Dual Therapeutic Effects Research Articles

Jiao-tai-wan and its effective component-coptisine alleviate cognitive impairment in db/db mice through the JAK2/STAT3 signaling pathway

BackgroundCognitive impairment (CI) is now well-accepted as a complication and comorbidity of diabetes mellitus (DM), becoming a serious medical and social problem. Jiao-tai-wan (JTW), one of noted traditional Chinese medicine (TCM), showed dual therapeutic effects on DM and CI. Nevertheless, the potential mechanism is unclear. PurposeThis study sought to investigate the mechanism how JTW protected against DM and CI and screen the active component in JTW. MethodsDb/db mice were used as mouse models. Mice were treated by gavage with 0.9 % saline (0.1 mL/10g/d), low dose of JTW (2.4 g/kg/d) or high dose of JTW (4.8 g/kg/d) for 8 weeks separately. To access the effects of JTW, the levels of OGTT, HOMA-IR, blood lipids, inflammatory cytokines in serum and hippocampus were measured, behavioral tests were conducted, and histopathological changes were observed. The mechanism exploration was performed via network pharmacology, RT-qPCR, western blot, and immunofluorescence staining (IF). The impact and mechanism of coptisine in vitro were investigated using BV2 cells induced by LPS as cellular models. In vitro experiments were conducted in two parts. The first part comprised four groups: Control group, LPS group, LPS+LCOP group and LPS+HCOP group. The second part consisted of four groups: Control group, LPS group, LPS+HCOP group, and LPS+ Fed group. The western blot and RT-qPCR methods were used to examine the changes in biomarkers of the JAK2/STAT3 signaling pathways in BV2 cells. ResultsThe results demonstrated that JTW could improve OGTT and HOMA-IR, reduce the serum levels of LDL-C, HDL-C, TG, and TC, restore neuronal dysfunction and synaptic plasticity, and decrease the deposition of Aβ in the hippocampus. The findings from ELISA, IF, and RT-qPCR revealed that JTW could alleviate microglial activation and inflammatory status in vivo and coptisine could play the same role in vitro. Moreover, the changes of the JAK2/STAT3 signaling pathway in LPS-induced BV2 cells or hippocampus of db/db mice were distinctly reversed by coptisine or JTW, respectively. ConclusionOur study suggested that JTW and its effective component coptisine could alleviate diabetes mellitus-related cognitive impairment, closely linked to the JAK2/STAT3 signaling pathway.

Research progress on effect evaluation and application status of acupoint drug delivery

Acupoint drug delivery is a traditional external therapy of traditional Chinese medicine(TCM). Guided by the meridian and collateral theory in TCM, it applies medications to the skin at acupoints, exerting a dual therapeutic effect by stimulating the acupoints and the conduction of meridians. Acupoint drug delivery is widely used in clinical practice. Different from traditional oral admi-nistration and injection, it absorbs medications through the skin, effectively avoiding the first-pass effect of drugs and the toxic side effects caused by injection. Acupoint selection and transdermal drug absorption are pivotal factors affecting the efficacy of acupoint drug delivery. Recent research on acupoint drug delivery mainly focuses on the evaluation of clinical efficacy, yet the systematic investigations on acupoint selection and pharmacodynamic factors are scarce. This study reviews the mechanism, efficacy evaluation and application status of acupoint drug delivery. It integrates the theory of TCM with modern medicine to explore the mechanism of acupoint drug delivery, evaluate its clinical efficacy, and assess the transdermal penetration in vivo and in vitro. The application status of acupoint drug delivery is also summarized, including the selection of acupoints, application dosage form, application time and the absorption of acupoints. This review aims to offer insights and references for the research, development and clinical application of acupoint drug delivery products.

The orchestrated feature of Cornus kousa fruit and gut microbiota against obesity via integrated pharmacology

AbstractCornus kousa fruit (CKF) has been utilized as anti‐obesity supplementation in East Asia, including Korea, and gut microbiota (GM) might have synergistic effects on obesity (OB) via its interplay. We aimed to decode molecule(s), mechanism(s), and target(s) on interplay between CKF and GM via network pharmacology analysis. The final targets were analyzed by protein–protein interaction (PPI) networks and a bubble plot. The GM interacted with significant targets identified by the gutMGene database. The relationships among CKF or GM, signaling pathways, targets, and molecules (CGSTM) were plotted by R package. Finally, molecular docking assay and density functional theory (DFT) were performed to validate its affinity. The final targets (22) were selected on OB‐responded targets, indicating that interleukin‐6 (IL6) was the most crucial protein‐coding target on PPI networks. A bubble plot and CGSTM networks suggested that the advanced glycation end‐receptor for advanced glycation end products signaling pathway in diabetic complications is inhibited by CKF and peroxisome proliferator–activated receptor (PPAR) signaling pathway is activated by GM. As the most stable conformers, IL6‐equol complex was attributed to GM, and PPAR alpha‐linoleic acid, PPAR delta‐stearic acid, and fatty acid–binding protein 4‐dimethyl 2,3‐bis(1,3‐dimethylindol‐2‐yl) fumarate complex were attributed to CKF. Noticeably, stearic acid was removed by DFT analysis; all other three molecules were proposed as good electron donators with the higher electronegativity compared with a standard drug (Orlistat). This study shows that integrated pharmacological analysis can enable to decode the unknown relationships between CKF and GM. Overall, this study reveals that the combination of CKF and favorable GM might exert dual therapeutic effects on OB.

Dual effects of TGF-β inhibitor in ALS - inhibit contracture and neurodegeneration.

As persistent elevation of transforming growth factor-β (TGF-β) promotes fibrosis of muscles and joints and accelerates disease progression in amyotrophic lateral sclerosis (ALS), we investigated whether inhibition of TGF-β would be effective against both exacerbations. The effects of TGF-β and its inhibitor on myoblasts and fibroblasts were tested invitro and confirmed invivo, and the dual action of a TGF-β inhibitor in ameliorating the pathogenic role of TGF-β in ALS mice was identified. In the peripheral neuromuscular system, fibrosis in the muscles and joint cavities induced by excessive TGF-β causes joint contracture and muscular degeneration, which leads to motor dysfunction. In an ALS mouse model, an increase in TGF-β in the central nervous system (CNS), consistent with astrocyte activity, was associated with M1 microglial activity and pro-inflammatory conditions, as well as with neuronal cell death. Treatment with the TGF-β inhibitor halofuginone could prevent musculoskeletal fibrosis, resulting in the alleviation of joint contracture and delay of motor deterioration in ALS mice. Halofuginone could also reduce glial cell-induced neuroinflammation and neuronal apoptosis. These dual therapeutic effects on both the neuromuscular system and the CNS were observed from the beginning to the end stages of ALS; as a result, treatment with a TGF-β inhibitor from the early stage of disease delayed the time of symptom exacerbation in ALS mice, which led to prolonged survival.

Deciphering the molecular pathways underlying dopaminergic neuronal damage in Parkinson's disease associated with SARS-CoV-2 infection

BackgroundThe COVID-19 pandemic caused by SARS-CoV-2 has led to significant global morbidity and mortality, with potential neurological consequences, such as Parkinson's disease (PD). However, the underlying mechanisms remain elusive. MethodsTo address this critical question, we conducted an in-depth transcriptome analysis of dopaminergic (DA) neurons in both COVID-19 and PD patients. We identified common pathways and differentially expressed genes (DEGs), performed enrichment analysis, constructed protein‒protein interaction networks and gene regulatory networks, and employed machine learning methods to develop disease diagnosis and progression prediction models. To further substantiate our findings, we performed validation of hub genes using a single-cell sequencing dataset encompassing DA neurons from PD patients, as well as transcriptome sequencing of DA neurons from a mouse model of MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. Furthermore, a drug-protein interaction network was also created. ResultsWe gained detailed insights into biological functions and signaling pathways, including ion transport and synaptic signaling pathways. CD38 was identified as a potential key biomarker. Disease diagnosis and progression prediction models were specifically tailored for PD. Molecular docking simulations and molecular dynamics simulations were employed to predict potential therapeutic drugs, revealing that genistein holds significant promise for exerting dual therapeutic effects on both PD and COVID-19. ConclusionsOur study provides innovative strategies for advancing PD-related research and treatment in the context of the ongoing COVID-19 pandemic by elucidating the common pathogenesis between COVID-19 and PD in DA neurons.

Uncovering the effect and mechanism of Jiawei Xiaoyao Wan in treating breast cancer complicated with depression based on network pharmacology and experimental analysis

BackgroundDepression is a clinically common co-morbidity in breast cancer cases that brings negative outcomes on quality of life and potentially survival. Jiawei Xiaoyao Wan (JXW) is widely used in treating breast cancer and depressive disorder, but its potential pharmacological mechanisms remain elusive. PurposeWe aimed to explore the dual therapeutic effects and mechanisms of JXW acting on breast cancer complicated with depression (BCCD) by network pharmacology and in vivo experimental verification. MethodsThe chemical constituents of JXW were characterized using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-Q-TOF/MS). The targets related to constituents of JXW were predicted by the TCMSP and Swiss Target Prediction databases, and targets of breast cancer and depression were screened by the GeneCards and OMIM databases. Gene Ontology annotation and KEGG enrichment analysis were performed with the DAVID database. Ultimately, a BCCD mouse model induced by chronic restraint stress (CRS) was used to explore therapeutic effects and mechanisms of JXW against BCCD. The efficacy of JXW in the treatment of BCCD was evaluated based on behavioral tests, tumor volume and weight, and pathological examination. Additionally, the underlying mechanisms were explored by measuring the levels of neurotransmitter and inflammatory factors, as well as detecting the expression of genes or proteins associated with candidate targets and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway through RT-PCR, western blotting, and immunohistochemistry. ResultsTotals of 108 components were identified in JXW using LC-Q-TOF/MS. By network pharmacology analysis, 714 compound targets of JXW, 2114 breast cancer targets, 1122 depression targets, and 98 overlapping proteins were obtained. PPI network and KEGG analysis implied that TP53, ESR1, VEGFA, AKT1, IL6, TNF, EGFR and the JAK/STAT pathway might be the potential targets of JXW in treating BCCD. In vivo experiments indicated that JXW significantly ameliorated depressive symptoms and tumor progression in BCCD mice. Further mechanistic studies showed that JXW could reduce the levels of inflammatory factors, increase 5-HT level, and regulate mRNA expression levels of TP53, VEGFA, AKT1, IL6, TNF, and EGFR targets. Moreover, the expression levels of proteins related to the JAK2/STAT3 signaling pathway in BCCD mice were effectively regulated by JXW. ConclusionJXW exerts dual therapeutic effects in a BCCD mouse via multiple targets. The underlying mechanisms might be associated with regulating the levels of neurotransmitter and inflammatory factors; more importantly, the JAK2/STAT3 pathway plays a significant role in this process.

Sema3A secreted by sensory nerve induces bone formation under mechanical loads

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling. Here, we focused on the role of Semaphorin 3A (Sema3A), expressed by sensory nerves, in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement (OTM) model. Firstly, bone formation was activated after the 3rd day of OTM, coinciding with a decrease in sensory nerves and an increase in pain threshold. Sema3A, rather than nerve growth factor (NGF), highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM. Moreover, in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells (hPDLCs) within 24 hours. Furthermore, exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload. Mechanistically, Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway, maintaining mitochondrial dynamics as mitochondrial fusion. Therefore, Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation, both as a pain-sensitive analgesic and a positive regulator for bone formation.

Exploring beetroot (Beta vulgaris L.) for diabetes mellitus and Alzheimer's disease dual therapy: in vitro and computational studies.

This study explored the flavonoid-rich extract of beetroot (Beta vulgaris L.) for type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD) dual therapy by using in vitro and molecular simulation studies. Flavonoid-rich extracts of B. vulgaris fruit were evaluated for their antidiabetic and anti-alzheimic activities. Molecular docking and dynamic simulation were performed to identify potential bioactive flavonoids with dual therapeutic effects on T2D and AD. Flavonoid-rich extracts of B. vulgaris fruit (IC50 = 73.062 ± 0.480 μg mL-1) had moderate activity against α-amylase compared to the standard acarbose (IC50 = 27.104 ± 0.270 μg mL-1). Compared with acarbose, flavonoid-rich extracts of B. vulgaris fruit had appreciable activity against α-glucosidase (IC50 = 17.389 ± 0.436 μg mL-1) (IC50 = 37.564 ± 0.620 μg mL-1). For AChE inhibition, flavonoid-rich extracts of B. vulgaris fruit exhibited (p < 0.0001) inhibitory activity (IC50 = 723.260 ± 5.466 μg mL-1), albeit weaker than that of the standard control, galantamine (IC50 = 27.950 ± 0.122 μg mL-1). Similarly, flavonoid-rich extracts of B. vulgaris fruit showed considerable (p < 0.0001) inhibitory effects on BChE (IC50 = 649.112 ± 0.683 μg mL-1). In contrast, galantamine (IC50 = 23.126 ± 0.683 μg mL-1) is more potent than the extracts of B. vulgaris fruit. Monoamine oxidase (MAO) activity increased in FeSO4-induced brain damage. In contrast, flavonoid-rich extracts of B. vulgaris fruit protected against Fe2+-mediated brain damage by suppressing MAO activity in a concentration-dependent manner. HPLC-DAD profiling of the extracts identified quercetrin, apigenin, rutin, myricetin, iso-quercetrin, p-coumaric acid, ferulic acid, caffeic acid, and gallic acid. Molecular docking studies revealed quercetrin, apigenin, rutin, iso-queretrin, and myricetin were the top docked bioactive flavonoids against the five top target proteins (α-amylase, α-glucosidase AchE, BchE, and MAO). Molecular dynamic simulations revealed that the complexes formed remained stable over the course of the simulation. Collectively, the findings support the prospect of flavonoid-rich extracts of B. vulgaris root functioning as a dual therapy for T2D and AD.

Dual source-powered multifunctional Pt/FePc@Mn-MOF spindle-like Janus nanomotors for active CT imaging-guided synergistic photothermal/chemodynamic therapy

Nanomaterials capable of dual therapeutic effects of chemodynamic therapy (CDT) and photothermal therapy (PTT) is an efficacious strategy in cancer treatment. It is still a challenge to achieve complete apoptosis of tumor tissue in CDT/PTT due to the poor permeability of nanomaterials in tumor tissue. Herein, we prepared a dual-source driven Pt/FePc@Mn-MOF spindle-like Janus nanomotor by a facile oriented connection growth method for computed tomography (CT) imaging-guided CDT and PTT. The high catalase (CAT)-like activity of nanomotors allows the generation of oxygen (O2) bubbles by catalyzing the decomposition of endogenous H2O2, which alleviates the hypoxic state of the tumor microenvironment (TME) and simultaneously drive nanomotors. Pt/FePc@Mn-MOF nanomotor with excellent photothermal conversion efficiency exhibited dual peroxidase (POD)-like and oxidase (OXD)-like activities, which can produce large amounts of ROS to obtain PTT enhanced CDT. Meanwhile, near-infrared light, as “optical brakes”, can trigger Janus nanomotor to realize self-thermophoretic movement. Chemical/NIR-assisted autonomous propulsion can significantly improve the accumulation of Janus nanomotors in solid tumors and enhance their ability to penetrate tumor tissue, thus brings synergistic enhancement effect to PTT and CDT. Moreover, Mn-MOF in nanomotor can deplete the antioxidant GSH by redox reaction to release massive Mn2+, which introduce Mn2+-based CT imaging properties. This novel dual-source controlled Janus nanomotor offers great potential for multimodal therapeutic medical applications.

Identifying Tumor-Specific Immune Response and Biomarkers of High-Risk Hodgkin Lymphoma Patients Treated with and without Brentuximab on Children's Oncology Group Trial AHOD1331

Introduction: There is an unmet need to examine anti-tumor immune responses and predictive biomarkers in the peripheral blood to guide effective combination immunotherapies in classic Hodgkin Lymphoma (cHL). We hypothesized that treatment with the anti-CD30 antibody drug conjugate brentuximab vedotin (Bv) in combination with chemotherapy will have dual therapeutic effects in HL, with direct antiproliferative effects and a restoration of favorable tumor specific cytotoxic T cell immune response. We evaluated tumor-specific cytotoxic T cell response, cytokine and chemokine milieu in the peripheral blood of pediatric patients with HL before and after treatment with either standard chemotherapy or chemotherapy + Bv. Methods: Children's Oncology Group clinical trial AHOD1331 was a randomized phase III trial for newly diagnosed high risk cHL ages ≥2 to 22 years which compared standard chemotherapy with doxorubicin, bleomycin, etoposide, prednisone and cyclophosphamide (ABVE-PC) to Bv + AVE-PC with response adapted radiation. Peripheral blood samples were collected at diagnosis (pre) and following completion of treatment (post). Peripheral blood mononuclear cells and plasma were isolated using Ficoll Density gradient. Plasma was cryopreserved for batch testing of Th1/Th2 cytokines, sCD30, sCD163 and TARC by Luminex assay. Cytotoxic T cell responses to non-EBV HL specific tumor associated antigens (TAAs) MAGEA4, PRAME, and survivin pre and post treatment were tested using the interferon-γ ELISPOT assay after ex vivo expansion. TAA-T cell specificity was reported as spot forming count (SFC per 10 5 T cells). Changes in cytokine levels and T cell responses pre versus post treatment were compared using paired t-tests and blinded to treatment arm.Levels of sCD30, sCD163 and TARC were compared both pre and post treatment. Thecox model was used to evaluate association between levels and event free survival (EFS) across both arms. Results There was no difference in patient or disease characteristics between the entire study cohort (n=587) and patients analyzed (n=216). There were 184 patients with pre and post cytokine data, 71 patients with pre and post ELISPOT-T cell data, 147 patients with pre and post sCD30/sCD163 data, and 146 with pre and post TARC data. Compared to pre-treatment levels, there was a significant reduction in the immunosuppressive cytokines IL-13 (p=0.004) and increase in pro-inflammatory cytokines IL17a (p=0.03), Interferon-γ (p=0.0008), GCSF(p=0.0012) and MCP1(p=0.02). This change in cytokine levels from baseline to post-treatment was similar for both treatment arms except a higher increase in IL17a(p=0.015) was noted in the standard chemotherapy arm compared to the Bv arm (Table 1). Among 147 paired samples evaluated, sCD30, sCD163 and TARC all were significantly lower post treatment (Figure 1), but did not differ across arms. Pre treatment sCD163 and TARC values were significantly associated with EFS (p = 0.005 and 0.045), as was the degree of change in sCD163 post-treatment levels as compared to pre-treatment levels (p = 0.0156). Among 71 patients with pre and post ELISPOT-T cell data, there was a significant increase in the T cell responses specific to PRAME(p=0.04) post treatment and a trend for increased MAGEA4, but no association with EFS. Conclusions Treatment results in an increased T cell response to HL-specific antigen PRAME post therapy in both treatment arms suggesting that recovery post anti-HL treatment can promote tumor antigen specific T cell immunity in vivo. Further, reduction in immunosuppressive cytokines IL-13 and changes in proinflammatory cytokines Interferon-γ following treatment suggest a favorable milieu for T cell expansion. Pre-treatment levels of soluble CD163 and TARC are associated with EFS and may present a potential predictive biomarker, as well as degree of change of CD163 post treatment, irrespective of addition of immunotherapy. Our results have implications for identifying immune markers of response to guide future immunotherapies and cytotoxic T cell therapy in cHL. (NCT02166463)

Antibacterial, anti-inflammatory and wet-adhesive poly(ionic liquid)-based oral patch for the treatment of oral ulcers with bacterial infection.

Oral aphthous ulcers are a common inflammatory efflorescence of oral mucosa, presenting as inflammation and oral mucosal damage and manifesting as pain. The moist and highly dynamic environment of the oral cavity makes the local treatment of oral aphthous ulcers challenging. Herein, a poly(ionic liquid)-based diclofenac sodium (DS)-loaded (PIL-DS) buccal tissue adhesive patch fabricated with intrinsically antimicrobial, highly wet environment adhesive properties and anti-inflammatory activities to treat oral aphthous ulcers was developed. The PIL-DS patch was prepared via polymerization of a catechol-containing ionic liquid, acrylic acid, and butyl acrylate, followed by anion exchange with DS-. The PIL-DS can adhere to wet tissues, including mucosa muscles and organs, and efficiently deliver the carried DS- at wound sites, exerting remarkable synergistic antimicrobial (bacteria and fungi) properties. Accordingly, the PIL-DS elicited dual therapeutic effects on oral aphthous ulcers with Staphylococcus aureus infection through antibacterial and anti-inflammatory activities, significantly accelerating oral aphthous ulcer healing as an oral mucosa patch. The results indicated that the PIL-DS patch, with inherently antimicrobial and wet adhesion properties, is promising for treating oral aphthous ulcers in clinical practice. STATEMENT OF SIGNIFICANCE: Oral aphthous ulcers are a common oral mucosal disease, which could lead to bacterial infection and inflammation in severe cases, especially for people with large ulcers or low immunity. However, moist oral mucosa and highly dynamic oral environment make it challenging to maintain therapeutic agents and physical barriers at the wound surface. Therefore, an innovative drug carrier with wet adhesion is urgently needed. Herein, a poly(ionic liquid)-based diclofenac sodium (DS)-loaded (PIL-DS) buccal tissue adhesive patch was developed to treat oral aphthous ulcers showing intrinsically antimicrobial and highly wet environment adhesive properties due to the presence of catechol-containing ionic liquid monomer. Additionally, the PIL-DS showed significantly therapeutic effects on oral aphthous ulcers with S. aureus infection through antibacterial and anti-inflammatory activities. We expect that our work can provide inspiration for the development of treatment for microbially infected oral ulcers.

Acupuncture Improves Sleep Disorders and Depression among Patients with Parkinson's Disease: A Meta-Analysis.

Parkinson's disease (PD) is associated with a range of non-motor symptoms that lack effective treatments. Acupuncture is a popular alternative therapy for PD patients that has been shown to improve motor symptoms. However, the efficacy of acupuncture in treating non-motor symptoms has remained controversial. The goal of our study was to systematically assess the existing evidence for acupuncture's efficacy in treating PD non-motor symptoms of sleep disorders, depression, anxiety, and fatigue. We conducted a meta-analysis of clinical trials by searching Pubmed, Embase, CINAHL, and Web of Science as electronic databases to evaluate acupuncture treatment for PD non-motor symptoms. Thirteen clinical trials met our inclusion criteria, and their methodological quality was assessed using the modified Jadad scale, indicating a moderate overall quality. Our results showed that acupuncture improved PD-related sleep disorders and depression but had no effect on anxiety and fatigue. Our meta-analysis suggests that acupuncture can be used as a complementary treatment for sleep disturbances and depression in PD patients and may exhibit a dual therapeutic effect on motor and non-motor symptoms. However, further well-designed clinical trials with larger sample sizes are needed to confirm these findings. Overall, our study highlights the potential of acupuncture as a viable complementary therapy for the treatment of PD non-motor symptoms of sleep disorders and depression, which can improve the quality of life of PD patients.

Targeting the Divergent Roles of STK3 Inhibits Breast Cancer Cell Growth and Opposes Doxorubicin-Induced Cardiotoxicity In Vitro

Breast cancer (BCa) is the most prevalent type of cancer in women. Several therapies used in the treatment of breast cancer are associated with clinically important rates of cardiovascular toxicity during or after treatment exposure, including anthracyclines. There is a need for new BCa therapeutics and treatments that mitigate chemotherapy-induced cardiotoxicity in BCa. In this study, we examine the effects of Serine/Threonine Kinase 3 (STK3) inhibition in the context of BCa therapy and cardioprotection from doxorubicin. STK3 (also known as MST2) is a key member of the Hippo Tumor-Suppressor Pathway, which regulates cell growth and proliferation by inhibiting YAP/TAZ co-transcription factors. Canonically, STK3 should restrict BCa growth; however, we observed that STK3 is amplified in BCa and associated with worse patient outcomes, suggesting a noncanonical pro-tumorigenic role. We found BCa cell lines have varying dependence on STK3. SUM52PE cells had the highest expression and dependence on STK3 in genetic and pharmacological assays. MCF-7 and MDA-MB-231 were less sensitive to STK3 targeting in standard proliferation assays, but were STK3 dependent in colony formation and matrigel invasion assays. In contrast, STK3 inhibition mitigated the toxic effects of doxorubicin in H9C2 rat cardiomyocytes by increasing YAP expression. Importantly, STK3 inhibition in BCa cells did not interfere with the therapeutic effects of doxorubicin. Our studies highlight STK3 is a potential molecular target for BCa with dual therapeutic effects: suppression of BCa growth and progression, and chemoprotection in cardiomyocytes.

RETRACTED: Theoretical simulation and experimental design of selenium and gold incorporated polymer-based microcarriers for ROS-mediated combined photothermal therapy

Recently, multi-modal combined photothermal therapy (PTT) with the use of photo-active materials has attracted significant attention for cancer treatment. However, drug carriers enabling efficient heating at the tumor site are yet to be designed: this is a fundamental requirement for broad implementation of PTT in clinics. In this work, we design and develop hybrid carriers based on multilayer capsules integrated with selenium nanoparticles (Se NPs) and gold nanorods (Au NRs) to realize reactive oxygen species (ROS)-mediated combined PTT. We show theoretically and experimentally that cooperative interaction of Se NPs with Au NRs improves the heat release efficiency of the developed capsules. In addition, after uptake by tumor cells, intracellular ROS level amplified by Se NPs inhibits the tumor growth. As a consequence, the synergy between Se NPs and Au NRs exhibits the advantages of hybrid carriers such as (i) improved photothermal conversion efficiency and (ii) dual-therapeutic effect. The results of in vitro and in vivo experiments demonstrate that the combination of ROS-mediated therapy and PTT has a higher tumor inhibition efficiency compared to the single-agent treatment (using only Se-loaded or Au-loaded capsules). Furthermore, the developed hybrid carriers show negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys and spleen. This study not only provides a potential strategy for the design of multifunctional “all-in-one” carriers, but also contributes to the development of combined PTT in clinical practice.

Sinus node dysfunction and atrial fibrillation-Relationships, clinical phenotypes, new mechanisms, and treatment approaches.

Although the anatomical basis of the pathogenesis of sinus node dysfunction (SND) and atrial fibrillation (AF) is located primarily in the left and right atria, increasing evidence suggests a strong correlation between SND and AF, in terms of both clinical presentation and formation mechanisms. However, the exact mechanisms underlying this association are unclear. The relationship between SND and AF may not be causal, but is likely to involve common factors and mechanisms, including ion channel remodeling, gap junction abnormalities, structural remodeling, genetic mutations, neuromodulation abnormalities, the effects of adenosine on cardiomyocytes, oxidative stress, and viral infections. Ion channel remodeling manifests primarily as alterations in the "funny" current (If) and Ca2+ clock associated with cardiomyocyte autoregulation, and gap junction abnormalities are manifested primarily as decreased expression of connexins (Cxs) mediating electrical impulse propagation in cardiomyocytes. Structural remodeling refers primarily to fibrosis and cardiac amyloidosis (CA). Some genetic mutations can also cause arrhythmias, such as SCN5A, HCN4, EMD, and PITX2. The intrinsic cardiac autonomic nervous system (ICANS), a regulator of the heart's physiological functions, triggers arrhythmias.In addition, we discuss arrhythmias caused by viral infections, notably Coronavirus Disease 2019 (COVID-19). Similarly to upstream treatments for atrial cardiomyopathy such as alleviating CA, ganglionated plexus (GP) ablation acts on the common mechanisms between SND and AF, thus achieving a dual therapeutic effect.

Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma

BackgroundImmunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells....

2D and 3D cultured human umbilical cord-derived mesenchymal stem cell-conditioned medium has a dual effect in type 1 diabetes model in rats: immunomodulation and beta-cell regeneration

BackgroundType 1 diabetes (T1D) is a T-cell-mediated autoimmune disease characterized by the irreversible destruction of insulin-producing β-cells in pancreatic islets. Helper and cytotoxic T-cells and cytokine production, which is impaired by this process, take a synergetic role in β-cell destruction, and hyperglycemia develops due to insulin deficiency in the body. Mesenchymal stem cells (MSCs) appear like an excellent therapeutic tool for autoimmune diseases with pluripotent, regenerative, and immunosuppressive properties. Paracrine factors released from MSCs play a role in immunomodulation by increasing angiogenesis and proliferation and suppressing apoptosis. In this context, the study aims to investigate the therapeutic effects of MSC’s secretomes by conditioned medium (CM) obtained from human umbilical cord-derived MSCs cultured in 2-dimensional (2D) and 3-dimensional (3D) environments in the T1D model.MethodsFirst, MSCs were isolated from the human umbilical cord, and the cells were characterized. Then, two different CMs were prepared by culturing MSCs in 2D and 3D environments. The CM contents were analyzed in terms of total protein, IL-4, IL-10, IL-17, and IFN-λ. In vivo studies were performed in Sprague-Dawley-type rats with an autoimmune T1D model, and twelve doses of CM were administered intraperitoneally for 4 weeks within the framework of a particular treatment model. In order to evaluate immunomodulation, the Treg population was determined in lymphocytes isolated from the spleen after sacrification, and IL-4, IL-10, IL-17, and IFN-λ cytokines were analyzed in serum. Finally, β-cell regeneration was evaluated immunohistochemically by labeling Pdx1, Nkx6.1, and insulin markers, which are critical for the formation of β-cells.ResultsTotal protein and IL-4 levels were higher in 3D-CM compared to 2D-CM. In vivo results showed that CMs induce the Treg population and regulate cytokine release. When the immunohistochemical results were evaluated together, it was determined that CM application significantly increased the rate of β-cells in the islets. This increase was at the highest level in the 3D-CM applied group.ConclusionThe dual therapeutic effect of MSC-CM on immunomodulation and homeostasis/regeneration of β-cells in the T1D model has been demonstrated. Furthermore, this effect could be improved by using 3D scaffolds for culturing MSCs while preparing CM.

Injectable Carrier-Free Hydrogel Dressing with Anti-Multidrug-Resistant Staphylococcus aureus and Anti-Inflammatory Capabilities for Accelerated Wound Healing.

Antibacterial hydrogels have gradually become a powerful weapon to treat bacterially infected wounds and accelerate healing. In this paper, we designed a small-molecule self-healing antibacterial hydrogel containing 100% drug-loaded benzyl 3β-amino-11-oxo-olean-12-en-30-oate (GN-Bn), which was governed by π-π stacking, hydrogen bonding, and van der Waals forces. Due to the carrier-free design concept, the problems of interbatch variability during sample preparation and carrier-related toxicity can be effectively avoided. Moreover, the GN-Bn hydrogel exhibited promising antibacterial activities against multidrug-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration (MIC) of the GN-Bn hydrogel was 1.5625 nmol/mL, which was lower than those against clinical agents such as norfloxacin, penicillin, and tetracycline. This is attributed to its unique antibacterial mechanism that aims at killing bacteria or preventing their growth by regulating arginine biosynthesis and metabolism through both transcriptomic (RNA-seq) analysis and quantitative polymerase chain reaction (qPCR) analysis. In addition, the GN-Bn hydrogel can also inhibit proinflammatory cytokines (TNF-α, IL-1β, and IL-6) to promote wound healing. Collectively, the GN-Bn hydrogel elicited dual therapeutic effects on an MRSA-infected full-thickness skin wound model through its antibacterial and anti-inflammatory activities, which is attributed to the fact that the GN-Bn hydrogel has multiple advantages including sufficient mechanical stability, biocompatibility, and unique antibacterial mechanisms, making it significantly accelerate MRSA-infected full-thickness skin wound healing as a wound dressing. In a word, the GN-Bn antibacterial hydrogel dressing with an anti-inflammatory and antibacterial bifunctional material holds great potential in clinical application.

The dual therapeutic effect of metformin nuclei‐based drugs modified with one of Tulbaghia violacea extract compounds

Novel Schiff base was synthesized from the condensation reaction of metformin with [4‐(Diethylamino) benzaldehyde (NBM). Different metal complexes were prepared using Pd (II), Pt (II), Cu (II), and V (IV) metal ions. All complexes showed the nonelectrolytic behavior. So, the expected molecular formulas for complexes were [Pd (NBM)Cl2], [Pt (NBM)Cl2], [Cu (NBM)2Cl2] and [VO (NBM)2]. The cytotoxicity of (NBM) Schiff base and its metal complexes on human cancer cell line, MCF‐7, was investigated. V (IV) and Cu (II) complexes showed potential blood glucose lowering effect higher than the commercial metformin drug. VO (II) complex has superior antioxidant activity more than the other synthesized compounds and the standard ascorbic acid. Molecular docking investigation proved the presence of interesting interactions between all synthesized compounds with the active site amino acids of EGFR tyrosine kinase (anticancer activity). The molecular docking of metal complexes has observed effective inhibition for the specific mTOR protein that is expected to aid the growth of the COVID‐19 virus.

SUMO2-mediated SUMOylation of SH3GLB1 promotes ionizing radiation-induced hypertrophic cardiomyopathy through mitophagy activation

Hypertrophic cardiomyopathy (HC) is characterized by the enlargement of individual cardiomyocytes, which is a typical pathophysiological process that occurs in various cardiovascular diseases. Ionizing radiation (IR) is an important independent risk factor for hypertrophic cardiomyopathy, but the underlying molecular mechanism is still unclear. In the present study, we aimed to clarify the role of IR in promoting cardiac hypertrophy and investigate the mechanism by which the SUMO2-mediated SUMOylation of SH3GLB1 affects mitophagy in IR-induced cardiac hypertrophy. In vivo, IR promoted cardiac hypertrophy by activating mitophagy. In vitro, IR upregulated PINK1 and Parkin protein expression and damaged mitochondrial morphological structure. We further demonstrated that SH3GLB1 deficiency inhibited mitophagy activation and restored mitochondrial cristae, revealing a regulatory role of SH3GLB1 in cardiac hypertrophy. IR promoted interactions between SH3GLB1 and mitochondrial membrane proteins, such as MFN1/2, TOM20 and Drp1, further indicating that the mechanism by which SH3GLB1 functions in cardiac hypertrophy might involve mitophagy. A bioinformatics prediction found that SUMO2 could SUMOylate SH3GLB1 at position K82. Consistent with this finding, both co-IP assays and laser confocal microscopy showed that IR promoted the interaction and colocalization of SUMO2 and SH3GLB1. In summary, our study identifies IR as an important factor that promotes hypertrophic cardiomyopathy by accelerating the activation of mitophagy through the SUMO2-mediated SUMOylation of SH3GLB1; thus, IR exerts dual therapeutic effects in the treatment of thoracic tumours with long-term radiotherapy. Additionally, this study provides novel treatment strategies and targets for preventing the hypertrophic cardiomyopathy caused by thoracic tumour radiotherapy. Furthermore, SH3GLB1 may be a promising experimental target for the development of strategies for treating cardiovascular diseases caused by IR.