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Integrity of epithelial and endothelial cell barriers is of critical importance for health, barrier disruption is a hallmark of numerous diseases, of which many are driven by carbonyl stressors such as methylglyoxal (MG). Carnosine and anserine exert some MG-quenching activity, but the impact of these and of other histidine containing dipeptides on cell barrier integrity has not been explored in detail. In human proximal tubular (HK-2) and umbilical vein endothelial (HUVEC) cells, exposure to 200 µM MG decreased transepithelial resistance (TER), i.e. increased ionic permeability and permeability for 4-, 10- and 70-kDa dextran, membrane zonula occludens (ZO-1) abundance was reduced, methylglyoxal 5-hydro-5-methylimidazolones (MG-H1) formation was increased. Carnosine, balenine (ß-ala-1methyl-histidine) and anserine (ß-ala-3-methyl-histidine) ameliorated MG-induced reduction of TER in both cell types. Incubation with histidine, 1-/3-methylhistidine, but not with ß-alanine alone, restored TER, although to a lower extent than the corresponding dipeptides. Carnosine and anserine normalized transport and membrane ZO-1 abundance. Aminoguanidine, a well-described MG-quencher, did not mitigate MG-induced loss of TER. Our results show that the effects of the dipeptides on epithelial and endothelial resistance and junction function depend on the methylation status of histidine and are not exclusively explained by their quenching activity.

The aim of this study was to analyse whether symptoms of temporomandibular disorders (TMD) or bruxism were associated with the progression of periodontitis. A potential association could be explained by a decreased level of oral hygiene in patients presenting with orofacial pain. 148 patients diagnosed with periodontitis received individual department specific screening for symptoms of TMD or bruxism prior to initial treatment and were stratified into patients with symptoms related to TMD or bruxism (STMDoB = 30) and without symptoms (NO_STMDoB = 118). Progression of periodontitis was determined by tooth loss (TL) as well as radiographic bone loss (RBL), using longitudinal radiographic data with a follow-up of at least 5 years. Patients presented with a median of 60 [52;68] years, 25 [21;27] teeth and a mean RBL of 50.5 ± 16.4% not showing difference among both study groups. Neither RBL [1.2 [0.0;6.0] % STMDoB vs. 2.9 [0.0;9.1] % NO_STMDoB,  = 0.165] nor TL [1 [0;3] STMDoB vs. 1 [0;3] NO_STMDoB;  = 0.195] differed significantly between both study groups, with equally low periodontal progression in both groups. Regression models revealed no association of any reported symptom of TMD or bruxism with periodontal progression ( : 9.07; CI: -4.09;22.23;  = 0.446 for RBL and rate ratio: 1.09; CI: 0.80;1.47;  = 0.587 for TL). The present data showed no association of STMDoB with periodontal disease progression on the patient level.

Carnosine and anserine supplementation markedLy reduce diabetic nephropathy in rodents. The mode of nephroprotective action of both dipeptides in diabetes, via local protection or improved systemic glucose homeostasis, is uncertain. Global carnosinase-1 knockout mice (Cndp1-KO) and wild-type littermates (WT) on a normal diet (ND) and high fat diet (HFD) (n = 10/group), with streptozocin (STZ)-induced type-1 diabetes (n = 21–23/group), were studied for 32 weeks. Independent of diet, Cndp1-KO mice had 2- to 10-fold higher kidney anserine and carnosine concentrations than WT mice, but otherwise a similar kidney metabolome; heart, liver, muscle and serum anserine and carnosine concentrations were not different. Diabetic Cndp1-KO mice did not differ from diabetic WT mice in energy intake, body weight gain, blood glucose, HbA1c, insulin and glucose tolerance with both diets, whereas the diabetes-related increase in kidney advanced glycation end-product and 4-hydroxynonenal concentrations was prevented in the KO mice. Tubular protein accumulation was lower in diabetic ND and HFD Cndp1-KO mice, interstitial inflammation and fibrosis were lower in diabetic HFD Cndp1-KO mice compared to diabetic WT mice. Fatalities occurred later in diabetic ND Cndp1-KO mice versus WT littermates. Independent of systemic glucose homeostasis, increased kidney anserine and carnosine concentrations reduce local glycation and oxidative stress in type-1 diabetic mice, and mitigate interstitial nephropathy in type-1 diabetic mice on HFD.

Anserine and carnosine have nephroprotective actions; hydrogen sulfide (H2S) protects from ischemic tissue damage, and the underlying mechanisms are debated. In view of their common interaction with HSP70, we studied possible interactions of both dipeptides with H2S. H2S formation was measured in human proximal tubular epithelial cells (HK-2); three endothelial cell lines (HUVEC, HUAEC, MCEC); and in renal murine tissue of wild-type (WT), carnosinase-1 knockout (Cndp1-KO) and Hsp70-KO mice. Diabetes was induced by streptozocin. Incubation with carnosine increased H2S synthesis capacity in tubular cells, as well as with anserine in all three endothelial cell lines. H2S dose-dependently reduced anserine/carnosine degradation rate by serum and recombinant carnosinase-1 (CN1). Endothelial Hsp70-KO reduced H2S formation and abolished the stimulation by anserine and could be restored by Hsp70 transfection. In female Hsp70-KO mice, kidney H2S formation was halved. In Cndp1-KO mice, kidney anserine concentrations were several-fold and sex-specifically increased. Kidney H2S formation capacity was increased 2–3-fold in female mice and correlated with anserine and carnosine concentrations. In diabetic Cndp1-KO mice, renal anserine and carnosine concentrations as well as H2S formation capacity were markedly reduced compared to non-diabetic Cndp1-KO littermates. Anserine and carnosine induce H2S formation in a cell-type and Hsp70-specific manner within a positive feedback loop with CN1.

Anserine and carnosine have nephroprotective actions; hydrogen sulfide (H S) protects from ischemic tissue damage, and the underlying mechanisms are debated. In view of their common interaction with HSP70, we studied possible interactions of both dipeptides with H S. H S formation was measured in human proximal tubular epithelial cells (HK-2); three endothelial cell lines (HUVEC, HUAEC, MCEC); and in renal murine tissue of wild-type (WT), carnosinase-1 knockout -KO) and -KO mice. Diabetes was induced by streptozocin. Incubation with carnosine increased H S synthesis capacity in tubular cells, as well as with anserine in all three endothelial cell lines. H S dose-dependently reduced anserine/carnosine degradation rate by serum and recombinant carnosinase-1 (CN1). Endothelial -KO reduced H S formation and abolished the stimulation by anserine and could be restored by transfection. In female -KO mice, kidney H S formation was halved. In -KO mice, kidney anserine concentrations were several-fold and sex-specifically increased. Kidney H S formation capacity was increased 2-3-fold in female mice and correlated with anserine and carnosine concentrations. In diabetic -KO mice, renal anserine and carnosine concentrations as well as H S formation capacity were markedly reduced compared to non-diabetic -KO littermates. Anserine and carnosine induce H S formation in a cell-type and Hsp70-specific manner within a positive feedback loop with CN1.

Carnosine and anserine supplementation markedLy reduce diabetic nephropathy in rodents. The mode of nephroprotective action of both dipeptides in diabetes, via local protection or improved systemic glucose homeostasis, is uncertain. Global carnosinase-1 knockout mice (Cndp1-KO) and wild-type littermates (WT) on a normal diet (ND) and high fat diet (HFD) (n = 10/group), with streptozocin (STZ)-induced type-1 diabetes (n = 21-23/group), were studied for 32 weeks. Independent of diet, Cndp1-KO mice had 2- to 10-fold higher kidney anserine and carnosine concentrations than WT mice, but otherwise a similar kidney metabolome; heart, liver, muscle and serum anserine and carnosine concentrations were not different. Diabetic Cndp1-KO mice did not differ from diabetic WT mice in energy intake, body weight gain, blood glucose, HbA1c, insulin and glucose tolerance with both diets, whereas the diabetes-related increase in kidney advanced glycation end-product and 4-hydroxynonenal concentrations was prevented in the KO mice. Tubular protein accumulation was lower in diabetic ND and HFD Cndp1-KO mice, interstitial inflammation and fibrosis were lower in diabetic HFD Cndp1-KO mice compared to diabetic WT mice. Fatalities occurred later in diabetic ND Cndp1-KO mice versus WT littermates. Independent of systemic glucose homeostasis, increased kidney anserine and carnosine concentrations reduce local glycation and oxidative stress in type-1 diabetic mice, and mitigate interstitial nephropathy in type-1 diabetic mice on HFD.

In response to cell swelling, volume-regulated anion channels (VRACs) participate in a process known as regulatory volume decrease (RVD). Only recently, first insight into the molecular identity of mammalian VRACs was obtained by the discovery of the leucine-rich repeats containing 8A (LRRC8A) gene. Here, we show that bestrophin 1 (BEST1) but not LRRC8A is crucial for volume regulation in human retinal pigment epithelium (RPE) cells. Whole-cell patch-clamp recordings in RPE derived from human-induced pluripotent stem cells (hiPSC) exhibit an outwardly rectifying chloride current with characteristic functional properties of VRACs. This current is severely reduced in hiPSC-RPE cells derived from macular dystrophy patients with pathologic BEST1 mutations. Disruption of the orthologous mouse gene (Best1 ⁻/⁻) does not result in obvious retinal pathology but leads to a severe subfertility phenotype in agreement with minor endogenous expression of Best1 in murine RPE but highly abundant expression in mouse testis. Sperm from Best1 ⁻/⁻ mice showed reduced motility and abnormal sperm morphology, indicating an inability in RVD. Together, our data suggest that the molecular identity of VRACs is more complex—that is, instead of a single ubiquitous channel, VRACs could be formed by cell type- or tissue-specific subunit composition. Our findings provide the basis to further examine VRAC diversity in normal and diseased cell physiology, which is key to exploring novel therapeutic approaches in VRAC-associated pathologies. Significance First insight into the molecular identity of volume-regulated anion channel (VRAC) emerged only recently by demonstrating a role for leucine-rich repeats containing 8A (LRRC8A) in channel activity. Our results now expand on VRAC biology, suggesting a model where VRAC subunit composition is cell type- or tissue-specific rather than a single ubiquitous channel formed solely by LRRC8A. Here, we show that bestrophin 1 (BEST1), but not LRCC8A, is crucial in cell volume regulation in retinal pigment epithelium (RPE) cells differentiated from human-induced pluripotent stem cells (hiPSCs). VRAC-mediated currents were strongly reduced in hiPSC-RPE from macular dystrophy patients with pathologic BEST1 mutations. Our model is further supported by in vivo effects of Best1 deficiency in the mouse that manifest as severe subfertility phenotype due to enhanced abnormal sperm morphology related to impaired volume regulation.

Ebola virus (EBOV) causes severe disease in humans, with mortality as high as 90%. The small-molecule antiviral drug remdesivir (RDV) has demonstrated a survival benefit in EBOV-exposed rhesus macaques. Here, we characterize the efficacy of multiple intravenous RDV dosing regimens on survival of rhesus macaques 42 days after intramuscular EBOV exposure. Thirty rhesus macaques underwent surgical implantation of telemetry devices for the fine-scale monitoring of body temperature and activity, as well as central venous catheters, to enable treatment administration and blood collection. Treatment, consisting of a loading dose of RDV followed by once-daily maintenance doses for 11 days, was initiated 4 days after virus exposure when all animals were exhibiting disease signs consistent with incipient EBOV disease as well as quantifiable levels of EBOV RNA in plasma. In the RDV treatment groups receiving loading/maintenance doses of 5/2.5 mg/kg, 10/5 mg/kg, and 20/10 mg/kg, a total of 6 of 8 (75%), 7 of 8 (87.5%), and 5 of 7 (71.4%) animals survived, respectively. In the vehicle control group, one of seven animals (14.3%) survived. The improved survival rate compared to the control group was statistically significant only for the 10/5 mg/kg RDV treatment group. This treatment regimen also resulted in a significantly lower systemic viral load compared to the vehicle control after a single RDV treatment. All three RDV regimens produced a significantly lower systemic viral load after two treatments. For most animals, RDV treatment, regardless of dose, resulted in the amelioration of many of the clinical–pathological changes associated with EBOV disease in this model.

Major surgery is associated with significant morbidity and a reduced quality of life, particularly among older adults and individuals with frailty and impaired functional capacity. Multimodal prehabilitation can enhance functional recovery after surgery and reduce postoperative complications. Digital prehabilitation has the potential to be a resource-sparing and patient-empowering tool that improves patients' preoperative status; however, little remains known regarding their safety and accuracy as medical devices. This study aims to test the accuracy and validity of a new software in comparison to the gold-standard electrocardiogram (ECG)-based heart rate measurement. The PROTEGO MAXIMA trial was a prospective interventional pilot trial assessing the validity, accuracy, and safety of an app-based exercise program. The Prehab App calculates a personalized, risk-stratified aerobic interval training plan based on individual risk factors and utilizes wearables to monitor heart rate. Healthy students and patients undergoing major surgery were enrolled. A structured risk assessment was conducted, followed by a 6-minute walking test and a 37-minute supervised interval session. During the exercise, patients wore app-linked wearables for heart rate and distance measurements, which were compared with standard ECG and treadmill measurements. Safety, accuracy, and usability assessments included testing alarm signals, while the occurrence of adverse events served as the primary and secondary outcome measures. A total of 75 participants were included. The mean heart rate differences between wearables and standard ECG were ≤5 bpm (beats per minute) with a mean absolute percentage error of ≤5%. Regression analysis revealed a significant impact of the BMI (odds ratio 0.90, 95% CI 0.82-0.98, P=.02) and Timed Up and Go Test score (odds ratio 0.12, 95% CI 0.03-0.55, P=.006) on the accuracy of heart rate measurement; 29 (39%) patients experienced adverse events: pain (5/12, 42%), ECG electrode-related skin irritations (2/42, 17%), dizziness (2/42, 17%), shortness of breath (2/42, 17%), and fatigue (1/42, 8%). No cardiovascular or serious adverse events were reported, and no serious device deficiency was detected. There were no indications of clinically meaningful overexertion based on laboratory values measured before and after the 6-minute walking test and exercise. The differences in means and ranges were as follows: lactate (mmol/l), mean 0.04 (range -3 to 6; P=.47); creatinine kinase (U/l), mean 12 (range -7 to 43; P<.001); and sodium (mmol/l), mean -2 (range -11 to 12; P<.001). The interventional trial demonstrated the high safety of the exercise program and the accuracy of heart rate measurements using commercial wearables in patients before major surgery, paving the way for potential remote implementation in the future. German Clinical Trials Register DRKS00026985; https://drks.de/search/en/trial/DRKS00026985 and European Database on Medical Devices (EUDAMED) CIV-21-07-0307311. RR2-10.1136/bmjopen-2022-069394.

The year 2021 has brought new momentum to climate protection efforts in Germany. The amendment to the Climate Protection Act stipulates a 65% reduction in greenhouse gas emissions by 2030 compared to 1990. A major contribution to this will come from a massive expansion of electricity generation from renewable energies. Following the tightening of the climate protection measures, the question arises as to whether the current electricity market design and the associated remuneration rules for electricity generation are still suitable for achieving the goals of security of supply and low prices stipulated in the Energy Industry Act, even with an electricity market dominated by renewable energies. Das Jahr 2021 hat in Deutschland neuen Schwung in die Bemuhungen zum Klimaschutz gebracht. Die Novelle des Klimaschutzgesetzes schreibt eine Reduktion der Treibhausgasemissionen um 65% bis zum Jahr 2030 gegenuber 1990 fest. Massgeblich dazu beitragen soll ein massiver Ausbau der Stromerzeugung aus erneuerbaren Energien. Nach Verscharfung der Klimaschutzmassnahmen stellt sich die Frage, ob das bisherige Strommarktdesign und die damit einhergehenden Vergutungsregeln fur die Stromerzeugung auch bei einem von erneuerbaren Energien dominierten Strommarkt weiterhin geeignet sind, um die im Energiewirtschaftsgesetz festgeschriebenen Ziele der Versorgungssicherheit und Preisgunstigkeit bestmoglich zu erreichen.