Ion channels in innate and adaptive immunity.

Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy.

Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease.

Self-reactive IgGs contribute to the pathology of autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. Paradoxically, IgGs are used to treat inflammatory diseases in the form of high-dose intravenous immunoglobulin (IVIG). Distinct glycoforms on the IgG crystallizable fragment (Fc) dictate these divergent functions. IgG anti-inflammatory activity is attributed to sialylation of the Fc glycan. We therefore sought to convert endogenous IgG to anti-inflammatory mediators in vivo by engineering solubilized glycosyltransferases that attach galactose or sialic acid. When both enzymes were administered in a prophylactic or therapeutic fashion, autoimmune inflammation was markedly attenuated in vivo. The enzymes worked through a similar pathway to IVIG, requiring DC-SIGN, STAT6 signaling, and FcγRIIB. Importantly, sialylation was highly specific to pathogenic IgG at the site of inflammation, driven by local platelet release of nucleotide-sugar donors. These results underscore the therapeutic potential of glycoengineering in vivo.

From synthesis to applications of biomolecule-protected luminescent gold nanoclusters.

Gold nanoclusters (AuNCs) are a class of novel luminescent nanomaterials that exhibit unique properties of ultra-small size, featuring strong anti-photo-bleaching ability, substantial Stokes shift, good biocompatibility, and low toxicity. Various biomolecules have been developed as templates or ligands to protect AuNCs with enhanced stability and luminescent properties for biomedical applications. In this review, the synthesis of AuNCs based on biomolecules including amino acids, peptides, proteins and DNA are summarized. Owing to the advantages of biomolecule-protected AuNCs, they have been employed extensively for diverse applications. The biological applications, particularly in bioimaging, biosensing, disease therapy and biocatalysis have been described in detail herein. Finally, current challenges and future potential prospects of bio-templated AuNCs in biological research are briefly discussed.

Mesenchymal Stem Cell-Derived Exosomes as Drug Delivery Vehicles in Disease Therapy.

Exosomes are small vesicles containing proteins, nucleic acids, and biological lipids, which are responsible for intercellular communication. Studies have shown that exosomes can be utilized as effective drug delivery vehicles to accurately deliver therapeutic substances to target tissues, enhancing therapeutic effects and reducing side effects. Mesenchymal stem cells (MSCs) are a class of stem cells widely used for tissue engineering, regenerative medicine, and immunotherapy. Exosomes derived from MSCs have special immunomodulatory functions, low immunogenicity, the ability to penetrate tumor tissues, and high yield, which are expected to be engineered into efficient drug delivery systems. Despite the promising promise of MSC-derived exosomes, exploring their optimal preparation methods, drug-loading modalities, and therapeutic potential remains challenging. Therefore, this article reviews the related characteristics, preparation methods, application, and potential risks of MSC-derived exosomes as drug delivery systems in order to find potential therapeutic breakthroughs.

Aggregation-Induced Emission-Based Chemiluminescence Systems in Biochemical Analysis and Disease Theranostics.

Chemiluminescence (CL) is of great significance in biochemical analysis and imaging due to its high sensitivity and lack of need for external excitation. In this review, we summarized the recent progress of AIE-based CL systems, including their working mechanisms and applications in biochemical analysis, bioimaging, and disease diagnosis and treatment. In ion and molecular detection, CL shows high selectivity and high sensitivity, especially in the detection of dynamic reactive oxygen species (ROS). Further, the integrated NIR-CL single-molecule system and nanostructural CL platform harnessing CL resonance energy transfer (CRET) have remarkable advantages in long-term imaging with superior capability in penetrating deep tissue depth and high signal-to-noise ratio, and are promising in the applications of in vivo imaging and image-guided disease therapy. Finally, we summarized the shortcomings of the existing AIE-CL system and provided our perspective on the possible ways to develop more powerful CL systems in the future. It can be highly expected that these promoted CL systems will play bigger roles in biochemical analysis and disease theranostics.

Designing Efficient Single Metal Atom Biocatalysts at the Atomic Structure Level.

Various nanomaterials as biocatalysts could be custom-designed and modified to precisely match the specific microenvironment of diseases, showing a promise in achieving effective therapy outcomes. Compared to conventional biocatalysts, single metal atom catalysts (SMACs) with maximized atom utilization through well-defined structures offer enhanced catalytic activity and selectivity. Currently, there is still a gap in a comprehensive overview of the connection between structures and biocatalytic mechanisms of SMACs. Therefore, it is crucial to deeply investigate the role of SMACs in biocatalysis from the atomic structure level and to elucidate their potential mechanisms in biocatalytic processes. In this minireview, we summarize catalysis regulation methods of SMACs at the atomic structure level, focusing on the optimization of catalytic active sites, coordination environment, and active site-support interactions, and briefly discuss biocatalytic mechanisms for biomedical applications.

Patients' Experiences With Therapeutic Approaches for Post-COVID Syndrome: Results of a Crowdsourced Research Survey.

Some patients develop multiple protracted sequelae after infection with SARS-CoV-2, collectively known as post-COVID syndrome or long COVID. To date, there is no evidence showing benefit of specific therapies for this condition, and patients likely resort to self-initiated therapies. We aimed to obtain information about therapies used by and needs of this population via inductive crowdsourcing research. Patients completed an online questionnaire about their symptoms and experiences with therapeutic approaches. Responses of 499 participants suggested few approaches (eg, mind-body medicine, respiratory therapy) had positive effects and showed a great need for patient-centered communication (eg, more recognition of this syndrome). Our findings can help design clinical studies and underscore the importance of the holistic approach to care provided by family medicine.

The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment.

The enzyme transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis. Active TG2 is located mainly extracellularly in the lamina propria but also in the villous enterocytes of the duodenum. The TG2 inhibitor ZED1227 is a promising drug candidate for treating CeD and is designed to block the TG2-catalyzed deamidation and crosslinking of gliadin peptides. Our aim was to study the accumulation of ZED1227 after oral administration of the drug. We studied duodenal biopsies derived from a phase 2a clinical drug trial using an antibody that detects ZED1227 when bound to the catalytic center of TG2. Human epithelial organoids were studied in vitro for the effect of ZED1227 on the activity of TG2 using the 5-biotin-pentylamine assay. The ZED1227-TG2 complex was found mainly in the villous enterocytes in post-treatment biopsies. The signal of ZED1227-TG2 was strongest in the luminal epithelial brush border, while the intensity of the signal in the lamina propria was only ~20% of that in the villous enterocytes. No signal specific to ZED1227 could be detected in pretreatment biopsies or in biopsies from patients randomized to the placebo treatment arm. ZED1227-TG2 staining co-localized with total TG2 and native and deamidated gliadin peptides on the enterocyte luminal surface. Inhibition of TG2 activity by ZED1227 was demonstrated in epithelial organoids. Our findings suggest that active TG2 is present at the luminal side of the villous epithelium and that inhibition of TG2 activity by ZED1227 occurs already there before gliadin peptides enter the lamina propria.

A review on the effect of gut microbiota on metabolic diseases.

Human gut microbiota are a huge and complex microbial community, which is recognized to play a significant role in regulating host metabolism. However, the destruction of gut microbiota leads to the pathological response of host, and thus results in a variety of metabolic diseases. This article gives a brief review of research progress on gut microbiota and some main metabolic diseases, including osteoporosis, obesity, type 2 diabetes, non-alcoholic fatty liver, and hypertension, with a specific focus on the effect of gut microbiota on diseases' occurrence and development. In addition, this review article also shows some case studies on the regulation of gut microbiota by new means, such as fecal microbiota transplantation and oral probiotics. Although gut microbiota are considered as a promising novel target for the treatment of metabolic diseases, it is also necessary to encourage further studies to provide more valuable data for guiding the application of gut microbiota on disease therapy in future.

Nanozymes-recent development and biomedical applications.

Nanozyme is a series of nanomaterials with enzyme-mimetic activities that can proceed with the catalytic reactions of natural enzymes. In the field of biomedicine, nanozymes are capturing tremendous attention due to their high stability and low cost. Enzyme-mimetic activities of nanozymes can be regulated by multiple factors, such as the chemical state of metal ion, pH, hydrogen peroxide (H2O2), and glutathione (GSH) level, presenting great promise for biomedical applications. Over the past decade, multi-functional nanozymes have been developed for various biomedical applications. To promote the understandings of nanozymes and the development of novel and multifunctional nanozymes, we herein provide a comprehensive review of the nanozymes and their applications in the biomedical field. Nanozymes with versatile enzyme-like properties are briefly overviewed, and their mechanism and application are discussed to provide understandings for future research. Finally, underlying challenges and prospects of nanozymes in the biomedical frontier are discussed in this review.

CLINICAL AND MICROBIOLOGICAL ASSESSMENT OF NON-SURGICAL TREATMENT OF CHRONIC PERIODONTITIS IN CONTROLLED AND UNCONTROLLED TYPE 2 DIABETIC PATIENTS.

Chronic periodontitis is a common complication in diabetes. The aim of this study was to evaluate some clinical and microbiological parameters in controlled and uncontrolled type 2 diabetes mellitus (type 2 DM) patients compared to non-diabetic (NDM) individuals, as well as to assess the effect of non-surgical periodontal therapy on these parameters. The study was performed in 61 type 2 DM patients with periodontitis (group 1A: 29 patients having achieved good metabolic control, HbA1c <7%; group 1B: 32 patients with poor metabolic control, HbA1c ≥7%), and 31 NDM individuals suffering from periodontitis. Periodontal indices (plaque index, PI; gingival index, GI; probing pocket depth, PPD; and clinical attachment level, CAL) were measured and subgingival plaque samples were analyzed using polymerase chain reaction prior to treatment initiation and 3 months post-treatment. The results recorded on the majority of measured parameters indicated that differences in treatment success achieved in the three treatment groups were not statistically significant (∆PI p=0.646; ∆GI p=0.303; and ∆CAL p=0.233). Likewise, comparison of the effectiveness in microorganism reduction revealed no significant differences between DM groups and NDM patients. Therefore, study results supported the hypothesis that periodontal therapy outcome was unaffected by the level of glycemic control in patients with diabetes.

Effect of applying inclusion and exclusion criteria of phase III clinical trials to multiple sclerosis patients in routine clinical care.

BACKGROUND: Newly approved, drug-modifying therapies are associated with still unknown adverse events, although clinical trials leading to approval have strict inclusion and exclusion criteria and analyse safety and efficacy. OBJECTIVES: The aim of this study was to analyse the eligibility of multiple sclerosis (MS) patients treated in routine care into the phase III clinical trial of the respective drug. METHODS: In total, 3577 MS patients with 4312 therapies were analysed. Patients with primary-progressive MS were excluded. Inclusion and exclusion criteria of phase III clinical trials in relapsing-remitting MS were adopted and subsequently applied. A comparison in clinical and sociodemographic characteristics was made between patient who met the criteria and those who did not. RESULTS: 83% of registered patients would not have been eligible to the respective phase III clinical trial. Relapse was the single most frequent criterion not fulfilled (74.7%), followed by medication history (21.2%). CONCLUSION: The majority of MS patients treated in routine care would not have met clinical trials criteria. Thus, the efficacy and safety of therapies in clinical trials can differ from those in the real world. Broader phase III inclusion criteria would increase their eligibility and contribute to a better generalizability of the results in clinical trials.

Micro- and nanoscale biophysical cues for cardiovascular disease therapy.

After cardiovascular injury, numerous pathological processes adversely impact the homeostatic function of cardiomyocyte, macrophage, fibroblast, endothelial cell, and vascular smooth muscle cell populations. Subsequent malfunctioning of these cells may further contribute to cardiovascular disease onset and progression. By modulating cellular responses after injury, it is possible to create local environments that promote wound healing and tissue repair mechanisms. The extracellular matrix continuously provides these mechanosensitive cell types with physical cues spanning the micro- and nanoscale to influence behaviors such as adhesion, morphology, and phenotype. It is therefore becoming increasingly compelling to harness these cell-substrate interactions to elicit more native cell behaviors that impede cardiovascular disease progression and enhance regenerative potential. This review discusses recent in vitro and preclinical work that have demonstrated the therapeutic implications of micro- and nanoscale biophysical cues on cell types adversely affected in cardiovascular diseases - cardiomyocytes, macrophages, fibroblasts, endothelial cells, and vascular smooth muscle cells.

Propargylamine-derived multi-target directed ligands for Alzheimer's disease therapy.

Current options for the treatment of Alzheimers disease have been restricted to prescription of acetylcholinesterase inhibitors or N-methyl-d-aspartate receptor antagonist, memantine. Propargylamine-derived multi-target directed ligands, such as ladostigil, M30, ASS234 and contilisant, involve different pathways. Apart from acting as inhibitors of both cholinesterases and monoamine oxidases, they show improvement of cognitive impairment, antioxidant activities, enhancement of iron-chelating activities, protect against tau hyperphosphorylation, block metal-associated oxidative stress, regulate APP and Aß expression processing by the non-amyloidogenic α-secretase pathway, suppress mitochondrial permeability transition pore opening, and coordinate protein kinase C signaling and Bcl-2 family proteins. Other hybrid propargylamine derivatives are also reported.

Recent Advances of pH-Induced Charge-Convertible Polymer-Mediated Inorganic Nanoparticles for Biomedical Applications.

The incorporation of functional polymers and inorganic nanoparticles into nanoplatforms has the potential to produce personalized nanomedicine systems for further biomedical applications. Polymers that endow inorganic nanoparticles with unique surface properties for prolonged blood circulation and improved tumor targeting and cellular uptake are especially desired. pH-induced charge-switchable polymers are sensitive to the pH of the tumor environment and maintain a negative or neutral charge in blood circulation, increasing their circulation time and enhancing tumor accumulation via the enhanced permeability and retention effect. This type of polymer further transforms its charge to positive in acidic tumor locations to promote cellular uptake. Furthermore, the combination of pH-induced charge-switchable polymers with various inorganic nanoparticles (e.g., magnetic nanoparticles, gold nanoparticles, quantum dots, and upconversion materials) activates their intrinsic functions in in situ diagnosis and disease therapy. This review briefly overviews the recent progress in the development and application of various pH-induced charge-convertible polymers functionalized with different types of inorganic nanoparticles for different biomedical applications. More importantly, future developments in this field are also discussed.

Imatinib as a potentially effective therapeutic alternative in corticosteroid-resistant eosinophilic fasciitis.

Eosinophilic fasciitis (EF) is a rare condition in children that is typically treated with systemic corticosteroids. We present the case of a 9-year-old boy with biopsy-proven EF, refractory to systemic corticosteroids and methotrexate. The tyrosine kinase inhibitor imatinib was added as adjuvant therapy, leading to improvement in joint function and skin laxity. Our case is the first to suggest the anti-fibrotic properties of imatinib may benefit EF patients.

A Curcumin Analog Exhibits Multiple Biologic Effects on the Pathogenesis of Alzheimer's Disease and Improves Behavior, Inflammation, and ß-Amyloid Accumulation in a Mouse Model.

Drugs for the treatment of Alzheimer's disease (AD) are in urgent demand due to the unmet need and the social burden associated with the disease. Curcumin has been historically considered as a beneficial product for anti-aging and AD. However, many efforts to develop curcumin for clinical use are hindered mainly due to its poor bioavailability. Recent development in drug delivery and structural design has resolved these issues. In this study, we identified a small molecule, TML-6, as a potential drug candidate for AD through screening a panel of curcumin derivatives using six biomarker platforms related to aging biology and AD pathogenesis. The structural modification of TML-6 is designed to improve the stability and metabolism of curcumin. Cell biological studies demonstrated that TML-6 could inhibit the synthesis of the ß-amyloid precursor protein and ß-amyloid (Aß), upregulate Apo E, suppress NF-κB and mTOR, and increase the activity of the anti-oxidative Nrf2 gene. In the 3x-Tg AD animal model, TML-6 treatment resulted in significant improvement in learning, suppression of the microglial activation marker Iba-1, and reduction in Aß in the brain. Although TML-6 exhibited a greater improvement in bioavailability as compared to curcumin, formulation optimization and toxicological studies are under development to assure its druggability. Taken together, TML-6 meets the current strategy to develop therapeutics for AD, targeting the combination of the Aß cascade and aging-related biology processes.

Targeting Oxidative Stress for Disease Prevention and Therapy: Where Do We Stand, and Where Do We Go from Here.

Oxidative stress (OxS) is one of the main processes related to aging and a common denominator of many different chronic/degenerative diseases (e.g., cardiovascular and neurodegenerative conditions and cancer). Thus, its potential modulation by supplementation/pharmacological therapy caused a lot of interest. However, these expectations have been mitigated by the obtainment of controversial results (beneficial, null, or adverse effects) following antioxidant interventions. Here, we discuss the current understanding of OxS assessment in health and disease, challenges and the potential of its evaluation in clinical practice, and available and future development for supplementation and pharmacologic strategies targeting OxS.

A pilot study to assess the pharmacy impact of implementing a chemotherapy-induced nausea or vomiting collaborative disease therapy management in the outpatient oncology clinics.

BACKGROUND: Collaborative drug therapy management is a formal partnership between a pharmacist and physician to allow the pharmacist to manage a patient's drug therapy. Literature supports collaborative disease therapy management can improve patient outcomes, improve medication adherence, enhance medication safety, and positively influence healthcare expenditures. Chemotherapy induced nausea or vomiting is considered one of the most distressing and feared adverse events among patients receiving chemotherapy. Chemotherapy induced nausea or vomiting can impact a patient's quality of life and may affect compliance with the treatment plan. PURPOSE: The objective of this pilot study was to determine the pharmacy impact of implementing a chemotherapy induced nausea or vomiting collaborative disease therapy management protocol in the outpatient oncology clinics at a National Cancer Institute (NCI)-designated cancer center associated with an academic medical center. The primary endpoint was to determine the number and type of chemotherapy induced nausea or vomiting clinical interventions made by the oncology pharmacists. Secondary endpoints included comparing patient's Multinational Association for Supportive Care in Cancer scores and revenue of pharmacists' services. METHODS: The credentialed oncology pharmacists were consulted by an oncologist to manage chemotherapy induced nausea or vomiting. Patients were included in the chemotherapy induced nausea or vomiting collaborative disease therapy management if they were seen in an outpatient oncology clinic from October 2016 to January 2017 and had a referral from a qualified provider to help manage chemotherapy induced nausea or vomiting. Patients admitted to the hospital at the time of consult were excluded from the study. The pharmacists interviewed patients and provided recommendations. The pharmacists followed up with the patient via a telephone call or during the next scheduled clinic visit to assess their symptoms. RESULTS: The chemotherapy induced nausea or vomiting collaborative disease therapy management pilot study was implemented in October 2016. From October 2016 to January 2017, there were 45 consults for the management of chemotherapy induced nausea or vomiting. The pharmacists made 188 clinical interventions, which included addition of new medications (37%), patient education (34%), deletion of medications (10%), changing a dose/duration/frequency (8%), and other interventions (11%). Multinational Association for Supportive Care in Cancer symptom scores were available for 5 patients, in which all showed improvements from baseline with the pharmacists' clinical interventions. CONCLUSIONS: The implementation of our chemotherapy induced nausea or vomiting collaborative disease therapy management pilot study has shown favorable results after a 4-month evaluation period. The pharmacists have made a substantial number of clinical interventions and provided patient education to patients undergoing chemotherapy.

Comparison between laparoscopic uterus/sacrocolpopexy and total pelvic floor reconstruction with vaginal mesh for the treatment of pelvic organ prolapse.

AIM: To compare total pelvic floor reconstruction with vaginal mesh (TVM) and laparoscopic uterus/sacrocolpopexy (LSC) for the treatment of pelvic organ prolapse (POP). METHODS: Six hundred and seventy patients with POP stage 3 and 4 underwent LSC (n = 350) or TVM (n = 320) at the West China Second Hospital, Sichuan University between January 2011 and December 2016. Retrospective analysis was done to compare the POP-Q value before operation and 6 months, 5 years after operation, also compare the, patient global impression of change (PGI-C), pelvic floor distress inventory (PFDI-20) and pelvic floor impact questionnaire (PFIQ-7). Patients were followed for a median 36 months. Thirty-five patients in the LSC and 37 in the TVM groups were lost to follow-up. RESULTS: Preoperative POP value and disease course were similar (P = 0.075). The LSC group was younger (52.8 ± 6.8 vs. 63.9 ± 8.7 years, P = 0.037). Intraoperative bleeding was smaller in the LSC group (74.4 ± 33.2 vs. 150.4 ± 80.3 mL, P < 0.01), with longer operation time (130.0 ± 34.1 min vs 100.4 ± 40.4 min, P < 0.035). The patients were followed for 10-60 months (median, 36 months). Postoperative PISQ-12 (P < 0.01) was better in the LSC group. PFDI-20 and PFIQ-7 were improved after operation in both groups. Objective satisfaction (94.9% vs 91.9%, P > 0.05) and recurrence rate (8.4% vs 5.1%, P = 0.064) were similar. No infection or fistula occurred after operation in both groups. The complication rate of intraoperative bladder injury and postoperative perineal pain in LSC group was lower than those in the TVM group (P < 0.05). CONCLUSION: LSC showed no serious adverse events and led to higher postoperative satisfaction than TVM in selected patients. Nevertheless, treatment should be selected in accordance with the willingness and condition of each patient.