Sepsis is accompanied by a less-known mismatch between hemodynamics and mitochondrial respiration. We aimed to characterize the relationship and time dependency of microcirculatory and mitochondrial functions in a rodent model of intraabdominal sepsis. Fecal peritonitis was induced in rats, and multi-organ failure (MOF) was evaluated 12, 16, 20, 24 or 28 h later (n = 8/group, each) using rat-specific organ failure assessment (ROFA) scores. Ileal microcirculation (proportion of perfused microvessels (PPV), microvascular flow index (MFI) and heterogeneity index (HI)) was monitored by intravital video microscopy, and mitochondrial respiration (OxPhos) and outer membrane (mtOM) damage were measured with high-resolution respirometry. MOF progression was evidenced by increased ROFA scores; microcirculatory parameters followed a parallel time course from the 16th to 28th h. Mitochondrial dysfunction commenced with a 4-h time lag with signs of mtOM damage, which correlated significantly with PPV, while no correlation was found between HI and OxPhos. High diagnostic value was demonstrated for PPV, mtOM damage and lactate levels for predicting MOF. Our findings indicate insufficient splanchnic microcirculation to be a possible predictor for MOF that develops before the start of mitochondrial dysfunction. The adequate subcellular compensatory capacity suggests the presence of mitochondrial subpopulations with differing sensitivity to septic insults.

Acquiring resistance against antiviral drugs is a significant problem in antimicrobial therapy. In order to identify novel antiviral compounds, the antiviral activity of eight plants indigenous to the southern region of Hungary against herpes simplex virus-2 (HSV-2) was investigated. The plant extracts and the plant compound carnosic acid were tested for their effectiveness on both the extracellular and intracellular forms of HSV-2 on Vero and HeLa cells. HSV-2 replication was measured by a direct quantitative PCR (qPCR). Among the tested plant extracts, Salvia rosmarinus (S. rosmarinus) exhibited a 90.46% reduction in HSV-2 replication at the 0.47 μg/mL concentration. Carnosic acid, a major antimicrobial compound found in rosemary, also demonstrated a significant dose-dependent inhibition of both extracellular and intracellular forms of HSV-2. The 90% inhibitory concentration (IC₉₀) of carnosic acid was between 25 and 6.25 μg/mL. Proteomics and high-resolution respirometry showed that carnosic acid suppressed key ATP synthesis pathways such as glycolysis, citrate cycle, and oxidative phosphorylation. Inhibition of oxidative phosphorylation also suppressed HSV-2 replication up to 39.94-fold. These results indicate that the antiviral action of carnosic acid includes the inhibition of ATP generation by suppressing key energy production pathways. Carnosic acid holds promise as a potential novel antiviral agent against HSV-2.

Despite their clinical effectiveness, a growing body of evidence has shown that many classes of antibiotics lead to mitochondrial dysfunction. Ceftriaxone and Rifaximin are first choice perioperative antibiotics in gastrointestinal surgery targeting fundamental processes of intestinal bacteria; however, may also have negative consequences for the host cells. In this study, we investigated their direct effect on mitochondrial functions in vitro, together with their impact on ileum, colon and liver tissue. Additionally, their impact on the gastrointestinal microbiome was studied in vivo, in a rat model. Rifaximin significantly impaired the oxidative phosphorylation capacity (OxPhos) and leak respiration in the ileal mucosa, in line with increased oxidative tissue damage and histological changes following treatment. Ceftriaxone prophylaxis led to similar changes in the colon mucosa. The composition and diversity of bacterial communities differed extensively in response to antibiotic pre-treatment. However, the relative abundances of the toxin producing species were not increased. We have confirmed the harmful effects of prophylactic doses of Rifaximin and Ceftriaxone on the intestinal mucosa and that these effects were related to the mitochondrial dysfunction. These experiments raise awareness of mitochondrial side effects of these antibiotics that may be of clinical importance when evaluating their adverse effects on bowel mucosa.

Background: Fixed‐ratio combinations (FRCs) provide an alternative to intensified conservative insulin treatments (ICTs); however, therapy simplification in patients with high total daily insulin dose (TDD) or high HbA _1c is a debated issue; additionally, its influence on target organ damage (TOD) is less known. Methods: Data were retrospectively collected from patients with Type 2 diabetes, including 58 patients who continued ICT and 104 patients who underwent therapy simplification between January 1, 2017, and January 1, 2023. Patient characteristics and therapy details are at baseline and 3, 6, 12, and 24 months after FRC initiation. Results: HbA _1c significantly decreased in both groups (−0.9% [−1.6%, −0.5%] with ICT vs. −1.3% [−2.1%, −0.3%] with FRC), whereas body weight significantly decreased only after simplification (−1 kg [−4, 1] vs. −5 kg [−7, −2]). Diabetes duration was not associated with therapy efficacy. Significant HbA _1c reduction and FRC dose elevation occurred earlier in patients with an initial HbA _1c > 8.0 % than in those with an initial HbA _1c < 8.0 % . FRC dose was significantly higher at 3 months in patients with a TDD of > 60 U/day than in those with lower TDD. Relative risk reduction with therapy simplification was 72.1%, 50.6%, 32.3%, and 59.7% for hypoglycemia, renal function decline, microalbuminuria, and macrovascular complications, respectively. Risk of retinopathy, neuropathy, and chronic kidney disease did not significantly change with FRCs. Discussion: FRCs are safe and as effective as ICT even in patients with high initial HbA _1c , high TDD, or long diabetes duration. A protective role of FRCs in diabetic ASCVD has been proven, but their protective role in CKD was not observed. Conclusions: The significant improvements in glycemic and weight control, as well as in TODs, suggest that therapy simplification may represent a more favorable approach compared to the continuation of previous ICT even in patients characterized by high baseline TDD and HbA _1c levels.

Background: Type 2 diabetes mellitus (T2DM) is often associated with hyperuricemia, both conditions worsening kidney function. Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve glycemic control and kidney function; however, data on their long-term antihyperuricemic effects in real-world clinical settings remain limited. Therefore, we aimed to compare the effects of SGLT2 inhibitors versus allopurinol on serum uric acid (sUA), kidney function, and clinical outcomes. Methods: This retrospective cohort study evaluated patients with T2DM and hyperuricemia initiated on 10 mg empagliflozin (n = 70), 10 mg dapagliflozin (n = 78), or 100 mg allopurinol (n = 66) between 1 January 2017, and 1 January 2020. Drug dosages were kept constant throughout the study. Baseline and follow-up data (3, 6, 12, 24, and 36 months) were collected. Results: Over 36 months, empagliflozin and dapagliflozin significantly reduced sUA (from 452 (95) to 399 (69) µmol/L and from 450 (81) to 364 (71) µmol/L, respectively) and stabilized eGFR without a significant decline. Allopurinol also reduced sUA (from 430 (89) to 345 (69) µmol/L) but was associated with a progressive eGFR decline (from 70 (35) to 57 (32) mL/min/1.73 m²). Mortality was the highest in the allopurinol group; however, therapy discontinuation was the lowest with this treatment. Conclusions: SGLT2 inhibitors achieved comparable sUA reduction to allopurinol by 36 months while preserving eGFR. Allopurinol was associated with higher mortality and hospitalization rates; SGLT2 inhibitor therapy was associated with favorable multidomain outcomes, but strategies to address adverse effects are needed to enhance adherence.

Background: Hyperuricemia frequently coexists with type 2 diabetes mellitus (T2DM), contributing to a heterogeneous patient population. While previous analyses compared the overall longitudinal effects of allopurinol and SGLT2 inhibitors in this cohort, it remains unclear whether baseline metabolic heterogeneity modifies treatment response. This study aimed to determine whether data-driven metabolic clustering identifies phenotypic subgroups with prognostic or predictive relevance in hyperuricemic T2DM. Methods: In a retrospective cohort of 224 patients with T2DM and hyperuricemia, model-based clustering was applied to age, diabetes duration, body mass index (BMI), serum uric acid (sUA), HbA1c, eGFR, and sex. A sensitivity analysis excluded outliers, yielding 207 patients. Longitudinal trajectories of eGFR and sUA were assessed using linear mixed-effects models and individual slopes. Effect modification by cluster was tested via three-way interactions and analysis of covariance. Results: Clustering identified two groups with weak separation: an adipose–metabolic cluster (n = 116; exclusively male, BMI 33.1 ± 5.7 kg/m², sUA 478 ± 62 µmol/L) and a lean–metabolic cluster (n = 91; exclusively female, BMI 31.3 ± 6.0 kg/m², sUA 426 ± 67 µmol/L). Treatment-agnostic analyses showed no differences in eGFR and sUA slopes or in all-cause mortality across clusters. In both clusters, SGLT2 inhibitors yielded significantly more favourable eGFR slopes than allopurinol, while sUA reductions were comparable across treatments. No significant three-way interactions were detected. Conclusions: In this cohort, although baseline metabolic characteristics differ among patients, using the selected baseline variables, no clinically actionable treatment-relevant phenotypes were identified.