The decade from 2016 to 2026 has witnessed an extraordinary transformation in cardiometabolic medicine, propelled by the maturation of cardiovascular outcome trials (CVOTs). What began as regulatory requirements to establish cardiovascular safety for novel glucose-lowering agents has evolved into a robust body of evidence demonstrating profound cardiorenal protective effects-often extending beyond diabetes itself. Landmark trials such as EMPA-REG OUTCOME, LEADER, SELECT, SURPASS-CVOT, and VESALIUS-CV have not only redefined therapeutic priorities but have also catalyzed a conceptual shift from glucocentric management to an integrated cardiorenal metabolic (CRM) framework. This narrative review traces the epidemiological imperatives driving this evolution, chronicles the historical trajectory of CVOTs, synthesizes key findings across major pharmacological classes, and reflects on emerging therapies and risk markers that are shaping the precision-medicine paradigm of 2026.

Type 2 diabetes mellitus (T2DM) and prostate cancer are closely linked, affecting overlapping age groups of predominantly male populations. Flutamide (FLU) is metabolized in the liver to hydroxyflutamide (OHF), exerting anti-androgenic effects and is mainly used for prostate cancer treatment. During its use, occasional adverse reactions such as elevated blood glucose and worsening conditions in T2DM patients have been observed, but the cause remains unknown. This study aims to investigate the effects and mechanisms of FLU on hepatic insulin resistance under T2DM conditions. In vitro, a primary mouse hepatocyte model of insulin sensitivity impairment induced by high glucose (HG) was established to observe the effects of FLU/OHF on cellular lipid accumulation, reactive oxygen species (ROS) production, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) signaling, and insulin signaling. NLRP3 inhibitors, ROS scavengers, and hepatocytes from Nlrp3-knockout mice were used to explore the mechanisms of FLU. In vivo, a high-fat diet (HFD)/streptozotocin (STZ) induced-T2DM mouse model was established to observe the effects of FLU gavage on glucose and lipid metabolism, insulin sensitivity, and histopathology. The results showed that FLU exposure exacerbated lipid accumulation, ROS production, over-activation of NLRP3 signaling, and impaired insulin signaling in HG-treated hepatocytes. Inhibition of NLRP3, scavenging of ROS, or knockout of Nlrp3 eliminated the above effects of FLU/OHF. FLU exacerbated glucose and lipid metabolism disorders in HFD/STZ induced-T2DM mice, increased hepatic insulin resistance, and activated the hepatic NLRP3 signaling pathway. The results of this study suggest that FLU treatment is associated with exacerbated hepatic insulin resistance in mice with T2DM, an effect that may be mediated through ROS overproduction and activation of NLRP3 signaling.

Despite similarities in the pathophysiology of type 2 diabetes mellitus in humans and cats, the specific role of the gut microbiota in feline diabetes remains unclear. We determined the ileal microbiota composition of lean, overweight, and diabetic cats, and assessed the association of the ileal gut microbiota with key markers of insulin signaling and glucose regulation in the pancreas and muscle, and liver fat content. Ileal contents were collected from a client-owned population of total 32 (lean, n = 13; overweight, n = 8; diabetic=11) cats, and DNA extracted for 16S rRNA analyses. Results revealed significant differences in beta diversity between lean and diabetic cats, indicating distinct microbial community compositions. At the phylum level, relative abundance of Bacteroidota decreased in diabetics compared to lean and overweight cats. At the genus level, Alloprevotella was elevated in lean compared to overweight and diabetic cats. Further, Turicibacter was increased in treated diabetics compared to other groups. Partial least squares regression unveiled distinct microbial and tissue markers associated with diabetic status. Lean and overweight cats were associated with higher relative abundances of the genera Sutterella and Oscillibacter, and elevated muscle insulin receptor substrate-1, and pancreas insulin and insulin receptor mRNA levels. Conversely, diabetic cats were associated with higher relative abundances of the genera Peptostreptococcus and Escherichia-Shigella, and a higher liver fat percent. Together, these findings indicate that diabetic and overweight cats have distinct compositional differences in ileal microbiota, and that alterations in enteric microbial diversity and composition are associated with markers of insulin signaling in feline diabetes.

Several reports have indicated an association between insulin resistance and hyperferritinemia, and a recent consensus statement has suggested the term metabolic hyperferritinemia (MHF) for patients with metabolic syndrome and increased serum ferritin. The objective of this study was to examine the association between serum ferritin levels and insulin resistance in an unselected Norwegian population.

Two thousand people were randomly selected from the public registry in one municipality in Nord-Trøndelag County, Norway. Of the respondents, 1115 completed a screening glucose tolerance test to determine the prevalence of impaired glucose tolerance (IGT)/type 2 diabetes mellitus (T2DM), and these individuals were then selected for further examination. A control group comprising 100 age- and gender-matched individuals with normal glucose tolerance and CRP less than 5 was retrospectively generated from the same cohort.

One hundred and seventy-six people were diagnosed with impaired glucose tolerance or diabetes mellitus type 2 (IGT/T2DM), and 17 (10%) of these patients had elevated ferritin levels according to the MHF definition. In the control group with normal glucose tolerance, 11% also had hyperferritinemia based on the same ferritin cut-off. Multiple regression revealed a significant association between serum ferritin, male sex, 2-hour glucose value after the glucose load and waist circumference among the patients with IGT/T2DM, while there was no association with age or transferrin saturation.

This study demonstrated a prevalence of metabolic hyperferritinemia in one out of ten people with IGT/T2DM; however, a comparable level of serum ferritin was also detected in the matched control group. Only one person in the IGT/T2DM group had ferritin levels higher than 550 mmol/L. Thus, hyperferritinemia is prevalent in this unselected Norwegian cohort. A relationship between s-ferritin and metabolic syndrome parameters was found in patients with IGT/T2DM, but hyperferritinemia is likely not related to iron overload.

We evaluated the perioperative outcomes of robotic spleen-preserving distal pancreatectomy (RSPDP) and compared articulated monopolar curved scissors (R-MCS) with the harmonic scalpel (R-HS) as the primary energy device.

We retrospectively reviewed consecutive single-centre RSPDPs (September 2020-August 2025) and compared baseline characteristics, intraoperative variables, and postoperative outcomes.

Sixty-nine patients were included (R-MCS, n = 31; R-HS, n = 38). Overall spleen preservation was 79.7%, with no between-group difference (80.6% vs. 78.9%, p = 0.852). Among spleen-preserved cases, Kimura completion was higher with R-MCS (88.0% vs. 66.7%, p = 0.032). Operative time and blood loss were comparable. Time to first flatus was shorter with R-MCS (3.2 ± 0.9 vs. 3.7 ± 0.7 days, p = 0.014). Overall complications occurred in 18.8%, including clinically relevant postoperative pancreatic fistula in 11.6%; no Clavien-Dindo grade ≥ IIIb complications or perioperative mortality occurred.

RSPDP is safe and feasible. R-MCS may improve Kimura completion and modestly shorten the time to first flatus, pending further validation.

Oral candidiasis is the most common opportunistic fungal infection in patients undergoing head and neck radiotherapy (RT). The present study is aimed at provide the best treatment for patients undergoing RT by determining the characteristics of the Candida species in these patients and investigating the antifungal sensitivity patterns against eight available drugs according to the Clinical and Laboratory Standards Institute (CLSI). In this descriptive cross-sectional study, 30 patients underwent head and neck RT. All patients were examined in three stages using oral and pharyngeal mucus swabs, and nystatin was prescribed for patients with symptoms of candidiasis infection. Subsequently, clinical fungal specimens were investigated by direct microscopy and culture and tested for sensitivity to antifungal drugs. MIC₅₀, MIC₉₀, and geometric mean MIC were calculated for each drug. Evidence of fungal colonization was observed in 17 specimens at various stages, with Candida albicans being the most frequently identified species. All tested Candida isolates were sensitive to nystatin and amphotericin B, whereas Trichosporon asahii showed intrinsic resistance to echinocandins (caspofungin, anidulafungin, and micafungin), and C. krusei exhibited the expected intrinsic resistance to fluconazole. The observed sensitivity of C. tropicalis to the tested antifungal drugs is based on a single isolate and should be considered descriptive rather than generalizable. Cases of C. albicans strains showed moderate or dose-dependent susceptibility to itraconazole, voriconazole, and caspofungin. The isolate of T. asahii was only sensitive to nystatin and amphotericin B. According to the laboratory and clinical results, nystatin is recommended for most patients. Finally, it is better to prescribe the antifungal drugs in each center according to their reported sensitivity.

Dysregulation of histone modifications contributes to the development of cancer. The loss of methylation on histone H3 and H4 and the loss of acetylation serve as indicators of tumors. Histone demethylase KDM3B, which contains a JmjC domain, plays an important role in tumorigenesis and development by removing H3K9me1/2 methylation. It also has a significant impact on regulating different types of cancer. KDM3B's role in prognosis and tumor formation in cancer has not been thoroughly studied. In this study, we analyzed KDM3B expression data from the TCGA database in a pan-cancer analysis. Our results show that KDM3B is highly expressed in many cancer types and is closely associated with poor prognosis. KDM3B expression is associated with immune checkpoint activities, lymphocyte infiltration, and immune landscape changes, suggesting that KDM3B could be a target for cancer therapy.

Breast cancer is the most frequently diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. Triple-negative breast cancer (TNBC) poses a major clinical challenge due to its aggressive nature, limited therapeutic options, and high propensity for drug resistance. Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR and histone deacetylase (HDAC) signaling pathways has been implicated in TNBC progression and therapeutic resistance, highlighting their potential as combinatorial targets. In this study, we report the design, synthesis, and biological evaluation of a novel series of triazine-based multitarget inhibitors aimed at the dual inhibition of PI3K and HDAC. Among the synthesized compounds, 5b and 5f demonstrated the most promising profiles, exhibiting low nanomolar IC₅₀ values against HDAC6 (2.33 and 6.02 nM) and PI3Kα (17.5 and 236 nM), respectively. Both compounds reduced cell viability in breast cancer cell lines, with IC₅₀ values below 5 µM in MDA-MB-231 cells. Western blot analysis confirmed inhibition of HDAC and PI3K signaling in treated cells. Molecular docking and dynamics simulations further revealed stable binding modes and favorable interactions within the active sites of both targets. Overall, 5b and 5f represent promising lead candidates for further optimization toward the development of novel dual HDAC/PI3K inhibitors with potential application in TNBC therapy, as evaluated in TNBC-relevant models.

Inhibition of DNA damage repair is a common mechanism to induce cancer cell death and, therefore, to treat cancers such as breast, prostate and ovarian cancer. This approach, although very attractive, has not been feasible for treating brain tumours due to the stringent structural features necessary for pharmaceutical agents to cross the blood-brain barrier (BBB). This study presents the proof of concept in vitro cellular activity of PARP1 (Poly(ADP-ribose) polymerase 1) enzyme inhibitor olaparib conjugated with a known BBB-crossing heptamethine cyanine dye. We also present evidence for cellular uptake and PARP1 inhibition by the conjugate, which contributes to the observed improvement in potency.