters were importantly decreased at the third and sixth months after treatment compared to baseline in both groups. At the sixth month, 25(OH)D3 levels in the test group were observed to be statistically significantly higher than in the control group (p = 0.02). Serum IL-1β showed a statistically significant decrease at the sixth month compared to baseline and the third month in control group.

According to this study, there is limited additional benefit of D3K2 given with NSPT in individuals with DM and periodontitis.

Breast cancer (BC) represents the most prevalent cancer in women at any age after puberty. From a pathogenetic prospective, despite a wide array of risk factors being identified thus far, poor metabolic health is emerging as a putative risk factor for BC. In particular, type 2 diabetes mellitus (T2DM) provides a perfect example bridging the gap between poor metabolic health and BC risk. Indeed, T2DM is preceded by a status of hyperinsulinemia and is characterised by hyperglycaemia, with both factors representing potential contributors to BC onset and progression. Additionally, the aberrant secretome of the dysfunctional, hypertrophic adipocytes, typical of obesity, characterised by pro-inflammatory mediators, is a shared pathogenetic factor between T2DM and BC. In this review, we provide an overview on the effects of hyperglycaemia and hyperinsulinemia, hallmarks of type 2 diabetes mellitus, on breast cancer risk, progression, treatment and prognosis. Furthermore, we dissect the role of the adipose-tissue-secreted adipokines as additional players in the pathogenesis of BC. Finally, we focus on microalgae as a novel superfood and a source of nutraceuticals able to mitigate BC risk by improving metabolic health and targeting cellular pathways, which are disrupted in the context of T2DM and obesity.

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. Drug-free and captopril-loaded hydrogels demonstrated excellent product stability and sterility. Rheology testing confirmed sol properties with low viscosity at ambient temperature and increased viscosity and gelation at 37 °C. Captopril-loaded hydrogels significantly inhibited Ang II production in comparison to drug-free hydrogels. DPN mice treated with captopril-loaded hydrogels displayed normalized mechanical sensitivity and reduced inflammation, without side-effects associated with systemic exposure. Our data demonstrate the feasibility of repurposing ACE inhibitors as locally delivered anti-inflammatories for the treatment of sensory deficits in DPN. To the best of our knowledge, this is the first example of a locally delivered ACE inhibitor for the treatment of DPN.

Type 2 diabetes mellitus (T2DM), a prevalent chronic metabolic disorder, is closely linked to persistent low-grade inflammation, significantly contributing to its development and progression. This review provides a comprehensive examination of the inflammatory mechanisms underlying T2DM, focusing on the role of the NLRP3 inflammasome and interleukin-1β (IL-1β) in mediating inflammatory responses. We discuss the therapeutic potential of IL-1 inhibitors and colchicine, highlighting their mechanisms in inhibiting the NLRP3 inflammasome and reducing IL-1β production. Recent studies indicate that these agents could effectively mitigate inflammation, offering promising avenues for the prevention and management of T2DM. By exploring the intricate connections between metabolic disturbances and chronic inflammation, this review underscores the need for novel anti-inflammatory strategies to address T2DM and its complications.

Pro-inflammatory markers are linked with the development and progression of type 2 diabetes mellitus and arterial stiffening. Pulse Wave Velocity (PWV) and Augmentation Index (Aix) are non-invasive standard markers of arterial elasticity and predictors of cardiovascular mortality and morbidity.

To investigate the effects of metformin alone and in combination with glimepiride on arterial elasticity, pro-inflammatory cytokines in black type 2 diabetes mellitus patients.

Participants were enrolled from Sefako Makgatho Health Sciences University community, Gauteng, South Africa.

PWV and Aix were measured using the AtCor SphygmoCor® system (AtCor Medical, Inc., Sydney, Australia). Cytokines levels were measured using Multiplexing with Bio-Plex Pro™ human inflammation panel I assay. Treatment naïve type 2 diabetes participants were divided into two groups: metformin (M) (n = 10) and metformin glimepiride (MS) (n = 14). The study participants were followed up at 4 and 8 months after treatment initiation.

In the M and MS, IL-1β increased significantly at four months (58.19 ± 0.03 pg/ml, 58.35 ± 0.30 pg/ml) when compared to baseline (33.05 ± 18.56 pg/ml, 34.79 ± 18.77 pg/ml) then decreased significantly at eight months (29.25 ± 11.64 pg/ml, 32.54 ± 14.26 pg/ml) when compared to four months (58.19 ± 0.03 pg/ml, 58.35 ± 0.3 pg/ml) (p < 0.05). There were no significant changes in PWV, Aix, IL-1ra, IL-2, IL-6, IL-8, TNF-α and hs-CRP levels at both treatment intervals.

Metformin alone or in combination with glimepiride did not improve arterial elasticity and did not reduce pro-inflammatory cytokines levels in T2DM black South African patients.

The context-based knowledge generated by the current study is expected to enhance the continuum of care for T2DM patients.

This study was conducted to examine the effects of daily intake of γ-oryzanol (ORZ)-fortified canola oil, as compared with plain canola and sunflower oils, on certain inflammatory and oxidative stress biomarkers in adult subjects with Type 2 Diabetes (T2D).

We randomly allocated 92 adult subjects with T2D from both sexes to one of the following groups to receive: (a) ORZ-fortified canola oil (ORZO; n1 = 30); (b) unfortified canola oil (CANO; n2 = 32); or (c) sunflower oil (SUFO; n3 = 30) for 12 weeks. Dietary and laboratory evaluations were performed initially and finally.

Serum hs-CRP concentrations significantly decreased in ORZO group (from 3.1 ± 0.2 to 1.2 ± 0.2 mg/L), as compared with CANO (p = 0.003) and SUFO (p < 0.001) groups. Serum IL-6 significantly decreased just in ORZO (- 22.8%, p = 0.042) and CANO groups (- 19.8%, p = 0.038). However, the between-group differences were not significant. Serum IL-1β slightly decreased in ORZO (- 28.1%, p = 0.11) and increased in SUFO (+ 20.6%, p = 0.079) but between-group difference was statistically significant (p = 0.017). Serum IFN-γ concentrations decreased significantly only in ORZO (from 3.3 ± 0.08 to 2.9 ± 0.21 IU/mL, p = 0.044). Salivary IgA concentrations increased significantly in all three intervention groups. Notwithstanding, only the difference between ORZO and CANO groups was statistically significant (p = 0.042). Similarly, circulating malondialdehyde concentrations significantly decreased in all three groups but with no between-group significant difference.

Daily consumption of ORZ-fortified canola oil, compared with unfortified canola and sunflower oils, for 12 weeks resulted in boosting of certain anti-inflammatory effects of canola oil. These findings may have preventive implications for both clinicians and policy makers. This clinical trial was registered at clinicaltrials.gov (03.08.2022; NCT05271045).

Chronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin; 20 μg/kg) in vivo reduced fasted and glucose-stimulated plasma insulin levels for up to 6 weeks in male and female mice. TCDD-exposed male mice were also modestly hypoglycemic and had increased insulin sensitivity, whereas TCDD-exposed females were transiently glucose intolerant. Whether these effects are driven by AhR activation in β-cells requires investigation.

We exposed female and male β-cell specific Ahr knockout (βAhrKO) mice and littermate Ins1-Cre genotype controls (βAhrWT) to a single high dose of 20 μg/kg TCDD and tracked the mice for 6 weeks.

Under baseline conditions, deleting AhR from β-cells caused hypoglycemia in female mice, increased insulin secretion ex vivo in female mouse islets, and promoted modest weight gain in male mice. Importantly, high-dose TCDD exposure impaired glucose homeostasis and β-cell function in βAhrWT mice, but these phenotypes were largely abolished in TCDD-exposed βAhrKO mice.

Our study demonstrates that AhR signaling in β-cells is important for regulating baseline β-cell function in female mice and energy homeostasis in male mice. We also show that β-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both sexes, suggesting that the effects of TCDD on β-cell function and health are driving metabolic phenotypes in peripheral tissues.

Altered microRNAs (miRNAs1) and cytokines expression levels are associated with several pregnancy-induced complications. We evaluated the profile of circulating miRNAs (miR-17, miR-29a and miR-181a) and proinflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-17) in women with gestational diabetes mellitus (GDM2), as well as their potential use as GDM biomarkers. The case-control study included 65 pregnant women divided into 2 groups - GDM and control. Expression levels of miRNAs in plasma samples and cytokines mRNA isolated from peripheral blood buffy coat were analyzed by quantitative real-time PCR (qPCR3). Significant miR-29a downregulation was found in GDM compared to the control group, and was even more significant after adjustments for covariates. miR-17 and miR-181a expression levels did not differ between the examined groups. Expression levels of IL-1β were significantly higher in GDM group compared to controls, while TNF-α, IL-6 and IL-17 did not show significant changes in expression between the two groups. As jugded from the ROC curve analysis, miR-29a and IL-1β had a significant capacity to discriminate between CG and GDM. Additionally, a positive correlation was established between IL-1β and TNF-α in the GDM group. GDM appeared to be associated with altered levels of miR-29a and IL-1β making them markers of this condition.

Vitamin D (VD) deficiency has been associated with inflammation and dysregulation of the immune system. The NLRP3 inflammasome, a critical immune response component, plays a pivotal role in developing inflammatory diseases. VD hinders NLRP3 inflammasome activation and thus exerts anti-inflammatory effects. This study aimed to analyze the effect of VD deficiency on circulating levels of NLRP3 inflammasomes (NLRP3 and caspase-1) and associated interleukins (IL-1α, IL-1β, IL-18, IL-33 and IL-37) in Saudi adults. Methods: A total of 338 Saudi adults (128 males and 210 females) (mean age = 41.2 ± 9.1 years and mean BMI 31.2 ± 6.5 kg/m2) were included. Overnight-fasting serum samples were collected. Participants were stratified according to their VD status. Serum levels of NLRP3 inflammasomes and interleukins of interest were assessed using commercially available immuno-assays. Individuals with VD deficiency had significantly lower mean 25(OH)D levels than those with a normal VD status (29.3 nmol/L vs. 74.2 nmol/L, p < 0.001). The NLRP3 levels were higher in the VD-deficient group than their VD-sufficient counterparts (0.18 vs. 0.16, p = 0.01). Significant inverse associations were observed between NLRP3 levels with age (r = -0.20, p = 0.003) and BMI (r = -0.17, p = 0.01). Stepwise regression analysis identified insulin (β = 0.38, p = 0.005) and NLRP3 (β = -1.33, p = 0.03) as significant predictors of VD status, explaining 18.3% of the variance. The findings suggest that the VD status modestly regulates NLRP3 inflammasome and interleukin activities. This may provide novel insights into the pathogenesis and management of inflammatory disorders.

The incidence of hypertensive disorders of pregnancy is increasing, which may be due to several factors, including an increased age at pregnancy and more comorbid health conditions during reproductive years. Preeclampsia, the most severe hypertensive disorder of pregnancy, has been associated with an increased risk of future disease, including cardiovascular and kidney diseases. Cellular senescence, the process of cell cycle arrest in response to many physiologic and maladaptive stimuli, may play an important role in the pathogenesis of preeclampsia and provide a mechanistic link to future disease. In this article, we will discuss the pathophysiology of preeclampsia, the many mechanisms of cellular senescence, evidence for the involvement of senescence in the development of preeclampsia, as well as evidence that cellular senescence may link preeclampsia to the risk of future disease. Lastly, we will explore how a better understanding of the role of cellular senescence in preeclampsia may lead to therapeutic trials. © 2023 American Physiological Society. Compr Physiol 13:5077-5114, 2023.

Circulating MicroRNAs (miRNAs) carried by microvesicles (MVs) have various physiological and pathological functions by post-transcriptional regulation of gene expression being considered markers for many diseases including diabetes and dyslipidemia. We aimed to identify new common miRNAs both in MVs and plasma that could be predictive biomarkers for diabetic dyslipidemia evolution.

For this purpose, plasma from 63 participants in the study (17 type 2 diabetic patients, 17 patients with type 2 diabetes and dyslipidemia, 14 patients with dyslipidemia alone and 15 clinically healthy persons without diabetes or dyslipidemia) was used for the analysis of circulating cytokines, MVs, miRNAs and MV-associated miRNAs.

The results uncovered three miRNAs, miR-218, miR-132 and miR-143, whose expression was found to be significantly up-regulated in both circulating MVs and plasma from diabetic patients with dyslipidemia. These miRNAs showed significant correlations with important plasma markers, representative of this pathology. Thus, MV/plasma miR-218 was negatively correlated with the levels of erythrocyte MVs, plasma miR-132 was positively connected with MV miR-132 and negatively with uric acid and erythrocyte plasma levels, and plasma miR-143 was negatively related with creatinine levels and diastolic blood pressure. Also, three miRNAs common to MV and plasma, namely miR-21, miR-122, and miR-155, were identified to be down-regulated and up-regulated, respectively, in diabetic dyslipidemia. In addition, MV miR-21 was positively linked with cholesterol plasma levels and plasma miR-21 with TNFα plasma levels, MV miR-122 was negatively correlated with LDL-c levels and plasma miR-122 with creatinine and diastolic blood pressure and positively with MV miR-126 levels, MV miR-155 was positively associated with cholesterol and total MV levels and negatively with HDL-c levels, whereas plasma miR-155 was positively correlated with Il-1β plasma levels and total MV levels and negatively with MV miR-223 levels.

In conclusion, miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 show potential as biomarkers for diabetic dyslipidemia, but there is a need for more in-depth studies. These findings bring new information regarding the molecular biomarkers specific to diabetic dyslipidemia and could have important implications for the treatment of patients affected by this pathology.

Type 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease.

The MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes.

In a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1β, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes.

Our study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets.

The MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).

Hyperglycemia associated with prediabetes (PD) alters NLRP3 inflammasome activity and related interleukins, yet no study has evaluated the expression of the NLRP3 inflammasome complex and related interleukins in individuals with a PD condition that did or did not develop type 2 diabetes mellitus (T2DM). This study investigated the effect of 6 months of lifestyle modification on the expression of the NLRP3 inflammasome and related interleukins (1α, 1β, 18, 33 and 37) in the sera of individuals with a PD condition that did or did not develop T2DM. This interventional study included 67 Saudi adults (mean age = 41.9 ± 8.0 years, mean BMI = 33.2 ± 5.5 kg/m2). Overnight-fasting serum samples were collected at baseline and at the 6-month follow-up. Serum levels of NLRP3, capsase-1 and related ILs were analyzed at both visits using commercially available immunoassay kits. Results showed that IL-1α increased in the PD group that developed T2DM (p = 0.046), IL-33 decreased in the PD group that reverted to normal (p < 0.001) and NLRP3 decreased in the PD group that remained PD (p = 0.01). Results also showed a positive over-time correlation between NLRP3 and both IL-1α and IL-33 (p < 0.001 and p = 0.028, respectively). In conclusion, glycemic control favorably altered NLRP3 inflammasome complex activity, and lifestyle modification in PD individuals is crucial in reversing harmful metabolic and inflammatory phenotypes.

The present report focuses on a rapid and convenient method applicable in the green synthesis of gold nanoparticles (AuNPs) using goji berry (Lycium barbarum-LB) extracts rich in antioxidant compounds, as well as on the structural analysis and evaluation of the induced antioxidant protection and anti-inflammatory effects of the synthesized gold nanoparticles upon endothelial cells (HUVECs) exposed to hyperglycemia. The synthesized AuNPs were characterized using ultraviolet-visible (UV-Vis) spectroscopy and transmission electron microscopy (TEM), whereas the presence of bioactive compounds from the L. barbarum fruit extract on the surface of the nanoparticles was confirmed using Fourier transform infrared spectroscopy (FTIR). The antioxidant activity of the biosynthesized gold nanoparticles was evaluated on the HUVEC cell line. The results reveal that AuNPs with a predominantly spherical shape and an average size of 30 nm were obtained. The UV-Vis spectrum showed a characteristic absorption band at λmax = 536 nm of AuNPs. FTIR analysis revealed the presence of phenolic acids, flavonoids and carotenoids acting as capping and stabilizing agents of AuNPs. Both the L. barbarum extract and AuNPs were well tolerated by HUVECs, increased the antioxidant defense and decreased the production of inflammatory cytokines induced via hyperglycemia-mediated oxidative damage.

Diabetes mellitus is a common metabolic disorder. About two-thirds of diabetic patients develop diabetic cardiomyopathy (DCM), which becomes a challenging issue as it severely threatens the patient's life. Hyperglycemia and the resulting advanced glycated end products (AGE) and their receptor (RAGE)/High Mobility Group Box-1 (HMGB-1) molecular pathway are thought to be key players. Recently, artemisinin (ART) has gained more attention owing to its potent biological activities beyond its antimalarial effect. Herein, we aim to evaluate the effect of ART on DCM and the possible underlying mechanisms. Twenty-four male Sprague-Dawley rats were divided into: control, ART, type 2 diabetic and type 2 diabetic treated with ART groups. At the end of the research, the ECG was recorded, then the heart weight to body weight (HW/BW) ratio, fasting blood glucose, serum insulin and HOMA-IR were evaluated. Cardiac biomarkers (CK-MB and LDH), oxidative stress markers, IL-1β, AGE, RAGE and HMGB-1 expression were also measured. The heart specimens were stained for H&E as well as Masson's trichrome. DCM induced disturbances in all studied parameters; contrary to this, ART improved these insults. Our study concluded that ART could improve DCM through modulation of the AGE-RAGE/HMGB-1 signaling pathway, with subsequent impacts on oxidative stress, inflammation and fibrosis. ART could therefore be a promising therapy for the management of DCM.

The study of the relationship between type 2 diabetes mellitus (T2DM) disease and other pathologies (comorbidities), together with patient age variation, poses a challenge for medical research. There is evidence that patients affected by T2DM are more likely to develop comorbidities as they grow older. Variation of gene expression can be correlated to changes in T2DM comorbidities insurgence and progression. Understanding gene expression changes requires the analysis of large heterogeneous data at different scales as well as the integration of different data sources into network medicine models. Hence, we designed a framework to shed light on uncertainties related to age effects and comorbidity by integrating existing data sources with novel algorithms. The framework is based on integrating and analysing existing data sources under the hypothesis that changes in the basal expression of genes may be responsible for the higher prevalence of comorbidities in older patients. Using the proposed framework, we selected genes related to comorbidities from existing databases, and then analysed their expression with age at the tissues level. We found a set of genes that changes significantly in certain specific tissues over time. We also reconstructed the associated protein interaction networks and the related pathways for each tissue. Using this mechanistic framework, we detected interesting pathways related to T2DM whose genes change their expression with age. We also found many pathways related to insulin regulation and brain activities, which can be used to develop specific therapies. To the best of our knowledge, this is the first study that analyses such genes at the tissue level together with age variations.

Type II diabetes mellitus (T2DM) is a metabolic disorder that poses a serious health concern worldwide due to its rising prevalence. Hypertension (HT) is a frequent comorbidity of T2DM, with the co-occurrence of both conditions increasing the risk of diabetes-associated complications. Inflammation and oxidative stress (OS) have been identified as leading factors in the development and progression of both T2DM and HT. However, OS and inflammation processes associated with these two comorbidities are not fully understood. This study aimed to explore changes in the levels of plasma and urinary inflammatory and OS biomarkers, along with mitochondrial OS biomarkers connected to mitochondrial dysfunction (MitD). These markers may provide a more comprehensive perspective associated with disease progression from no diabetes, and prediabetes, to T2DM coexisting with HT in a cohort of patients attending a diabetes health clinic in Australia.

Three-hundred and eighty-four participants were divided into four groups according to disease status: 210 healthy controls, 55 prediabetic patients, 32 T2DM, and 87 patients with T2DM and HT (T2DM+HT). Kruskal-Wallis and χ2 tests were conducted between the four groups to detect significant differences for numerical and categorical variables, respectively.

For the transition from prediabetes to T2DM, interleukin-10 (IL-10), C-reactive protein (CRP), 8-hydroxy-2'-deoxyguanosine (8-OHdG), humanin (HN), and p66^Shc were the most discriminatory biomarkers, generally displaying elevated levels of inflammation and OS in T2DM, in addition to disrupted mitochondrial function as revealed by p66^Shc and HN. Disease progression from T2DM to T2DM+HT indicated lower levels of inflammation and OS as revealed through IL-10, interleukin-6 (IL-6), interleukin-1β (IL-1β), 8-OHdG and oxidized glutathione (GSSG) levels, most likely due to antihypertensive medication use in the T2DM +HT patient group. The results also indicated better mitochondrial function in this group as shown through higher HN and lower p66^Shc levels, which can also be attributed to medication use. However, monocyte chemoattractant protein-1 (MCP-1) levels appeared to be independent of medication, providing an effective biomarker even in the presence of medication use. The results of this study suggest that a more comprehensive review of inflammation and OS biomarkers is more effective in discriminating between the stages of T2DM progression in the presence or absence of HT. Our results further indicate the usefulness of medication use, especially with respect to the known involvement of inflammation and OS in disease progression, highlighting specific biomarkers during disease progression and therefore allowing a more targeted individualized treatment plan.

Inflammasome activation of the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) has been observed to be involved in the pathogenesis of numerous inflammatory diseases, including prediabetes (PD) and type 2 diabetes mellitus (T2DM). Varying levels of glycemia can trigger inflammasome activation; yet, limited studies have reported the associations between NLRP3 levels or other circulating interleukins (ILs) and glycemic status. This study investigated the differences and associations between serum levels of NLRP3 and IL-1α, IL-1β, IL-33 and IL-37 in Arab adults with PD and T2DM. A total of 407 Saudi adults (151 males and 256 females) (mean age = 41.4 ± 9.1 years and mean BMI = 30.7 ± 6.4 kg/m²) were included. Overnight-fasting serum samples were collected. The participants were stratified according to T2DM status. Serum levels of NLRP3 and ILs of interest were assessed using commercially available assays. In all participants, age- and BMI-adjusted circulating levels of IL-37 were significantly higher in the T2DM group (p = 0.02) than in healthy controls (HC) and the PD group. A general linear model analysis revealed that NLRP3 levels were significantly influenced by T2DM status; age; and ILs 18, 1α and 33 (p-values 0.03, 0.04, 0.005, 0.004 and 0.007, respectively). IL-1α and triglycerides significantly predicted NLRP3 levels by as much as 46% of the variance perceived (p < 0.01). In conclusion, T2DM status significantly influenced NLRP3 expression and other IL levels in varying degrees. Whether these altered levels of inflammasome markers can be favorably reversed through lifestyle interventions needs to be investigated prospectively in the same population.

Inflammasomes have been implicated in the pathogenesis of type 2 diabetes (T2D). However, their expression and functional importance in pancreatic β-cells remain largely unknown. Mitogen-activated protein kinase 8 interacting protein-1 (MAPK8IP1) is a scaffold protein that regulates JNK signaling and is involved in various cellular processes. The precise role of MAPK8IP1 in inflammasome activation in β-cells has not been defined. To address this gap in knowledge, we performed a set of bioinformatics, molecular, and functional experiments in human islets and INS-1 (832/13) cells. Using RNA-seq expression data, we mapped the expression pattern of proinflammatory and inflammasome-related genes (IRGs) in human pancreatic islets. Expression of MAPK8IP1 in human islets was found to correlate positively with key IRGs, including the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3), Gasdermin D (GSDMD) and Apoptosis-associated speck-like protein containing a CARD (ASC), but correlate inversely with Nuclear factor kappa β1 (NF-κβ1), Caspase-1 (CASP-1), Interleukin-18 (IL-18), Interleukin-1β (IL-1β) and Interleukin 6 (IL-6). Ablation of Mapk8ip1 by siRNA in INS-1 cells down-regulated the basal expression levels of Nlrp3, NLR family CARD domain containing 4 (Nlrc4), NLR family CARD domain containing 1 (Nlrp1), Casp1, Gsdmd, Il-1β, Il-18, Il-6, Asc, and Nf-κβ1 at the mRNA and/or protein level and decreased palmitic acid (PA)-induced inflammasome activation. Furthermore, Mapk8ip1-silened cells substantially reduced reactive oxygen species (ROS) generation and apoptosis in palmitic acid-stressed INS-1 cells. Nonetheless, silencing of Mapk8ip1 failed to preserve β-cell function against inflammasome response. Taken together, these findings suggest that MAPK8IP1 is involved in regulating β-cells by multiple pathways.