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Chronic kidney disease (CKD) progression is associated with persisting oxidative stress, which impairs the NO-sGC-cGMP signaling cascade through the formation of oxidized and heme-free apo-sGC that cannot be activated by NO. Runcaciguat (BAY 1101042) is a novel, potent, and selective sGC activator that binds and activates oxidized and heme-free sGC and thereby restores NO-sGC-cGMP signaling under oxidative stress. Therefore, runcaciguat might represent a very effective treatment option for CKD/DKD. The potential kidney-protective effects of runcaciguat were investigated in ZSF1 rats as a model of CKD/DKD, characterized by hypertension, hyperglycemia, obesity, and insulin resistance. ZSF1 rats were treated daily orally for up to 12 weeks with runcaciguat (1, 3, 10 mg/kg/bid) or placebo. The study endpoints were proteinuria, kidney histopathology, plasma, urinary biomarkers of kidney damage, and gene expression profiling to gain information about relevant pathways affected by runcaciguat. Furthermore, oxidative stress was compared in the ZSF1 rat kidney with kidney samples from DKD patients. Within the duration of the 12-week treatment study, kidney function was significantly decreased in obese ZSF1 rats, indicated by a 20-fold increase in proteinuria, compared to lean ZSF1 rats. Runcaciguat dose-dependently and significantly attenuated the development of proteinuria in ZSF1 rats with reduced uPCR at the end of the study by −19%, −54%, and −70% at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo treatment. Additionally, average blood glucose levels measured as HbA1C, triglycerides, and cholesterol were increased by five times, twenty times, and four times, respectively, in obese ZSF1 compared to lean rats. In obese ZSF1 rats, runcaciguat reduced HbA1c levels by −8%, −34%, and −76%, triglycerides by −42%, −55%, and −71%, and cholesterol by −16%, −17%, and −34%, at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo. Concomitantly, runcaciguat also reduced kidney weights, morphological kidney damage, and urinary and plasma biomarkers of kidney damage. Beneficial effects were accompanied by changes in gene expression that indicate reduced fibrosis and inflammation and suggest improved endothelial stabilization. In summary, the sGC activator runcaciguat significantly prevented a decline in kidney function in a DKD rat model that mimics common comorbidities and conditions of oxidative stress of CKD patients. Thus, runcaciguat represents a promising treatment option for CKD patients, which is in line with recent phase 2 clinical study data, where runcaciguat showed promising efficacy in CKD patients (NCT04507061). [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx/mTRG2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx/mTRG2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx/mTRG2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx/mTRG2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx/mTRG2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD. [ABSTRACT FROM AUTHOR]

Simple Summary: Optimising horse–human relationships can promote positive experiences and advance the welfare and safety of both dyad members. Attachment and bonding are key components in such relationships, and horses are good candidate subjects for studying bonding processes due to their social nature, artificial selection for trainability and their dependence on human care in a domestic context. However, the factors that contribute to successful relationships remain unclear. This preliminary study on 12 horses investigated whether horses develop an attachment bond with their trainer after a short period of frequent interactions. The study also aimed to explore how the type of training method (negative reinforcement and two types of combined reinforcement) may affect the horse–human relationship and how this manifests as ease of handling in a novel environment. The horses showed reduced reactions in both the fear test (encountering novel objects with the trainer and a stranger present while moving freely) and handling test (encountering novel objects while being led by the trainer versus a stranger) after training compared to before training. However, we could not provide conclusive evidence that horse–human relationships established during training constitute an attachment. Suggestions for future studies are provided. The study investigated equine responses to novelty and handling, aiming to reveal whether horse–human relationships reflect criteria of an attachment bond. Twelve adult Standardbreds were subjected to a fear-eliciting test (novel objects presented close to two humans) and a handling test (being led passing novel objects) to study attachment-related behaviours and ease of handling. The tests were performed both before (pre-test) and after (post-test) horses had been trained by the same female handler (10 sessions of 15 min). Horses were assigned to three groups of four, each of which underwent different operant conditioning protocols: negative reinforcement (NR; pressure, release of lead, and whip tap signals) or combined NR with either positive reinforcement using food (PRf) or wither scratching (PRs). Results showed that neither familiarity of the person nor training method had a significant impact on the horses' behavioural responses in the post-tests. However, horses showed decreased heart rates between pre- and post-tests, which may indicate habituation, an effect of training per se, or that the presence of the familiar trainer served to calm the horses during the challenging situations. There were large individual variations among the horses' responses and further studies are needed to increase our understanding of horse–human relationships. [ABSTRACT FROM AUTHOR]