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Background: Macrophage migration inhibitory factor (MIF) is a highly conserved cytokine with pleiotropic properties, mainly pro-inflammatory. MIF seems to exert its pro-inflammatory features by binding to its transmembrane cellular receptor CD74. MIF also has CXCR4, which acts as a co-receptor in this inflammatory process. Apart from MIF, D-dopachrome tautomerase (DDT) or MIF2, which belongs to the MIF superfamily, also binds to receptor CD74. Therefore, these molecules, MIF, CD74, DDT and CXCR4 are suggested to work together orchestrating an inflammatory process. Diabetes mellitus is characterised by chronic low-grade inflammation. Therefore, the aim of the present study was to evaluate serum and urinary levels of the aforementioned molecules among patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and among healthy controls. Methods: We enrolled 13 patients with T1DM, 74 patients with T2DM and 25 healthy individuals as controls. Levels of CD74, CXCR4, DDT, and MIF were measured using ELISA Kits according to the manufacturer's instructions. Results: We documented increased serum MIF levels together with higher urinary CD74 levels among patients with T1DM, when compared to patients with T2DM and healthy adults. In particular, patients with T1DM showed significantly increased levels of MIF compared to T2DM (p = 0.011) and healthy controls (p = 0.0093). CD74 in urine were significantly higher in patients with T1DM compared to those affected with T2DM (p = 0.0302) and healthy group (p = 0.0099). On the contrary, serum CD74 were similar among the three groups. No statistical differences were identified in CXCR4 levels both in serum and in urine of all groups. Patients with T2DM and overweight/obesity had increased urinary levels of CD74, when compared to lean patients with T2DM. Conclusion: The increased serum MIF levels and urinary CD74 levels among patients with T1DM may be attributed to the autoimmune milieu, which characterises patients with T1DM, when compared to patients with T2DM. These two findings merit further attention as they could pave the way for further research regarding the potential beneficial effects of inhibitors of MIF among patients with T1DM, especially in the early stages of T1DM. Finally, the role of inhibitors of MIF could be further explored in the context of obesity among patients with T2DM.

Hypovitaminosis D is highly prevalent in critically ill patients, and it has been suggested to be a risk factor for infections, sepsis and higher mortality. We sought to investigate whether serum 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) in critically ill patients with new onset sepsis are associated with severity and outcome. We prospectively included 50 consecutive critically ill adult cases with new onset sepsis and 50 healthy controls matched for age and sex. PTH and 25(OH)D were determined in serum via electrochemiluminescence immunoassays at inclusion in the study in all cases and controls, and one week after sepsis onset in cases. Patients had reduced 25(OH)D compared to controls at sepsis onset (7.9 ± 3 vs 24.6 ± 6.7 ng/mL, p 0.05). 25(OH)D was positively correlated with ionized calcium (r = 0.46, p

Bisalbuminemia is a rare, typically benign condition marked by the presence of a bifid albumin band on serum protein electrophoresis. It can either be inherited due to a point mutation or acquired in association with various medical conditions, most commonly diabetes mellitus. Bisalbuminuria, the presence of bifid albumin in urine, may or may not accompany bisalbuminemia. Both conditions are often discovered incidentally during screening for monoclonal gammopathy. Bisalbuminemia and related variants provide insights into albumin's genetic diversity and functional roles, influencing clinical diagnostics and research in human genetics. Understanding these variants aids in distinguishing benign conditions from potential disease states, guiding appropriate clinical management. In this case-based review, we present a case of hereditary bisalbuminemia identified unexpectedly during an investigation of a positive Direct Antiglobulin Test Coombs in an adult female patient. This review aims to highlight the key features of bisalbuminemia, a rare condition that should be recognized by clinicians.

Paraneoplastic hypoglycemia, also known as non-islet cell tumor hypoglycemia (NICTH), is a rare but critical condition occurring in patients with different types of malignancy. This condition is commonly linked to tumors producing insulin-like growth (IGF) factors, particularly IGF-2 and its precursors, which disrupt glucose homeostasis and lead to excessive glucose consumption. The diagnosis typically involves documenting symptomatic hypoglycemia and ruling out other potential causes. Essential diagnostic tools include imaging studies and laboratory tests, specifically measuring IGF-2 levels and the IGF-2:IGF-1 ratio. Treatment strategies for NICTH are multifaceted and may include surgical resection of the tumor if feasible, pharmacological interventions such as corticosteroids to suppress IGF-2 production, or supportive measures to manage acute hypoglycemic episodes. Novel therapeutic approaches targeting IGF-2, such as monoclonal antibodies or siRNA, are also being explored and hold promise for future treatment options. This review aims to enhance understanding of paraneoplastic hypoglycemia, focusing on its pathogenesis and diagnosis, to guide optimal medical treatment.

Background: Diabetes mellitus (DM) is tightly associated with the increased prevalence of diabetic kidney disease (DKD). Nonetheless, severe renal function impairment and/or nephrotic range-proteinuria could also result from non-diabetic renal disease (non-DRD) among patients with DM. The ‘Gold standard’ for the differential diagnosis between DKD and non-DRD is kidney biopsy, although no real consensus exists. Thus, this study intends to associate the clinical and biochemical profile of patients with DM and renal disease with the histopathological data of kidney biopsy.In addition, we aimed to evaluate the role of kidney biopsy, especially when other causes, other than DM, are highly suspected among patients with DM and kidney disease. Methods: Thirty two patients with T2DM and nephrotic range levels of proteinuria or with co-existing factors pointing towards a non-diabetic origin of kidney disease were studied, retrospectively. All 32 patients underwent kidney biopsy and were classified according to histopathological findings into 3 groups: a) isolated diabetic kidney disease (DKD), b) non-diabetic kidney disease (NDKD) and c) mixed kidney disease (MKD). Results: Fifteen out of the 32 patients had findings of an isolated DKD, while 17 out of 32 patients suffered from NDKD (13 patients) or MKD (4 patients). DKD patients were younger (p = 0.016) and had a higher HbA1c value (p = 0.069, borderline statistical significance), while the NDKD patients had significantly shorter disease duration (p = 0.04). Furthermore, the incidence of diabetic retinopathy (DR) was lower among the NDKD patients (p

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and secondary prevention by effectively reducing cardiovascular risk through lipid profile enhancements. Beyond their primary lipid-lowering effects, extensive research indicates that these therapies exhibit pleiotropic actions, offering additional health benefits. These include anti-inflammatory properties, improvements in vascular health and glucose metabolism, and potential implications in cancer management. While statins and ezetimibe have been extensively studied, newer lipid-lowering agents also demonstrate similar pleiotropic effects, even in the absence of direct cardiovascular benefits. This narrative review explores the diverse pleiotropic properties of lipid-modifying therapies, emphasizing their non-lipid effects that contribute to reducing cardiovascular burden and exploring emerging benefits for non-cardiovascular conditions. Mechanistic insights into these actions are discussed alongside their potential therapeutic implications

Non-alcoholic fatty liver disease (NAFLD) is a major public health issue worldwide. It is the most common liver disease in Western countries, andits global prevalence is estimated to be up to 35%. However, its diagnosis may be elusive, because liver biopsy is relatively rarely performed and usually only in advanced stages of the disease. Therefore, several non-invasive scores may be applied to more easily diagnose and monitor NAFLD. In this review, we discuss the various biomarkers and imaging scores that could be useful in diagnosing and managing NAFLD. Despite the fact that general measures, such as abstinence from alcohol and modulation of other cardiovascular disease risk factors, should be applied, the mainstay of prevention and management is weight loss. Bariatric surgery may be suggested as a means to confront NAFLD. In addition, pharmacological treatment with GLP-1 analogues or the GIP agonist tirzepatide may be advisable. In this review, we focus on the utility of GLP-1 analogues and GIP agonists in lowering body weight, their pharmaceutical potential, and their safety profile, as already evidenced inanimal and human studies. We also elaborate on other options, such as the use of vitamin E, probiotics, especially next-generation probiotics, and prebiotics in this context. Finally, we explore future perspectives regarding the administration of GLP-1 analogues, GIP agonists, and probiotics/prebiotics as a means to prevent and combat NAFLD. The newest drugs pegozafermin and resmetiron, which seem to be very promising, arealso discussed.

Worldwide, sepsis is a well-recognized cause of death. Acute kidney injury (AKI) may be related to sepsis in up to 70% of AKI cases. Sepsis-associated AKI (SA-AKI) is defined as the presence of AKI according to the Kidney Disease: Improving Global Outcomes criteria in the context of sepsis. SA-AKI is categorized into early, which presents during the first 48 h of sepsis, and late, presenting between 48 h and 7 days of sepsis. SA-AKI is associated with a worse prognosis among patients with sepsis. However, there are different SA-AKI phenotypes as well as different pathophysiological pathways of SA-AKI. The aim of this review is to provide an updated synopsis of the pathogenetic mechanisms underlying the development of SA-AKI as well as to analyze its different phenotypes and prognosis. In addition, potential novel diagnostic and prognostic biomarkers as well as therapeutic approaches are discussed. A plethora of mechanisms are implicated in the pathogenesis of SA-AKI, including inflammation and metabolic reprogramming during sepsis; various types of cell death such as apoptosis, necroptosis, pyroptosis and ferroptosis; autophagy and efferocytosis; and hemodynamic changes (macrovascular and microvascular dysfunction). Apart from urine output and serum creatinine levels, which have been incorporated in the definition of AKI, several serum and urinary diagnostic and prognostic biomarkers have also been developed, comprising, among others, interleukins 6, 8 and 18, osteoprotegerin, galectin-3, presepsin, cystatin C, NGAL, proenkephalin A, CCL-14, TIMP-2 and L-FABP as well as biomarkers stemming from multi-omics technologies and machine learning algorithms. Interestingly, the presence of long non-coding RNAs (lncRNAs) as well as microRNAs (miRNAs), such as PlncRNA-1, miR-22-3p, miR-526b, LncRNA NKILA, miR-140-5p and miR-214, which are implicated in the pathogenesis of SA-AKI, may also serve as potential therapeutic targets. The combination of omics technologies represents an innovative holistic approach toward providing a more integrated view of the molecular and physiological events underlying SA-AKI as well as for deciphering unique and specific phenotypes. Although more evidence is still necessary, it is expected that the incorporation of integrative omics may be useful not only for the early diagnosis and risk prognosis of SA-AKI, but also for the development of potential therapeutic targets that could revolutionize the management of SA-AKI in a personalized manner.

ApoB is the main protein of triglyceride-rich lipoproteins and is further divided into ApoB48 in the intestine and ApoB100 in the liver. Very low-density lipoprotein (VLDL) is produced by the liver, contains ApoB100, and is metabolized into its remnants, intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL). ApoB100 has been suggested to play a crucial role in the formation of the atherogenic plaque. Apart from being a biomarker of atherosclerosis, ApoB100 seems to be implicated in the inflammatory process of atherosclerosis per se. In this review, we will focus on the structure, the metabolism, and the function of ApoB100, as well as its role as a predictor biomarker of cardiovascular risk. Moreover, we will elaborate upon the molecular mechanisms regarding the pathophysiology of atherosclerosis, and we will discuss the disorders associated with the APOB gene mutations, and the potential role of various drugs as therapeutic targets.

Irisin, a novel adipo-myokine with metabolic regulatory functions, exerts anti-inflammatory, antioxidant, and anti-apoptotic actions that may confer protection against sepsis-induced organ injury in experimental studies. Until now, only one human study has explored circulating irisin at sepsis onset. We aimed to examine serum irisin and its kinetics in critically ill patients with sepsis and septic shock with regard to sepsis severity and outcome. We enrolled 102 critically ill patients with sepsis or septic shock within 48 h of diagnosis and 102 age- and gender-matched healthy controls. Irisin was determined in serum upon enrollment in all participants and one week later in patients using an immunoenzymatic method. The outcome of sepsis was recorded 28 days after enrollment. At enrollment, circulating irisin was significantly lower in patients than controls (22.3 ± 6.8 μg/L vs. 28.1 ± 6.7 μg/L, p < 0.001), and increased significantly one week later (22.3 ± 6.8 μg/L vs. 26.6 ± 9.5 μg/L, p < 0.001). Irisin was significantly lower in patients who presented with septic shock than those with sepsis, and in non-survivors than survivors both at enrollment and one week later. However, kinetics of irisin did not differ between the groups (p > 0.05). Patients with higher circulating irisin during the first week of sepsis had a better outcome (p < 0.001). Lower irisin was independently associated with 28-day mortality (sepsis onset: HR 0.44, 95% C.I. 0.26–0.77, p = 0.004 and one week after: HR 0.37, 95% C.I. 0.23–0.58, p < 0.001). Irisin was negatively correlated with severity scores, metabolic, and inflammatory biomarkers. Circulating irisin decreases early in sepsis and is an independent predictor of 28-day mortality. Irisin may be a promising diagnostic and prognostic sepsis biomarker; nevertheless, larger studies are needed to explore its role in sepsis.

Chronic hypokalemia is the main finding in patients with Gitelman’s syndrome (GS). GS, a variant of Bartter’s syndrome, is an autosomal recessive renal disorder characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. GS is caused by inactivating mutations in the thiazide-sensitive sodium-chloride cotransporter gene. It is also called the “milder” form of Bartter’s syndrome, as patients with GS are usually diagnosed in adulthood during routine investigation. Our objective is to highlight the impact of correct distinction between the causes of hypokalemia on management and the need of long-term follow- up after the restoration of normokalemic status. Herein, we report an asymptomatic 40-year-old male, whose persistent hypokalemia was due to GS. The diagnosis was first established by laboratory tests, and he was treated with low-dose aldosterone antagonists (spironolactone), angiotensin-converting enzyme inhibitors, and potassium and magnesium supplements. Genetic testing confirmed the diagnosis of GS and revealed a rare mutation. We conclude that GS is a rare and real diagnostic and therapeutic challenge, for which a close collaboration between endocrinologists and nephrologists is mandatory, as also the thorough genetic investigation of the mutations associated with this syndrome.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD begins as a relatively benign hepatic steatosis which can evolve to non-alcoholic steatohepatitis (NASH); the risk of cirrhosis and hepatocellular carcinoma (HCC) increases when fibrosis is present. NAFLD represents a complex process implicating numerous factors—genetic, metabolic, and dietary—intertwined in a multi-hit etiopathogenetic model. Recent data have highlighted the role of gut dysbiosis, which may render the bowel more permeable, leading to increased free fatty acid absorption, bacterial migration, and a parallel release of toxic bacterial products, lipopolysaccharide (LPS), and proinflammatory cytokines that initiate and sustain inflammation. Although gut dysbiosis is present in each disease stage, there is currently no single microbial signature to distinguish or predict which patients will evolve from NAFLD to NASH and HCC. Using 16S rRNA sequencing, the majority of patients with NAFLD/NASH exhibit increased numbers of Bacteroidetes and differences in the presence of Firmicutes, resulting in a decreased F/B ratio in most studies. They also present an increased proportion of species belonging to Clostridium, Anaerobacter, Streptococcus, Escherichia, and Lactobacillus, whereas Oscillibacter, Flavonifaractor, Odoribacter, and Alistipes spp. are less prominent. In comparison to healthy controls, patients with NASH show a higher abundance of Proteobacteria, Enterobacteriaceae, and Escherichia spp., while Faecalibacterium prausnitzii and Akkermansia muciniphila are diminished. Children with NAFLD/NASH have a decreased proportion of Oscillospira spp. accompanied by an elevated proportion of Dorea, Blautia, Prevotella copri, and Ruminococcus spp. Gut microbiota composition may vary between population groups and different stages of NAFLD, making any conclusive or causative claims about gut microbiota profiles in NAFLD patients challenging. Moreover, various metabolites may be involved in the pathogenesis of NAFLD, such as short-chain fatty acids, lipopolysaccharide, bile acids, choline and trimethylamine-N-oxide, and ammonia. In this review, we summarize the role of the gut microbiome and metabolites in NAFLD pathogenesis, and we discuss potential preventive and therapeutic interventions related to the gut microbiome, such as the administration of probiotics, prebiotics, synbiotics, antibiotics, and bacteriophages, as well as the contribution of bariatric surgery and fecal microbiota transplantation in the therapeutic armamentarium against NAFLD. Larger and longer-term prospective studies, including well-defined cohorts as well as a multi-omics approach, are required to better identify the associations between the gut microbiome, microbial metabolites, and NAFLD occurrence and progression.

Aberrant circulating omentin-1, which is an anti-inflammatory and pro-apoptotic adipokine, has been reported in various solid tumors. Therefore, we investigated whether or not circulating omentin-1 could be associated with postmenopausal BC (PBC) and could be used as a potential diagnostic and clinical tool taking into consideration clinicopathologic features, tumor markers, as well as anthropometric, metabolic, and inflammatory parameters. Serum omentin-1, tumor markers (CA15-3 and CEA); metabolic (insulin, glucose, HOMA index, and serum lipids), anthropometric (BMI, waist circumference, and fat mass), and inflammatory (TNF-α, IL-6, hsCRP) parameters; classic adipokines (leptin and adiponectin); the Mediterranean diet (MedDiet) score; and cardiovascular (CVD) risk were determined in 103 postmenopausal women with pathologically confirmed incident invasive BC, 103 controls matched on age, 51 patients with benign breast lesions (BBL), and 50 obese postmenopausal women of similar age. The mean serum omentin-1 was significantly lower in cases than in controls and patients with BBL (p < 0.001). In the patients, omentin-1 was inversely associated with tumor, metabolic and inflammatory biomarkers, cancer stage, and the number of infiltrated lymph nodes (p < 0.05). In all study participants, omentin-1 was negatively correlated with CVD risk and positively correlated with MedDiet score. Lower circulating omentin-1 was independently associated with PBC occurrence above and beyond known risk factors. According to the ROC curve analysis, the overall diagnostic performance of omentin-1 (0.84, 95% CI 0.79–0.89) is similar to CA15-3. Circulating omentin-1 may be a biomarker at the intersection of PBC and cardiometabolic risk in postmenopausal women, and could be modulated by the adoption of a MedDiet. Further mechanistic and large multicentric prospective and longitudinal studies are required to elucidate the ontological role of omentin-1 in BC and CVD risks, as well as its diagnostic and prognostic ability and its therapeutic potential.