Therapeutic Medicine Research Articles

Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP)2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

MRNA vaccination, a model of transition from basic biology to medicine

Sixty years elapsed between the discovery of messenger RNA (mRNA) and the use of this molecule in an unprecedented global vaccination campaign that brought the Covid-19 pandemic under control. Sixty years of doubts for some and certainties for others about the possibility of using mRNA-an example of synthetic biology-in therapeutic medicine and vaccinology. Years of "translational" research and development have culminated in the success of anti-Covid-19 mRNA vaccines and the promise of more to come against emerging pathogens. A new paradigm in vaccinology, enabling pandemics to be tackled as they emerge. A lesson to be learned: medical progress is less a question of time than of the critical nature of the biological discovery that underpins it. Before leaving us, François Gros, who played a key role in the discovery of mRNA, was able to appreciate the relevance of this obvious fact.

Design, synthesis, and molecular docking of new phenothiazine incorporated N-Mannich bases as promising antimicrobial agents

The present work aims to synthesize four series of phenothiazine incorporation Mannich bases. Therefore, 10-methyl-10H-phenothiazine-3-sulfonamide (4) which was subjected to react with some secondary amines and formaldehyde to give the Mannich bases 5a-f, and 6–13. Compound 13 was then subjected to react with some secondary amines and formaldehyde to give the corresponding Mannich bases 14a-f. In total, twenty-two new compounds were synthesized and evaluated for in vitro growth inhibition activity against P. aeruginosa, E. coli, and S. aureus. Among the tested compounds, compounds 3, 5a, 5c, 6, 12, 13, 14d, and 14e exhibited good activity with a MIC value (12.5 μg/mL), compounds 5b, 10, 11, 14a, and 14c exhibited strong activity against the growth of S. aureus with a MIC value (6.25 μg/mL), and compound 14b superior against S. aureus with a MIC value (3.125 μg/mL) compared to drug reference ciprofloxacin with MIC value (2 μg/mL). The molecular docking investigation revealed the presence of many derivatives with high binding affinities and distinct interaction patterns with the target protein. Derivatives 14a-e emerged as the most promising possibilities, displaying the greatest binding energies and a varied variety of interaction types, including hydrogen bonding and pi interactions, over different distances, with derivative 14b exhibiting the highest binding energy at S = −8.3093 kcal/mol. These derivatives displayed superior binding affinities and various interaction mechanisms with the target protein, suggesting that they have great promise as lead compounds for future development into therapeutic medicines.

Therapeutic Potential of Nanomaterial-based Drug Delivery

The medical market for sophisticated therapeutic medicine delivery systems is growing at a breakneck pace. There are many benefits to using nanotechnology and nanomaterials in treating chronic human illnesses, such as the ability to target the delivery of drugs to particular areas. Improving the therapeutic effectiveness of current and future medications might be as simple as creating new drug delivery methods. The prime applications related to nanomaterial drug delivery include immunotherapeutic agents, diagnostic testing, cancer therapy and nutraceutical delivery. Nanotechnology has the capacity to collaborate with physics, biologists, chemists and pharmaceutics to form a multidisciplinary contribution in the rise of novel diagnostic and therapeutic technology. Nanomaterials can be used in specific sites targeted by drugs for brain illnesses. These nanodrugs can cause lesser immune response and maintain low inflammatory conditions compared to heavy drug particles. Along with this, nanodrugs can cause damage at the genetic level, create oxidative stress and inhibit cell death according to their particle size, shape, surface and its composition. In this current review various applications, current trends and recent developments in nanomaterials are elucidated. The detailed mechanism and cutting edge nanomaterial based drug delivery were explained along with this.

Current Update on Electrospun Nanofiber Mats as a Wound Healing Drug Carrier

Electrospun nanofiber mats are being researched as attractive wound-healing drug carriers owing to their exclusive features, large active surface area, interlinked porosity, and customizable drug release kinetics. These mats may be infused with antibiotics, growth hormones, or stem cells to hasten the process of healing and lessen the likelihood of problems. Controlled and sustained medication delivery is the key payback of electrospun nanofiber mats. Electrospun nanofiber mats promote wound healing in part because of the favorable milieu they provide cell adhesion and proliferation of the affected tissue due to their enhanced active surface area. Mats of many kinds are discussed in the review. Electrospun nanofiber membranes can be created in a diversity of configurations, along with a single layer, a coaxial structure, and many layers. Recent studies have shown the efficacy of using electrospun nanofiber mats to deliver a variety of therapeutic compounds for wound healing. Treatment of wound infections using antibiotic-loaded electrospun nanofiber mats may help slow the spread of antibiotic-resistant bacteria. Electrospun nanofiber mats supplemented with growth hormones are known to hasten wound healing by encouraging the local tissue’s proliferation and differentiation. Delivery of stem cells to the wound site, where they may develop into new skin cells and stimulate tissue regeneration, can be accomplished with the help of electrospun nanofiber mats. In conclusion, electrospun nanofiber mats provide an exciting new platform for the delivery of drugs to promote wound healing. Their enormous surface area, interconnected porosity, and adaptable drug release kinetics all make them excellent vehicles for delivering a wide range of therapeutic medicines to the wound site.

Ferroptosis in organ fibrosis: From mechanisms to therapeutic medicines.

Fibrosis occurs in many organs, and its sustained progress can lead to organ destruction and malfunction. Although numerous studies on organ fibrosis have been carried out, its underlying mechanism is largely unknown, and no ideal treatment is currently available. Ferroptosis is an iron-dependent process of programmed cell death that is characterized by lipid peroxidation. In the past decade, a growing body of evidence demonstrated the association between ferroptosis and fibrotic diseases, while targeting ferroptosis may serve as a potential therapeutic strategy. This review highlights recent advances in the crosstalk between ferroptosis and organ fibrosis, and discusses ferroptosis-targeted therapeutic approaches against fibrosis that are currently being explored.

Filamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models

Monoclonal antibodies are an increasingly important tool for prophylaxis and treatment of acute virus infections like SARS-CoV-2 infection. However, their use is often restricted due to the time required for development, variable yields and high production costs, as well as the need for adaptation to newly emerging virus variants. Here we use the genetically modified filamentous fungus expression system Thermothelomyces heterothallica (C1), which has a naturally high biosynthesis capacity for secretory enzymes and other proteins, to produce a human monoclonal IgG1 antibody (HuMab 87G7) that neutralises the SARS-CoV-2 variants of concern (VOCs) Alpha, Beta, Gamma, Delta, and Omicron. Both the mammalian cell and C1 produced HuMab 87G7 broadly neutralise SARS-CoV-2 VOCs in vitro and also provide protection against VOC Omicron in hamsters. The C1 produced HuMab 87G7 is also able to protect against the Delta VOC in non-human primates. In summary, these findings show that the C1 expression system is a promising technology platform for the development of HuMabs in preventive and therapeutic medicine.

DT-13 attenuates inflammation by inhibiting NLRP3-inflammasome related genes in RAW264.7 macrophages

Plant derived saponins or other glycosides are widely used for their anti-inflammatory, antioxidant, and anti-viral properties in therapeutic medicine. In this study, we focus on understanding the function of the less known steroidal saponin from the roots of Liriope muscari L. H. Bailey – saponin C (also known as DT-13) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages in comparison to the well-known saponin ginsenoside Rk1 and anti-inflammatory drug dexamethasone. We proved that DT-13 reduces LPS-induced inflammation by inhibiting nitric oxide (NO) production, interleukin-6 (IL-6) release, cycloxygenase-2 (COX-2), tumour necrosis factor-alpha (TNF-α) gene expression, and nuclear factor kappa-B (NFκB) translocation into the nucleus. It also inhibits the inflammasome component NOD-like receptor family pyrin domain containing protein 3 (NLRP3) regulating the inflammasome activation. This was supported by the significant inhibition of caspase-1 and interleukin-1 beta (IL-1β) expression and release. This study demonstrates the anti-inflammatory effect of saponins on LPS-stimulated macrophages. For the first time, an in vitro study shows the attenuating effect of DT-13 on NLRP3-inflammasome activation. In comparison to the existing anti-inflammatory drug, dexamethasone, and triterpenoid saponin Rk1, DT-13 more efficiently inhibits inflammation in the applied cell culture model. Therefore, DT-13 may serve as a lead compound for the development of new more effective anti-inflammatory drugs with minimised side effects.

Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features

Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%–25% of patients with frontotemporal lobar degeneration (FTLD). Data from patients and in vitro/ex vivo pre-clinical studies indicate that anti-GluA3 hIgGs negatively affect glutamatergic neurotransmission. However, whether and how the chronic presence of anti-GluA3 hIgGs triggers synaptic dysfunctions and the appearance of FTLD-related neuropathological and behavioural signature has not been clarified yet. To address this question, we developed and characterized a pre-clinical mouse model of passive immunization with anti-GluA3 hIgGs purified from patients. In parallel, we clinically compared FTLD patients who were positive for anti-GluA3 hIgGs to negative ones.Clinical data showed that the presence of anti-GluA3 hIgGs defined a subgroup of patients with distinct clinical features. In the preclinical model, anti-GluA3 hIgGs administration led to accumulation of phospho-tau in the postsynaptic fraction and dendritic spine loss in the prefrontal cortex. Remarkably, the preclinical model exhibited behavioural disturbances that mostly reflected the deficits proper of patients positive for anti-GluA3 hIgGs. Of note, anti-GluA3 hIgGs-mediated alterations were rescued in the animal model by enhancing glutamatergic neurotransmission with a positive allosteric modulator of AMPA receptors. Overall, our study clarified the contribution of anti-GluA3 autoantibodies to central nervous system symptoms and pathology and identified a specific subgroup of FTLD patients. Our findings will be instrumental in the development of a therapeutic personalised medicine strategy for patients positive for anti-GluA3 hIgGs.

Synthesis, evaluation, and computational chemistry of novel selenenyl sulfides as 3C protease inhibitors with strong cell-based antiviral activity

The 3C protease (3Cpro) is an important enzyme for developing therapeutic medicines against some severe viral infections. In order to discover new classes of antiviral agents, 42 novel selenenyl sulfides were prepared and characterized by 1H NMR, 13C NMR, 77Se NMR and HRMS. The target compounds demonstrated promising inhibitions against 3Cpro from either enterovirus 71 (EV71) or coxsackievirus B3 (CVB3), as well as desirable cell-based antiviral activity against these viruses. Among them, 11f displayed the most potent IC50 value of 0.28 ± 0.05 μM against EV71-3Cpro, and the strongest IC50 value of 0.72 ± 0.15 μM against CVB3, with a selectivity index of 51.5 against Hela cell, superior to the control drug rupintrivir. In addition, molecular docking was undertaken to predict a possible binding mode for compound 11f, and a comparative molecular field analysis (CoMFA) model was subsequently generated to understand the structure-activity relationships. Overall, the present research has provided some new insights to design a distinct family of antiviral compounds.

Challenges in the Therapeutic Targeting of KCa Channels: From Basic Physiology to Clinical Applications.

Calcium-activated potassium (KCa) channels are ubiquitously expressed throughout the body and are able to regulate membrane potential and intracellular calcium concentrations, thereby playing key roles in cellular physiology and signal transmission. Consequently, it is unsurprising that KCa channels have been implicated in various diseases, making them potential targets for pharmaceutical interventions. Over the past two decades, numerous studies have been conducted to develop KCa channel-targeting drugs, including those for disorders of the central and peripheral nervous, cardiovascular, and urinary systems and for cancer. In this review, we synthesize recent findings regarding the structure and activating mechanisms of KCa channels. We also discuss the role of KCa channel modulators in therapeutic medicine. Finally, we identify the major reasons behind the delay in bringing these modulators to the pharmaceutical market and propose new strategies to promote their application.

Role of Human Oral Microbiome in Diseases

The human oral microbiome represents a diverse and intricate ecosystem comprising bacteria, fungi, viruses, and protozoa. It plays a vital role in numerous physiological processes, ranging from digestion to immunity. Recent research endeavors have focused on delineating the composition and functions of the oral microbiome. Changes in the oral microbiome have been associated with both oral diseases (such as dental caries, periodontitis, halitosis) and systemic conditions (including cardiovascular disease, diabetes, and cancer). Despite significant advancements, numerous questions about the role of the oral microbiome in health and disease remain unanswered. Further research is imperative to explore the intricate interactions between the oral microbiome and other microbiomes within the body. Additionally, there is a need to develop targeted interventions capable of selectively modulating the oral microbiome without disrupting other beneficial microorganisms. In summary, delving into the study of the human oral microbiome has the potential to revolutionize our comprehension of health and disease, opening avenues for innovative approaches to preventive and therapeutic medicine.

EANM guidance document: dosimetry for first-in-human studies and early phase clinical trials

The numbers of diagnostic and therapeutic nuclear medicine agents under investigation are rapidly increasing. Both novel emitters and novel carrier molecules require careful selection of measurement procedures. This document provides guidance relevant to dosimetry for first-in human and early phase clinical trials of such novel agents. The guideline includes a short introduction to different emitters and carrier molecules, followed by recommendations on the methods for activity measurement, pharmacokinetic analyses, as well as absorbed dose calculations and uncertainty analyses. The optimal use of preclinical information and studies involving diagnostic analogues is discussed. Good practice reporting is emphasised, and relevant dosimetry parameters and method descriptions to be included are listed. Three examples of first-in-human dosimetry studies, both for diagnostic tracers and radionuclide therapies, are given.

Validation of an in-house developed therapeutic dosimetric software tool for the treatment of 177Lutetium-DOTATATE peptide receptor radionuclide therapy

BackgroundComputer software for absorbed dose quantification has been used widely in nuclear medicine. Different software tools have been written to improve the dose assessment, especially in therapeutic nuclear medicine. Some software tools focusing on computational phantom models from the international commission of radiation protection and units (ICRP) whilst others on Monte Carlo simulated models. While many studies have investigated therapeutic nuclear medicine dosimetry. The authors have noticed that very few papers compare the therapeutic software tools to each other, hence a doctor of philosophy study was embarked on. The aim of our study was therefore to validate our in-house developed software tool Masterdose using the commercial software OLINDA/EXM 1.0 that was available in our department.MethodsMethodology was based on clinical patient data treated for neuroendocrine tumours with 177Lutetium (Lu)-DOTATATE at a South African hospital. All patients underwent the same SPECT acquisition protocol and were corrected for scatter, partial volume, collimator-detector response, gamma camera calibration and attenuation. Correction factors were applied to images to convert counts to activity. The first cycle of peptide receptor radionuclide therapy (PRRT) for 11 single photon emission computed tomography (SPECT) patients were compared on the Masterdose and OLINDA/EXM 1.0 software tools at 1, 24, 72 and 168 h. Cumulated activity and the absorbed dose were compared for the two software tools. The absorbed dose difference was then compared using statistical Bland-Altman analysis.ResultsMasterdose and OLINDA/EXM 1.0 had different peptide receptor radionuclide therapy methodologies. This led to different results obtained for the software tools. Cumulated activities of Masterdose and DTK was 10.5% and 10.9% for the kidneys and tumours respectively. On average tumour absorbed doses were nine-times that of the kidneys. Bland–Altman analysis show a non-systematic difference between the two software.ConclusionOn average the relative percentage difference between the cumulated activities and absorbed dose of the two software were 10.7%.

Precision medicine in cardiovascular therapeutics: Evaluating the role of pharmacogenetic analysis prior to drug treatment.

Pharmacogenomics is the examination of how genetic variation influences drug metabolism and response, in terms of both efficacy and safety. In cardiovascular disease, patient-specific diplotypes determine phenotypes, thereby influencing the efficacy and safety of drug treatments, including statins, antiarrhythmics, anticoagulants and antiplatelets. Notably, polymorphisms in key genes, such as CYP2C9, CYP2C19, VKORC1 and SLCO1B1, significantly impact the outcomes of treatment with clopidogrel, warfarin and simvastatin. Furthermore, the CYP2C19 polymorphism influences the pharmacokinetics and safety of the novel hypertrophic cardiomyopathy inhibitor, mavacamten. In this review, we critically assess the clinical application of pharmacogenomics in cardiovascular disease and delineate present and future utilization of pharmacogenomics. This includes insights into identifying missing heritability, the integration of whole genome sequencing and the application of polygenic risk scores to enhance the precision of personalized drug therapy. Our discussion encompasses health economic analyses that underscore the cost benefits associated with pre-emptive genotyping for warfarin and clopidogrel treatments, albeit acknowledging the need for further research in this area. In summary, we contend that cardiovascular pharmacogenomic analyses are underpinned by a wealth of evidence, and implementation is already occurring for some of these gene-drug pairs, but as with any area of medicine, we need to continually gather more information to optimize the use of pharmacogenomics in clinical practice.

Potential Disorders Caused by Traditional Herbal Medicines based on Forensic Case Studies

Abstract: Herbal medicines have long been used in therapeutic medicine owing to their minimal side effects. However, contamination, inadequate purification, and adulteration can lead to adverse outcomes upon intake. Several forensic case studies have reported that these compounds can be overdosed, leading to serious effects and death. Furthermore, their interactions with pharmacological agents are poorly studied. In forensic settings, mass spectrometry along with liquid chromatography is the most practiced method to detect and quantity these agents.

Decoding Therapeutic Applications of Quercetin: Recent Advancements in Nanotechnological Strategies.

For centuries, people have used herbal medicine to treat a diversity of health complications and as a natural substance, they have a favourable effect on our health. Herbal ingredients can be utilized as lead molecules in the innovation and development of a new drug. Flavonoids are a class of chemical compounds with diverse phenolic structures, and they are found in a wide variety of foods, including fruits, vegetables, cereals, bark, roots, stems, flowers, tea, and wine. Quercetin is the most prevalent polyphenolic bioflavonoid or flavonoid. Quercetin is found in many food products and has demonstrated a wide range of pharmacological activities, including the treatment of allergies, ocular diseases, metabolic ailments, inflammatory illnesses, cardiovascular ailments and arthritis. Quercetin has attracted interest as an emerging pharmacophore with the potential to significantly advance research and the development of novel therapeutic medicines for a variety of diseases. Despite having a huge therapeutic potential, these flavonoids have unfavourable pharmacokinetic characteristics, low bioavailability, and poor solubility, limiting their application in therapeutics. The objective of the current study is to present a new update on the major therapeutic uses of quercetin and other types of nanocarriers that contain quercetin to treat various ailments.

Abstract C061: Therapeutic profiling, patient response prediction, and tumor evolution in pancreatic cancer organoids

Abstract Pancreatic cancer (PC) is characterized by an aggressive biology and high tumor heterogeneity causing considerable variations in therapy response. Patient-derived organoids (PDOs) reflect parental tumor features and represent a powerful preclinical tool to predict drug response and harness personalized treatment. We have derived >100 PDO lines from treatment-naïve and pretreated PC patient primary tumor and metastases with a reliable efficacy and previously developed a pharmacotyping-guided prediction model to prognosticate patient therapy response (Beutel, 2021). Following up our initial feasibility trial, we now validated the model accuracy in real-life in a higher number of PC patients (43 cases). Additionally, a limited set of 7 PDO pairs were derived from the same patients at two distinct timepoints, followed by pharmacotyping and whole exome sequencing (WES). Our model allowed overall a successful drug-response prediction in naïve patients with an accuracy of 85.7% for first and second-line regimens. Prediction power was nevertheless lower in pretreated patients with a precision of 57.1% for subsequent chemotherapy lines. Intriguingly, a trend was observed towards a better performance of our system in prognosticating chemoresponsiveness vs. unresponsiveness (89.5% vs. 68.8%). Retrospective analysis of patient clinical data finally showed that the administration of a regimen predicted to be efficient ultimately translated into a longer progression-free survival. Importantly, the implementation of an automated pipetting system and the subsequent miniaturization of drug screenings enhanced our process capacity, conferring the possibility to extend our panel to a second list of approved targeted substances and significantly reducing the time before pharmacotyping. The access to longitudinal biopsies allowed to conduct WES on 14 PDOs to capture a comprehensive genetic profiling over the time of treatment, notably revealing a CHEK2-mutated patient responding over time upon PARP inhibitor maintenance therapy, in line with our PDO-based prediction, further highlighting the robustness of our method and algorithm. WES revealed a lower mutational burden and amount of nonsynonymous mutations upon chemotherapy, while tracking clonal evolution also revealed therapy-linked changes. Finally, to decipher the molecular mechanisms driving PC chemoresistance with an unprecedented level of accuracy, we took advantage of our phenotypically and therapeutically-profiled PDO living biobank and employed a true single-nucleus multiome approach to fully capture the transcriptome, as well as the chromatin accessibility landscape, of chemotherapy responsive and non-responsive PC PDOs. Overall, we report a robust and clinically-relevant preclinical tool for drug-response prediction, paving the way towards a PDO therapeutic profiling-guided true precision medicine in clinical routine. The identification of gene-regulatory networks and expression signatures driving chemoresistance may dramatically improve patient stratification and thus, foster true precision oncology. Citation Format: Johann Gout, Yazid J. Resheq, Jessica Lindenmayer, Thomas Ettrich, Lukas Perkhofer, Thomas Seufferlein, Alexander Kleger. Therapeutic profiling, patient response prediction, and tumor evolution in pancreatic cancer organoids [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C061.

Effects of toxin metalloproteinases from jellyfish Nemopilema nomurai nematocyst on the dermal toxicity and potential treatment of jellyfish dermatitis

Jellyfish dermatitis is a common medical problem in many countries due to the jellyfish envenomation. However, there are no specific and targeted medications for their treatment. Here we investigated the possible therapeutic effects of metalloproteinase inhibitors on the dermal toxicity of Nemopilema nomurai nematocyst venom (NnNV), a giant venomous jellyfish from China, using the jellyfish dermatitis model, focusing on inflammatory effector molecules during jellyfish envenomation. Metalloproteinase may further stimulate inflammation by promoting oxidative stress in the organism and play key roles by activating MAPK and NF-κB, in the pathogenesis of jellyfish dermatitis. And the metalloproteinase inhibitors batimastat and EDTA disodium salt may treat the Jellyfish dermatitis by inhibiting the metalloproteinase activity in NnNV. These observations suggest that the metalloproteinase components of NnNV make a considerable contribution to dermal toxicity as the inflammation effect molecular, and metalloproteinase inhibitors can be regarded as novel therapeutic medicines in jellyfish envenomation. This study contributes to understanding the mechanism of jellyfish dermatitis and suggests new targets and ideas for the treatment of jellyfish envenomation.

Antioxidative single atomic nanocatalysts facilitate orally administered probiotic inulin gels for acute colitis amelioration

Acute colitis is characterized by the microenvironment with a high level of inflammation, oxidative stress as well as a disordered microbiome. Sustained delivery of the therapeutic medicine into the colitis foci is limited due to the harsh condition of the gastric environment and fast excretion kinetics in the gut. Herein, we have designed an orally administrable probiotic inulin gel (igel) containing living Bacillus subtilis (B. subt) engineered with outperformed antioxidative single manganese atomic nanocatalyst (SAM NCs) for effective, sustained, and biocompatible therapeutics against acute colitis. Based on the multi-catalytic antioxidative activities (superoxide dismutase, glutathione peroxidase, and catalase) of the synthetic SAM NCs, these nanocatalysts are capable of eliminating the oxidative stresses both in vitro and in vivo. With further engineering onto the living Bacillus subtilis and subsequent in situ gelation inside the inulin, the as-formed probiotic igel(SAM NCs@B. subt) could effectively target and colonize inside the colon region, triggering the in vivo anti-inflammatory, anti-oxidative and gut microbiome modulation performance with high biocompatibility. The present study provides a promising probiotic gelation therapeutic strategy against acute colitis, shedding light on the exploration and clinical transformation of gastrointestinal disease.