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Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of hematopoietic stem cell transplantation in which systemic complement activation induces endothelial injury, leading to microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction. TA-TMA often progresses rapidly and has historically been associated with high mortality. Over the last decade, increasing recognition of complement activation as a central driver of TA-TMA has shifted management from largely empirical supportive care toward mechanism-based therapy. This review summarizes recent advances in complement-targeted therapies for TA-TMA and outlines key aspects of pathophysiology, risk factors, and monitoring that inform therapeutic decision-making. Earlier non–complement-directed therapies, including calcineurin inhibitor modification, plasma exchange, defibrotide, and rituximab, showed limited and inconsistent benefit. In contrast, complement-targeted therapies have advanced the treatment of TA-TMA. Prospective and large cohort data support the clinical activity of eculizumab (C5 inhibitor), with meaningful improvements in survival and organ recovery. Ravulizumab (long-acting C5 inhibitor) has shown encouraging phase 3 results, and narsoplimab (MASP-2 inhibitor), which became the first approved treatment for TA-TMA, has demonstrated promising outcomes, including activity in some patients previously exposed to C5 inhibition. In addition, newer agents targeting C5, C3, or factor B are expanding the therapeutic horizon for TA-TMA, although efficacy data are still limited for some of these therapies. Overall, complement-targeted therapies represent a therapeutic advance in TA-TMA, and ongoing prospective studies will be crucial to define optimal agent selection, sequencing, and integration into clinical practice.

In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug–drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme–intermediate complex that irreversibly reduces enzyme activity. This type of inhibition can cause interactions with drugs such as omeprazole, paroxetine, macrolide antibiotics, or mirabegron. A good understanding of mechanism-based inhibition and proper clinical management is needed by clinicians when such drugs are prescribed. It is important to recognize mechanism-based inhibition since it cannot be prevented by separating the time of administration of the interacting drugs. Here, we provide a comprehensive overview of the different types of mechanism-based inhibition, along with illustrative examples of how mechanism-based inhibition might affect prescribing and clinical behaviors.

The preBötzinger Complex (preBötC), a medullary network critical for breathing, relies on excitatory interneurons to generate the inspiratory rhythm. Yet, half of preBötC neurons are inhibitory, and the role of inhibition in rhythmogenesis remains controversial. Using optogenetics and electrophysiology in vitro and in vivo, we demonstrate that the intrinsic excitability of excitatory neurons is reduced following large depolarizing inspiratory bursts. This refractory period limits the preBötC to very slow breathing frequencies. Inhibition integrated within the network is required to prevent overexcitation of preBötC neurons, thereby regulating the refractory period and allowing rapid breathing. In vivo, sensory feedback inhibition also regulates the refractory period, and in slowly breathing mice with sensory feedback removed, activity of inhibitory, but not excitatory, neurons restores breathing to physiological frequencies. We conclude that excitation and inhibition are interdependent for the breathing rhythm, because inhibition permits physiological preBötC bursting by controlling refractory properties of excitatory neurons. Excitatory neurons in the preBötzinger Complex generate bursting activity responsible for breathing, but these alone cannot generate physiological breathing frequencies. Here the authors show how inhibition regulates refractory properties of excitatory neurons to allow dynamic breathing rhythms.

Central post-stroke pain (CPSP) is a neuropathic pain syndrome that can occur after a cerebrovascular accident. This syndrome is characterised by pain and sensory abnormalities in the body parts that correspond to the brain territory that has been injured by the cerebrovascular lesion. The presence of sensory loss and signs of hypersensitivity in the painful area in patients with CPSP might indicate the dual combination of deafferentation and the subsequent development of neuronal hyperexcitability. The exact prevalence of CPSP is not known, partly owing to the difficulty in distinguishing this syndrome from other pain types that can occur after stroke (such as shoulder pain, painful spasticity, persistent headache, and other musculoskeletal pain conditions). Future prospective studies with clear diagnostic criteria are essential for the proper collection and processing of epidemiological data. Although treatment of CPSP is difficult, the most effective approaches are those that target the increased neuronal hyperexcitability.

Partial reversible inhibition of enzymes, also called hyperbolic inhibition, is an uncommon mechanism of reversible inhibition, resulting from a productive enzyme–inhibitor complex. This type of inhibition can involve competitive, mixed, non-competitive and uncompetitive inhibitors. While full reversible inhibitors show linear plots for reciprocal enzyme initial velocity versus inhibitor concentration, partial inhibitors produce hyperbolic plots. Similarly, dose–response curves show residual fractional activity of enzymes at high doses. This article reviews the theory and methods of analysis and discusses the significance of this type of reversible enzyme inhibition in metabolic processes, and its implications in pharmacology and toxicology.

Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth-leading cause of cancer-related death in North America. Matrix metalloproteinases (MMPs) have long been targeted as a potential anticancer therapy because of their seminal role in angiogenesis and extracellular matrix (ECM) degradation of tumor survival and invasion. However, the inhibition specificity to MMPs and the molecular-level understanding of the inhibition mechanism remain largely unresolved. Here, we found that endohedral metallofullerenol Gd@C 82 (OH) 22 can successfully inhibit the neoplastic activity with experiments at animal, tissue, and cellular levels. Gd@C 82 (OH) 22 effectively blocks tumor growth in human pancreatic cancer xenografts in a nude mouse model. Enzyme activity assays also show Gd@C 82 (OH) 22 not only suppresses the expression of MMPs but also significantly reduces their activities. We then applied large-scale molecular-dynamics simulations to illustrate the molecular mechanism by studying the Gd@C 82 (OH) 22 –MMP-9 interactions in atomic detail. Our data demonstrated that Gd@C 82 (OH) 22 inhibits MMP-9 mainly via an exocite interaction, whereas the well-known zinc catalytic site only plays a minimal role. Steered by nonspecific electrostatic, hydrophobic, and specific hydrogen-bonding interactions, Gd@C 82 (OH) 22 exhibits specific binding modes near the ligand-specificity loop S1′, thereby inhibiting MMP-9 activity. Both the suppression of MMP expression and specific binding mode make Gd@C 82 (OH) 22 a potentially more effective nanomedicine for pancreatic cancer than traditional medicines, which usually target the proteolytic sites directly but fail in selective inhibition. Our findings provide insights for de novo design of nanomedicines for fatal diseases such as pancreatic cancer.

Reciprocal inhibition (RI) between leg muscles is crucial for smooth movement. Pedaling is a rhythmic movement that can increase RI in healthy individuals. Transcutaneous spinal cord stimulation (tSCS) stimulates spinal neural circuits by targeting the afferent fibers. Pedaling with simultaneous tSCS may modulate the plasticity of the spinal neural circuit and alter neural activity based on movement and muscle engagement. This study investigated the RI changes after pedaling and tSCS and determined the phase of pedaling in which tSCS should be applied for optimal RI modulation in healthy individuals. Eleven subjects underwent three interventions: pedaling combined with tSCS during the early phase of lower extension (phase 1), pedaling combined with tSCS during the late phase of lower flexion (phase 4) of the pedaling cycle, and pedaling combined with sham tSCS. The RI from the tibialis anterior to the soleus muscle was assessed before, immediately after, 15 min, and 30 min after the intervention. RI increased immediately after phase 4 and pedaling combined with sham tSCS, whereas no changes were observed after phase 1. These results demonstrate that tSCS modulates RI changes induced by pedaling in a stimulus phase-dependent manner in healthy individuals. However, the mechanism involved in this intervention needs to be explored to achieve higher efficacy.

Cryopreservation technology has developed into a fundamental and important supporting method for biomedical applications such as cell‐based therapeutics, tissue engineering, assisted reproduction, and vaccine storage. The formation, growth, and recrystallization of ice crystals are the major limitations in cell/tissue/organ cryopreservation, and cause fatal cryoinjury to cryopreserved biological samples. Flourishing anti‐icing materials and strategies can effectively regulate and suppress ice crystals, thus reducing ice damage and promoting cryopreservation efficiency. This review first describes the basic ice cryodamage mechanisms in the cryopreservation process. The recent development of chemical ice‐inhibition molecules, including cryoprotectant, antifreeze protein, synthetic polymer, nanomaterial, and hydrogel, and their applications in cryopreservation are summarized. The advanced engineering strategies, including trehalose delivery, cell encapsulation, and bioinspired structure design for ice inhibition, are further discussed. Furthermore, external physical field technologies used for inhibiting ice crystals in both the cooling and thawing processes are systematically reviewed. Finally, the current challenges and future perspectives in the field of ice inhibition for high‐efficiency cryopreservation are proposed. This work describes the fundamental mechanisms of ice injury during cryopreservation, and introduces the state‐of‐the‐art ice‐inhibition materials and strategies, both in the cooling and thawing processes, for high‐efficiency cryopreservation. Future perspectives and challenges are also proposed to motivate the development of cell, tissue, and organ cryopreservation and offer bright new inspiration for cryobiology.

Abstract A new series of bis-triazole 19a-l was synthesised for the purpose of being hybrid molecules with both anti-inflammatory and anti-cancer activities and assessed for cell cycle arrest, NO release. Compounds 19c, 19f, 19h, 19 l exhibited COX-2 selectivity indexes in the range of 18.48 to 49.38 compared to celecoxib S.I. = 21.10), inhibit MCF-7 with IC50 = 9–16 μM compared to tamoxifen (IC50 = 27.9 μM). and showed good inhibitory activity against HEP-3B with IC50 = 4.5–14 μM compared to sorafenib (IC50 = 3.5 μM) (HEP-3B). Moreover, derivatives 19e, 19j, 19k, 19 l inhibit HCT-116 with IC50 = 5.3–13.7 μM compared to 5-FU with IC50 = 4.8 μM (HCT-116). Compounds 19c, 19f, 19h, 19 l showed excellent inhibitory activity against A549 with IC50 = 3–4.5 μM compared to 5-FU with IC50 = 6 μM (A549). Compounds 19c, 19f, 19h, 19 l inhibit aromatase (IC50 of 22.40, 23.20, 22.70, 30.30 μM), EGFR (IC50 of 0.112, 0.205, 0.169 and 0.066 μM) and B-RAFV600E (IC50 of 0.09, 0.06, 0.07 and 0.05 μM).

The contingent negative variation, a slow cortical potential, occurs when humans are warned by a stimulus about an upcoming task. The cognitive processes that give rise to this EEG potential are not yet well understood. To explain these processes, we adopt a recently developed theoretical framework from the area of perceptual decision-making. This framework assumes that the basal ganglia control the tradeoff between fast and accurate decision-making in the cortex. It suggests that an increase in cortical excitability serves to lower response caution, which results in faster but more error prone responding. We propose that the CNV reflects this increased cortical excitability. To test this hypothesis, we conducted an EEG experiment in which participants performed the random dot motion task either under speed or under accuracy stress. Our results show that trial-by-trial fluctuations in participants' response speed as well as model-based estimates of response caution correlated with single-trial CNV amplitude under conditions of speed but not accuracy stress. We conclude that the CNV might reflect adjustments of response caution, which serves to enhance quick decision-making. •A neurophysiological model of decision-making is applied to EEG data.•Single-trial estimates of speed-accuracy tradeoff are correlated with EEG data.•Contingent negative variation reflects the setting of the speed-accuracy tradeoff.•Speed-accuracy tradeoff is set before the decision process.