Toxins

Blarina paralytic peptides (BPPs), neurotoxins from shrew saliva that paralyze mealworms, share high sequence similarity with human synenkephalin [1–53] (hSYN), a peptide released from proenkephalin together with opioid peptides that mediate analgesic and antidepressant effects in the brain. Both synthetic BPP2 and hSYN induce a hyperpolarizing shift in the human T-type voltage-gated calcium channel (hCa_v3.2) at sub-micromolar concentrations, although only BPP2 causes paralysis in insects. To gain insight into the functions of these insectivorous animal-specific neurotoxins and the largely uncharacterized brain peptides, we investigated the structure prediction of BPPs and SYNs and their interactions with hCa_v3.2. AlphaFold 3 modeling complemented available cryo-EM data and accurately reproduced the overall channel architecture; however, this inactivated-state model proved unsuitable for predicting agonistic binding of BPPs and SYNs. In contrast, docking simulations using an activated-state hCa_v3.2 homology model revealed distinct ligand-dependent differences in binding energies, affinity, and conformational flexibility. Notably, the C-terminal tail of BPPs—particularly its variable length and flexibility—was identified as a key determinant for the interactions with the S4 voltage-sensing domain of the channel. These findings provide new insights into the evolutionary adaptation of venom peptides in mammals and into potential therapeutic strategies targeting neurological disorders.

Aim: To explore the associations between protein-bound uraemic toxins (PBTs), fibre intake and patient-focused outcomes in patients on kidney replacement therapy. Background: Despite removal of small water-soluble uraemic toxins, dialysis patients continue to experience high morbidity and mortality. Recent evidence suggests strong associations between PBTs and poorer patient outcomes and symptom burden. Reducing the generation of PBTs by increasing dietary fibre may be an alternate approach to better patient outcomes. Method: This was a cross-sectional study of haemodialysis (HD), peritoneal dialysis (PD) and kidney transplant patients to determine the associations between uraemic toxins [p-cresyl sulfate (PCS) and indoxyl sulfate (IS)], fibre intake and patient-focused outcomes, incorporating the Integrated Palliative Outcome Scale-Renal (IPOS-renal) and EQ-5D-5L to determine symptom burden and quality of life, while physical capacity was determined using the timed up and go(TUG) test and handgrip strength (HGS). Results: Ninety participants completed the study (n = 30 in each group). There was a correlation between PBTs and the IPOS-renal score, where higher toxin levels were associated with a higher symptom burden. This was the strongest for PCS, where the significance remained after accounting for age and co-morbidities (p < 0.05). Higher PBT levels were also associated with lower HGS (p < 0.05). There was a negative correlation between fibre intake and PBTs, serum PCS (r = −0.36, p < 0.05) and serum IS (r = −0.27, p < 0.05). Lower fibre intake was also associated with a higher symptom burden measured by the IPOS-renal (p < 0.05). Transplant patients consistently performed better, with a reduced symptom burden and improved physical ability compared to dialysis patients. Conclusion: PBTs were associated with symptom burden, and lower physical ability was associated with both PBTs and patient-focused outcomes, and this needs to be further investigated in larger studies.

Background: This study, designed by the Greek Research Alliance for the Study of Headache and Pain (GRASP), sought to prospectively examine whether the treatment with two consecutive OnabotulinumtoxinA (BoNTA) cycles might improve the frequency and severity of chronic migraine (CM) with comorbid bruxism. We also explored whether the potential BoNTA-related alleviation of bruxism can directly influence the improvements in migraine efficacy outcomes. Methods: A total of 58 CM patients with comorbid bruxism at baseline, attaining two consecutive (quarterly given) BoNTA cycles, were studied. The changes in bruxism-related pain were assessed with the 0–10 numeric scale PI-NRS. Bruxism was clinically diagnosed using the self-report Bruxscreen-Q questionnaire. Any phenotypic changes in bruxism, according to Bruxscreen-Q, from baseline (T0) to the last efficacy evaluation follow-up (T1), were analyzed and then compared. Migraine-related efficacy and disability outcomes, mostly mean headache days (MHD), were also compared between T0 and T1. Results: BoNTA exerted significant improvements in bruxism-related pain, with PI-NRS median scores being significantly reduced from 7 at T0 to 3 at T1 (p < 0.001). The rates of masseter hypertrophy at T1 significantly dropped, compared to T0 (chi-square: 16; p < 0.001). Patients also self-reported significant improvements in the Bruxscreen-Q items at T1, compared to T0. At T1, 41/58 (70.7%) patients responded to BoNTA. The significant decrease in MHD frequency at T1 was positively correlated with improvements in bruxism-related pain severity (Pearson’s correlation: 0.710; p < 0.001). Conclusions: BoNTA exerts dual beneficial effects towards both the reduction of migraine frequency and the alleviation of bruxism-related pain and disability. Both of these effects seem closely interrelated in our study.