Background: The search for effective natural alternatives to synthetic non-steroidal antiinflammatory drugs (NSAIDs), which are often associated with undesirable side effects, is an important axis of current research. The slime of the snail Helix aspersa Müller, is a traditional remedy that deserves scientific investigation for its potential therapeutic properties. Purpose: This study aimed to comprehensively evaluate the anti-inflammatory effects of Helix aspersa Müller slime using a combination of in vitro, in vivo, and in silico methodologies. Methods: In vitro analyses included assays for inhibition of protein denaturation, antiprotease and antilipoxygenase activities, and membrane stabilization, with diclofenac and indomethacin as reference standards. The in vivo component involved a rat model of auricular edema to measure the reduction of swelling and attenuation of oxidative stress. Molecular docking simulations were conducted to analyze the binding affinity of slime constituents for key inflammatory targets. Results: The slime exhibited potent, dose-dependent anti-inflammatory activity. In vitro, it inhibited protein denaturation by up to 90.41% at 500 µg/mL, with antiprotease, antilipoxygenase, and membrane-stabilizing effects comparable to standard drugs. In vivo, it reduced auricular edema in rats by 76.68% at a dose of 500 µg/mL, exceeding the efficacy of diclofenac and reducing oxidative stress. Molecular docking confirmed strong binding affinities with key inflammatory receptors, delineating a multimodal mechanism of action. Conclusion: The secretion of H. aspersa Müller demonstrates exceptional anti-inflammatory and antioxidant properties, validating its potential as a viable natural alternative to conventional NSAIDs for the management of inflammatory conditions and oxidative stress-related disorders.
Background: The HSP90 and CDC37 molecular chaperone complex governs the stability and function of numerous client protein kinases, making it a crucial cancer target. Given their central role, disrupting this interaction induces proteotoxic stress and inhibits tumor progression. Therapeutic peptides are the mainstay of treatment for disruption of key interactions, yet they face limitations such as toxicity, resistance, and poor stability. Aim: This study aims to leverage peptidomimetics as novel disruptors of the HSP90–CDC37 interaction. Methods: Two peptides, a 9-mer and a 7-mer, were rationally designed by analyzing key regions facilitating HSP90–CDC37 complex formation. In silico mutational analysis identified crucial residues essential for interaction and ultimately supported the retrieval of peptidomimetic compounds. Molecular docking and binding free energy analysis were employed to explore the affinity of the mimetics for HSP90. The ADMET screening ensured drug-like properties of the compounds. Results: Among the tested compounds, MMs02350546 emerged as the most promising, maintaining strong interactions with the critical Glu47 residue, disrupting ATPase activity, and destabilizing oncogenic proteins. Molecular dynamics simulations provided insight into the atomic-level fluctuations upon ligand binding and confirmed the favorable positioning of the molecule in the binding pocket of HSP90. Conclusion: Collectively, the findings highlight MMs02350546 as a potential disruptor of HSP90–CDC37 interaction, presenting a promising therapeutic strategy against cancer via chaperone complex destabilization. The molecular feature, particularly the presence of the triazole moiety in the mimetic, is hypothesized to play a pivotal role in the compound’s bioactivity. This study may further pave the way toward preclinical evaluation of peptidomimetics as a novel modulator of oncogenic protein stability.
A 70-year-old woman with a history of hepatocellular carcinoma and bone metastasis underwent percutaneous vertebroplasty for multilevel pathological vertebral compression fractures due to back pain persisting despite conservative treatment. Subsequently, she reported significant pain relief; however, on postoperative day 1, she complained of intermittent, diffuse, and severe abdominal pain. Imaging examination revealed free air in the retroperitoneum and paraspinal space, suggesting hollow organ perforation. She refused exploratory surgery and was consequently discharged against medical advice with only oral antibiotics. Two weeks later, she returned for follow-up. She was in good condition with stable vital signs and no signs of toxic infection. Another follow-up appointment was suggested 2 weeks later, but the patient refused, citing a lack of discomfort.
Background: Although observational studies show a positive association between alkaline phosphatase (ALP) levels and mortality, a causal study is not yet available. Objective: We conducted a retrospective cohort study and a systematic one-sample Mendelian randomization (MR) study to investigate the causality of ALP on natural-cause mortality. Methods: The study used a hospital-based cohort of Asian patients recruited from the China Medical University Hospital (CMUH) and a community-based cohort of white European participants from the UK Biobank (UKB). Two retrospective cohorts included 43,994 patients from CMUH and 80,941 participants from UKB, all aged 50–55 years, with ALP measurements. For the MR analysis, the study included 114,692 patients from CMUH and 436,583 participants from UKB, with both ALP measurements and genetic data. Natural-cause mortality excluded deaths from suicide, homicide, or accidents. Results: Compared with patients with normal ALP levels, those with high ALP levels had a significantly increased risk of natural-cause mortality in both the CMUH (adjusted hazard ratio [aHR], 3.43; 95% confidence interval [CI], 2.98–3.95) and UKB (aHR, 2.08; 95% CI, 1.85–2.34) cohorts. A significant dose-response relationship was observed. However, the MR analysis did not provide evidence for causality between elevated ALP levels and natural-cause mortality in either the CMUH or UKB cohorts. Conclusions: Our study reinforced a dose-dependent relationship between total ALP levels and natural-cause mortality across ancestries. However, MR analyses in both Asian and European populations did not support a causal role of total ALP. Future research should focus on verifying whether these findings are consistent for specific ALP isoforms and disease outcomes.
