ABSTRACT
BACKGROUND: The pathogenesis of psoriasis involves the interaction between keratinocytes and immune cells, leading to immune imbalance. While most current clinical treatment regimens offer rapid symptom relief, they often come with significant side effects. Tetrastigma hemsleyanum polysaccharides (THP), which are naturally nontoxic, possess remarkable immunomodulatory and anti-inflammatory properties. METHODS: In this study, we utilized an imiquimod (IMQ)-induced psoriasis mouse model and a LPS/IL-6-stimulated HaCaT model. The potential and mechanism of action of THP in psoriasis treatment were assessed through methods including Psoriasis Area Severity Index (PASI) scoring, histopathology, flow cytometry, immunoblotting, and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Percutaneous administration of THP significantly alleviated symptoms and manifestations in IMQ-induced psoriatic mice, including improvements in psoriatic skin appearance (erythema, folds, scales), histopathological changes, decreased PASI scores, and spleen index. Additionally, THP suppressed abnormal proliferation of Th17 cells and excessive proliferation and inflammation of keratinocytes. Furthermore, THP exhibited the ability to regulate the JAK/STAT3 signaling pathway. CONCLUSION: Findings from in vivo and in vitro studies suggest that THP can inhibit abnormal cell proliferation and excessive inflammation in lesional skin, balance Th17 immune cells, and disrupt the interaction between keratinocytes and Th17 cells. This mechanism of action may involve the modulation of the JAK/STAT3 signaling pathway, offering potential implications for psoriasis treatment.
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BACKGROUND: Type 2 diabetes is a chronic disease with a significant medical burden. eHealth care integrates medicine and technology to enhance the outcomes of such patients; however, adequate eHealth literacy (eHL) is necessary for that to happen. Fostering eHL is crucial for patients with diabetes to engage with eHealth care and receive quality care and timely support. Experiential learning theory can enhance patients' eHL and skills to use eHealth care technology in their daily care. OBJECTIVE: This study explored the effectiveness of an eHealth care experiential learning program in improving eHL, patient health engagement, and eHealth care use status among patients with type 2 diabetes in 3 months. METHODS: In this randomized controlled trial, patients under case management services from various clinics in Taiwan were randomly assigned to either the intervention group receiving the 6-session eHealth care experiential learning program or the control group receiving the usual care. Data were collected using structured questionnaires at 3 time points: pretest, postintervention, and 3 months after the intervention. Descriptive data were presented using frequency distribution, percentage, mean, and SD. The outcomes were analyzed using a generalized estimating equation method by intention-to-treat analysis. RESULTS: A total of 92 participants (46 in each group) were recruited in this study. Of these, 86 completed the course and follow-up evaluations with a mean age of 62.38 (SD 12.91) years. After completing the intervention, the intervention group had significantly higher posttest scores in eHL (ß=19.94, SE 3.52; P<.001), patient health engagement (ß=.28, SE 0.13; P=.04), and eHealth use (ß=3.96, SE 0.42; P<.001) than the control group. Furthermore, the intervention group maintained these significant improvements in eHL (ß=18.19, SE 3.82; P<.001) and eHealth use (ß=3.87, SE 0.49; P<.001) after 3 months. CONCLUSIONS: Participating in the eHealth care experiential learning program resulted in significant improvements in eHL, patient health engagement, and eHealth use among patients with type 2 diabetes. Our interventional program can inform future clinical practice and policies to strengthen self-management skills and facilitate the use of health technology in caring for patients with chronic diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT05180604; https://clinicaltrials.gov/ct2/show/NCT05180604.
Subject(s)
Diabetes Mellitus, Type 2 , Problem-Based Learning , Telemedicine , Humans , Diabetes Mellitus, Type 2/therapy , Middle Aged , Female , Male , Problem-Based Learning/methods , Taiwan , Aged , Adult , Surveys and QuestionnairesABSTRACT
Anticancer peptides (ACPs) are bioactive compounds known for their selective cytotoxicity against tumor cells via various mechanisms. Recent studies have demonstrated that in silico machine learning methods are effective in predicting peptides with anticancer activity. In this study, we collected and analyzed over a thousand experimentally verified ACPs, specifically targeting peptides derived from natural sources. We developed a precise prediction model based on their sequence and structural features, and the model's evaluation results suggest its strong predictive ability for anticancer activity. To enhance reliability, we integrated the results of this model with those from other available methods. In total, we identified 176 potential ACPs, some of which were synthesized and further evaluated using the MTT colorimetric assay. All of these putative ACPs exhibited significant anticancer effects and selective cytotoxicity against specific tumor cells. In summary, we present a strategy for identifying and characterizing natural peptides with selective cytotoxicity against cancer cells, which could serve as novel therapeutic agents. Our prediction model can effectively screen new molecules for potential anticancer activity, and the results from in vitro experiments provide compelling evidence of the candidates' anticancer effects and selective cytotoxicity.
Subject(s)
Antineoplastic Agents , Computer Simulation , Peptides , Humans , Peptides/pharmacology , Peptides/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/metabolism , Biological Products/pharmacology , Biological Products/chemistry , Cell Survival/drug effects , Machine Learning , Drug Screening Assays, AntitumorABSTRACT
Ulcerative colitis (UC) is characterized by a chronic and protracted course and often leads to a poor prognosis. Patients with this condition often experience postoperative complications, further complicating the management of their condition. Tetrastigma hemsleyanum polysaccharide (THP) has demonstrated considerable potential as a treatment for inflammatory bowel disease. However, its underlying mechanism in the treatment of UC remains unclear. This study systematically and comprehensively investigated the effects of THP on dextran sulfate-induced UC mice and illustrated its specific mechanism of action. The colon and spleen in UC mice were restored after THP treatment. The levels of key markers, such as secretory immunoglobulin A, ß-defensin, and mucin-2 were increased, collagen deposition and epithelial cell apoptosis were decreased. Notably, THP administration led to increased levels of Ki67 and tight junction proteins in colon tissue and reduced colon tissue permeability. THP contributed to the restored balance of intestinal flora. Furthermore, THP downregulated the expressions of the proinflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-17 and promoted those of the regulatory factors forkhead box protein P3. It also exerted anti-inflammatory effects by promoting suppressor of cytokine signaling (SOCS1) expression and inhibiting the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Our results demonstrated that THP had an efficacy comparable to that of JAK inhibitor in treating UC. In addition, THP might play a role in UC therapy through modulation of the SOCS1/JAK2/STAT3 signaling pathway and remodeling of the intestinal mucosal barrier.
Subject(s)
Colitis, Ulcerative , Intestinal Barrier Function , Intestinal Mucosa , Polysaccharides , Signal Transduction , Vitaceae , Animals , Male , Mice , Anti-Inflammatory Agents/pharmacology , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Colon/drug effects , Colon/pathology , Cytokines/metabolism , Dextran Sulfate , Disease Models, Animal , Intestinal Barrier Function/drug effects , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Janus Kinase 2/metabolism , Mice, Inbred C57BL , Polysaccharides/pharmacology , Signal Transduction/drug effects , STAT3 Transcription Factor/metabolism , Suppressor of Cytokine Signaling 1 Protein/metabolism , Suppressor of Cytokine Signaling 1 Protein/genetics , Vitaceae/chemistryABSTRACT
Neuroimaging studies in rapid eye movement sleep behavior disorder (RBD) can inform fundamental questions about the pathogenesis of Parkinson's disease (PD). Across modalities, functional magnetic resonance imaging (fMRI) may be better suited to identify changes between neural networks in the earliest stages of Lewy body diseases when structural changes may be subtle or absent. This review synthesizes the findings from all fMRI studies of RBD to gain further insight into the pathophysiology and progression of Lewy body diseases. A total of 32 studies were identified using a systematic review conducted according to PRISMA guidelines between January 2000 to February 2024 for original fMRI studies in patients with either isolated RBD (iRBD) or RBD secondary to PD. Common functional alterations were detectable in iRBD patients compared with healthy controls across brainstem nuclei, basal ganglia, frontal and occipital lobes, and whole brain network measures. Patients with established PD and RBD demonstrated decreased functional connectivity across the whole brain and brainstem nuclei, but increased functional connectivity in the cerebellum and frontal lobe compared with those PD patients without RBD. Finally, longitudinal changes in resting state functional connectivity were found to track with disease progression. Currently, fMRI studies in RBD have demonstrated early signatures of neurodegeneration across both motor and non-motor pathways. Although more work is needed, such findings have the potential to inform our understanding of disease, help to distinguish between prodromal PD and prodromal dementia with Lewy bodies, and support the development of fMRI-based outcome measures of phenoconversion and progression in future disease modifying trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an disease characterized by pulmonary edema and widespread inflammation, leading to a notably high mortality rate. The dysregulation of both pro-inflammatory and anti-inflammatory systems, results in cytokine storm (CS), is intricately associated with the development of ALI/ARDS. Tetrastigma hemsleyanum polysaccharide (THP) exerts remarkable anti-inflammatory and immunomodulatory effects against the disease, although its precise role in pathogenesis remains unclear. In the present study, an ALI/ARDS model was established using bacterial lipopolysaccharides. THP administration via aerosol inhalation significantly mitigated lung injury, reduced the number of inflammatory cells, and ameliorated glycerophospholipid metabolism. Furthermore, specific CS-related pathways were investigated by examining the synergy between tumor necrosis factor-α and interferon-γ used to establish CS models. The results indicated that THP effectively decreased inflammatory damage and cell death. The RNA sequencing revealed the involvement of the Janus kinase (JAK) 2-signal transducers and activators of transcription (STAT) signaling pathway in exerting the mentioned effects. Additionally, THP inhibited the activation of the JAK-STAT pathway, thereby alleviating the CS both in vivo and in vitro. Overall, THP exhibited marked therapeutic potential against ALI/ARDS and CS, primarily by targeting the IFN-γ-JAK2/STAT signaling pathway.
Subject(s)
Cytokine Release Syndrome , Interferon-gamma , Polysaccharides , Signal Transduction , Vitaceae , Animals , Humans , Male , Mice , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Cytokine Release Syndrome/drug therapy , Disease Models, Animal , Interferon-gamma/metabolism , Janus Kinase 2/metabolism , Lipopolysaccharides , Polysaccharides/pharmacology , Polysaccharides/chemistry , Signal Transduction/drug effects , STAT Transcription Factors/metabolism , Vitaceae/chemistryABSTRACT
The absence of effective therapeutic targets poses considerable obstacles to the treatment of triple-negative breast cancer (TNBC). This study aimed to explore the function and mechanism of polysaccharides derived from the aerial parts of Tetrastigma hemsleyanum (THP) for the treatment of TNBC. THP exerts notable anti-TNBC effects when used alone, and its combination with Doxorubicin (DOX) effectively augments the sensitivity of TNBC cells to DOX. Through RNA sequencing, Fe2+ assays, western blotting, and transmission electron microscopy, THP was identified as a natural inducer of ferroptosis and ferritinophagy through the xCT/GSH/GPX4 and Nrf2/NCOA4/FTH1 pathways. Further research revealed that the THP branched-chain hexose directly binds to the xCT protein to inhibit its expression and promotes ferroptosis. In vivo experiments confirmed the role of THP in inducing ferroptosis and showed that THP improves the tumor microenvironment and immune function by increasing the ratio of CD4+ and CD8+ T cells to regulatory T cells and modulating cytokine levels. As demonstrated by electrocardiography, blood chemistry, and histological analyses, THP alleviates organ toxicity caused by DOX. Overall, these results suggest that THP has significant clinical potential as a natural macromolecular drug and may provide a safe and effective treatment strategy for TNBC when combined with DOX.
Subject(s)
Doxorubicin , Ferroptosis , Polysaccharides , Triple Negative Breast Neoplasms , Ferroptosis/drug effects , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Humans , Doxorubicin/pharmacology , Polysaccharides/pharmacology , Polysaccharides/chemistry , Animals , Female , Mice , Cell Line, Tumor , Vitaceae/chemistry , Tumor Microenvironment/drug effects , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVES: The long-term risk of developing glaucoma after vitrectomy remains uncertain. This retrospective population-based cohort study aimed to explore this risk following vitrectomy for macular pucker or hole. METHODS: Utilizing Taiwan's National Health Insurance Research Database (NHIRD), we included patients who were older than 18 years and had undergone vitrectomy surgery between 2011 and 2019. Exclusions were made for patients with prior diagnoses of glaucoma, congenital or secondary glaucoma, as well as those who had received previous vitreoretinal treatments or had undergone multiple vitrectomies. RESULTS: After an average follow-up period of 51 and 53 months respectively for the vitrectomized and non-vitrectomized group, our results showed a relative risk of 1.71 for glaucoma development in the vitrectomized group. Higher adjusted hazard ratios were also observed for open-angle glaucoma and normal tension glaucoma. Increased risks were associated with male sex, obstructive sleep apnoea, and migraine. In the subgroup analysis, phakic eyes at baseline and those who had undergone cataract surgery post-vitrectomy were associated with a lower risk of glaucoma development during follow-up. Among all glaucoma events, pseudophakic status at baseline had the shortest interval to glaucoma development following vitrectomy. CONCLUSIONS: These findings underscore the potential relationship between vitrectomy and glaucoma onset, emphasizing the need for vigilant monitoring and early detection of glaucoma in post-vitrectomy patients.
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The management of diabetic ulcers poses a significant challenge worldwide, and persistent hyperglycemia makes patients susceptible to bacterial infections. Unfortunately, the overuse of antibiotics may lead to drug resistance and prolonged infections, contributing to chronic inflammation and hindering the healing process. To address these issues, a photothermal therapy technique was incorporated in the preparation of wound dressings. This innovative solution involved the formulation of a self-healing and injectable hydrogel matrix based on the Schiff base structure formed between the oxidized Bletilla striata polysaccharide (BSP) and hydroxypropyltrimethylammonium chloride chitosan. Furthermore, the introduction of CuO nanoparticles encapsulated in polydopamine imparted excellent photothermal properties to the hydrogel, which promoted the release of berberine (BER) loaded on the nanoparticles and boosted the antibacterial performance. In addition to providing a reliable physical protection to the wound, the developed hydrogel, which integrated the herbal components of BSP and BER, effectively accelerated wound closure via microenvironment regulation, including alleviated inflammatory reaction, stimulated re-epithelialization, and reduced oxidative stress based on the promising results from cell and animal experiments. These impressive outcomes highlighted their clinical potential in safeguarding the wound against bacterial intrusion and managing diabetic ulcers.
Subject(s)
Chitosan , Hydrogels , Polysaccharides , Wound Healing , Chitosan/chemistry , Chitosan/analogs & derivatives , Chitosan/pharmacology , Wound Healing/drug effects , Animals , Hydrogels/chemistry , Hydrogels/pharmacology , Polysaccharides/chemistry , Polysaccharides/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Photothermal Therapy/methods , Mice , Humans , Berberine/pharmacology , Berberine/chemistry , Rats , Diabetes Mellitus, Experimental/drug therapy , Copper/chemistry , Copper/pharmacology , Male , Polymers/chemistry , Polymers/pharmacology , Indoles/chemistry , Indoles/pharmacology , Wound Infection/drug therapy , Wound Infection/microbiology , Nanoparticles/chemistry , Staphylococcus aureus/drug effects , Metal Nanoparticles/chemistryABSTRACT
AIMS: This study investigates the impact of IbACP (Ipomoea batatas anti-cancer peptide) on defense-related gene expression in tomato leaves, focusing on its role in plant defense mechanisms. BACKGROUND: Previously, IbACP was isolated from sweet potato leaves, and it was identified as a peptide capable of inducing an alkalinization response in tomato suspension culture media. Additionally, IbACP was found to regulate the proliferation of human pancreatic adenocarcinoma cells. OBJECTIVE: Elucidate IbACP's molecular influence on defense-related gene expression in tomato leaves using next-generation sequencing analysis. METHOD: To assess the impact of IbACP on defense-related gene expression, transcriptome data were analyzed, encompassing various functional categories such as photosynthesis, metabolic processes, and plant defense. Semi-quantitative reverse-transcription polymerase chain reaction analysis was employed to verify transcription levels of defense-related genes in tomato leaves treated with IbACP for durations ranging from 0 h (control) to 24 h. RESULTS: IbACP induced jasmonic acid-related genes (LoxD and AOS) at 2 h, with a significant up-regulation of salicylic acid-dependent gene NPR1 at 24 h. This suggested a temporal antagonistic effect between jasmonic acid and salicylic acid during the early hours of IbACP treatment. Downstream ethylene-responsive regulator genes (ACO1, ETR4, and ERF1) were consistently down-regulated by IbACP at all times. Additionally, IbACP significantly up-regulated the gene expressions of suberization-associated anionic peroxidases (TMP1 and TAP2) at all time points, indicating enhanced suberization of the plant cell wall to prevent pathogen invasion. CONCLUSION: IbACP enhances the synthesis of defense hormones and up-regulates downstream defense genes, improving the plant's resistance to biotic stresses.
ABSTRACT
BACKGROUND/AIM: Cancer cachexia is a wasting syndrome that has a devastating impact on the prognosis of patients with cancer. It is well-documented that pro-inflammatory cytokines are involved in the progression of this disorder. Therefore, this study was conducted to investigate the protective effect of taurine, an essential nonprotein amino acid with great anti-inflammatory properties, in attenuating muscle atrophy induced by cancer. MATERIALS AND METHODS: Conditioned media (CM) derived from T24 human bladder carcinoma cells with or without 5 mM taurine were incubated with human skeletal muscle cells (HSkMCs) and their differentiation was examined. The intracellular reactive oxygen species (ROS), morphology, and the catabolic pathway were monitored. RESULTS: T24-derived CM with high levels of TNF-α and IL-6 caused aberrant ROS accumulation and formation of atrophic myotubes by HSkMCs. In T24 cancer cells, taurine significantly inhibited the production of TNF-α and IL-6. In HSkMCs, taurine increased ROS clearance during differentiation and preserved the myotube differentiation ability impaired by the inflammatory tumor microenvironment. In addition, taurine ameliorated myotube atrophy by regulating the Akt/FoxO1/MuRF1 and MAFbx signaling pathways. CONCLUSION: Taurine rescues cancer-induced atrophy in human skeletal muscle cells by ameliorating the inflammatory tumor microenvironment. Taurine supplementation may be a promising approach for intervening with the progression of cancer cachexia.
Subject(s)
Muscular Atrophy , Reactive Oxygen Species , Taurine , Tumor Microenvironment , Humans , Taurine/pharmacology , Tumor Microenvironment/drug effects , Muscular Atrophy/pathology , Muscular Atrophy/drug therapy , Muscular Atrophy/metabolism , Muscular Atrophy/etiology , Reactive Oxygen Species/metabolism , Cell Line, Tumor , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Cell Differentiation/drug effects , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscle, Skeletal/drug effects , Signal Transduction/drug effects , Cachexia/drug therapy , Cachexia/pathology , Cachexia/metabolism , Cachexia/etiology , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/metabolism , Culture Media, Conditioned/pharmacology , Inflammation/drug therapy , Inflammation/pathology , Inflammation/metabolism , Tumor Necrosis Factor-alpha/metabolism , Interleukin-6/metabolismABSTRACT
Current cancer therapy can be effective, but the development of drug resistant disease is the usual outcome. These drugs can eliminate most of the tumor burden but often fail to eliminate the rare, "Drug Tolerant Persister" (DTP) cell subpopulations in residual tumors, which can be referred to as "Persister" cells. Therefore, novel therapeutic agents specifically targeting or preventing the development of drug-resistant tumors mediated by the remaining persister cells subpopulations are needed. Since approximately ninety percent of cancer-related deaths occur because of the eventual development of drug resistance, identifying, and dissecting the biology of the persister cells is essential for the creation of drugs to target them. While there remains uncertainty surrounding all the markers identifying DTP cells in the literature, this review summarizes the drugs and therapeutic approaches that are available to target the persister cell subpopulations expressing the cellular markers ATP-binding cassette sub-family B member 5 (ABCB5), CD133, CD271, Lysine-specific histone demethylase 5 (KDM5), and aldehyde dehydrogenase (ALDH). Persister cells expressing these markers were selected as the focus of this review because they have been found on cells surviving following drug treatments that promote recurrent drug resistant cancer and are associated with stem cell-like properties, including self-renewal, differentiation, and resistance to therapy. The limitations and obstacles facing the development of agents targeting these DTP cell subpopulations are detailed, with discussion of potential solutions and current research areas needing further exploration.
Subject(s)
Antineoplastic Agents , Drug Resistance, Neoplasm , Neoplasms , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Animals , Drug Resistance, Neoplasm/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Drug Tolerance , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/geneticsABSTRACT
Skeletal muscle atrophy is a common complication of chronic kidney disease (CKD) that affects the quality of life and prognosis of patients. We aimed to investigate the effects and mechanisms of caffeic acid (CA), a natural phenolic compound, on skeletal muscle atrophy in CKD rats. Male Sprague-Dawley rats underwent 5/6 nephrectomy (NPM) and were treated with CA (20, 40, or 80â¯mg/kg/day) for 10 weeks. The body and muscle weights, renal function, hemoglobin, and albumin were measured. The histological, molecular, and biochemical changes in skeletal muscles were evaluated using hematoxylin-eosin staining, quantitative real-time PCR, malondialdehyde/catalase/superoxide dismutase/glutathione level detection, and enzyme-linked immunosorbent assay. Western blotting and network pharmacology were applied to identify the potential targets and pathways of CA, CKD, and muscle atrophy. The results showed that CA significantly improved NPM-induced muscle-catabolic effects, reduced the expression of muscle atrophy-related proteins (muscle atrophy F-box and muscle RING finger 1) and proinflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-alpha, and IL-1ß), and attenuated muscle oxidative stress. Network pharmacology revealed that CA modulated the response to oxidative stress and nuclear factor kappa B (NF-κB) signaling pathway and that Toll-like receptor 4 (TLR4) was a key target. In vivo experiment confirmed that CA inhibited the TLR4/myeloid differentiation primary response 88 (MYD88)/NF-kB signaling pathway, reduced muscle iron levels, and restored glutathione peroxidase 4 activity, thereby alleviating ferroptosis and inflammation in skeletal muscles. Thus, CA might be a promising therapeutic agent for preventing and treating skeletal muscle atrophy in CKD by modulating the TLR4/MYD88/NF-κB pathway and ferroptosis.
Subject(s)
Caffeic Acids , Muscular Atrophy , Myeloid Differentiation Factor 88 , Renal Insufficiency, Chronic , Signal Transduction , Animals , Male , Rats , Caffeic Acids/pharmacology , Cytokines/metabolism , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , Muscle, Skeletal/metabolism , Muscular Atrophy/drug therapy , Muscular Atrophy/pathology , Muscular Atrophy/etiology , Muscular Atrophy/prevention & control , Muscular Atrophy/metabolism , Myeloid Differentiation Factor 88/metabolism , Nephrectomy/adverse effects , NF-kappa B/metabolism , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/pathology , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolismABSTRACT
The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.
Subject(s)
Pilocarpine , Proto-Oncogene Proteins c-abl , Seizures , Animals , Male , Mice , Apoptosis/drug effects , Mice, Inbred C57BL , Neurons/drug effects , Neurons/pathology , Neurons/metabolism , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-abl/metabolism , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Seizures/chemically induced , Seizures/drug therapy , Seizures/pathology , Status Epilepticus/chemically induced , Status Epilepticus/drug therapy , Status Epilepticus/pathologyABSTRACT
The anti-inflammatory activity of polysaccharides derived from Melastoma dodecandrum Lour. was evaluated in pyretic mice and HEK-Blue™ hTLR4 cells. The testing led to the identification of MDP2-1, which was then investigated for its structural characteristics and anti-inflammatory effects. Results showed that MDP2-1 had a molecular weight of 29.234 kDa and primarily consisted of galactose, arabinose, rhamnose, glucose, glucuronic acid, and galacturonic acid. Its main backbone was composed of â4)-α-D-GalpA-(1â, â2)-α-L-Rhap-(1â, â3,4)-α-D-GalpA-(1â, â2,4)-α-D-GlcpA-(1â, and its side chains were connected by â4)-α-D-Galp-(1â, α-D-Galp-(1â, â4)-ß-D-Glcp-(1â, and α-L-Araf-(1â. In vivo experiments on mice demonstrated that MDP2-1 attenuated LPS-induced acute lung injury, and in vitro experiments on RAW264.7 cells showed that MDP2-1 reduced the levels of inflammatory mediators and mitigated LPS-induced inflammatory damage by inhibiting the activation of the TLR4 downstream NF-κB/MAPK pathway. These findings suggest that MDP2-1 is a novel anti-inflammatory agent for therapeutic interventions.
Subject(s)
Lipopolysaccharides , Polysaccharides , Mice , Animals , Polysaccharides/pharmacology , Polysaccharides/chemistry , Galactose , Glucose , Anti-Inflammatory Agents/pharmacologyABSTRACT
As populations age, average life expectancy increases and the complexity of diseases rises, leading to nursing care and healthcare systems facing severe challenges related to inadequate resources. Artificial intelligence (AI), including elements such as investigation, integration, learning, prediction, and decision-making, holds significant potential for application in clinical care not only to enhance care quality but also to help guide the future direction of healthcare. AI applications are already being increasingly utilized to improve the quality of clinical care and to streamline workflows. However, because nursing education has lagged behind in terms of adopting AI, greater attention must be given to training up nursing students with AI-related knowledge and application skills. AI technologies should be integrated into nursing curricula and clinical internships to adapt to the rapidly changing high-tech healthcare environment, enabling the more-effective use of AI technology in providing high-quality and safe nursing care.
Subject(s)
Artificial Intelligence , Education, Nursing , Humans , Learning , Curriculum , KnowledgeABSTRACT
This article underscores the importance of integrating comprehensive palliative care for noncancer patients who are undergoing hemodialysis, with an emphasis on the aging populations in Asian nations such as Taiwan, Japan, the Republic of Korea, and China. As the global demographic landscape shifts towards an aging society and healthcare continues to advance, a marked increase has been observed in patients undergoing hemodialysis who require palliative care. This necessitates an immediate paradigm shift to incorporate this care, addressing the intricate physical, psychosocial, and spiritual challenges faced by these individuals and their families. Numerous challenges impede the provision of effective palliative care, including difficulties in prognosis, delayed referrals, cultural misconceptions, lack of clinician confidence, and insufficient collaboration among healthcare professionals. The article proposes potential solutions, such as targeted training for clinicians, the use of telemedicine to facilitate shared decision-making, and the introduction of time-limited trials for dialysis to overcome these obstacles. The integration of palliative care into routine renal treatment and the promotion of transparent communication among healthcare professionals represent key strategies to enhance the quality of life and end-of-life care for people on hemodialysis. By embracing innovative strategies and fostering collaboration, healthcare providers can deliver more patient-centered, holistic care that meets the complex needs of seriously ill patients within an aging population undergoing hemodialysis.
ABSTRACT
Voxel-based morphometry (VBM) and surface-based morphometry (SBM) are two widely used neuroimaging techniques for investigating brain anatomy. These techniques rely on statistical inferences at individual points (voxels or vertices), clusters of points, or a priori regions-of-interest. They are powerful tools for describing brain anatomy, but offer little insights into the generative processes that shape a particular set of findings. Moreover, they are restricted to a single spatial resolution scale, precluding the opportunity to distinguish anatomical variations that are expressed across multiple scales. Drawing on concepts from classical physics, here we develop an approach, called mode-based morphometry (MBM), that can describe any empirical map of anatomical variations in terms of the fundamental, resonant modes-eigenmodes-of brain anatomy, each tied to a specific spatial scale. Hence, MBM naturally yields a multiscale characterization of the empirical map, affording new opportunities for investigating the spatial frequency content of neuroanatomical variability. Using simulated and empirical data, we show that the validity and reliability of MBM are either comparable or superior to classical vertex-based SBM for capturing differences in cortical thickness maps between two experimental groups. Our approach thus offers a robust, accurate, and informative method for characterizing empirical maps of neuroanatomical variability that can be directly linked to a generative physical process.
Subject(s)
Brain , Neuroanatomy , Humans , Reproducibility of Results , Brain/diagnostic imaging , Head , NeuroimagingABSTRACT
A novel acidic glucuronogalactomannan (STHP-5) was isolated from the aboveground part of Tetrastigma hemsleyanum Diels et Gilg with a molecular weight of 3.225 × 105 kDa. Analysis of chain conformation showed STHP-5 was approximately a random coil chain. STHP-5 was composed mainly of galactose, mannose, and glucuronic acid. Linkages of glycosides were measured via methylation analysis and verified by NMR. In vitro, STHP-5 induced the production of nitric oxide (NO) and secretion of IL-6, MCP-1, and TNF-α in RAW264.7 cells, indicating STHP-5 had stimulatory activity on macrophages. STHP-5 was proven to function as a TLR4 agonist by inducing the secretion of secreted embryonic alkaline phosphatase (SEAP) in HEK-Blue™-hTLR4 cells. The TLR4 activation capacity was quantitatively measured via EC50, and it showed purified polysaccharides had stronger effects (lower EC50) on activating TLR4 compared with crude polysaccharides. In conclusion, our findings suggest STHP-5 may be a novel immunomodulator.
Subject(s)
Toll-Like Receptor 4 , Vitaceae , Animals , Mice , Vitaceae/chemistry , Polysaccharides/chemistry , Macrophages , RAW 264.7 CellsABSTRACT
BACKGROUND: Diabetic kidney disease (DKD) represents a microvascular complication of diabetes mellitus. Shenkang Pills (SKP), a traditional Chinese medicine formula, has been widely used in the treatment of DKD and has obvious antioxidant effect. Ferroptosis, a novel mode of cell death due to iron overload, has been shown to be associated with DKD. Nevertheless, the precise effects and underlying mechanisms of SKP on ferroptosis in diabetic kidney disease remain unclear. METHODS: The active components of SKP were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Protein-protein interaction (PPI) network and Herb-ingredient-targets gene network were constructed using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted utilizing the Metascape system database. Additionally, an in vivo model of DKD induced by Streptozotocin (STZ) was established to further investigate and validate the possible mechanisms underlying the effectiveness of SKP. RESULTS: We retrieved 56 compounds and identified 223 targets of SKP through the TCMSP database. Key targets were ascertained using PPI network analysis. By constructing a Herb-Ingredient-Targets gene network, we isolated the primary active components in SKP that potentially counteract ferroptosis in diabetic kidney disease. KEGG pathway enrichment analysis suggested that SKP has the potential to alleviate ferroptosis through HIF signaling pathway, thereby mitigating renal injury in DKD. In animal experiments, fasting blood glucose, 24 h urine protein, urea nitrogen and serum creatine were measured. The results showed that SKP could improve DKD. Results from animal experiments were also confirmed the efficacy of SKP in alleviating renal fibrosis, oxidative stress and ferroptosis in DKD mice. These effects were accompanied by the significant reductions in renal tissue expression of HIF-1α and HO-1 proteins. The mRNA and immunohistochemistry results were the same as above. CONCLUSIONS: SKP potentially mitigating renal injury in DKD by subduing ferroptosis through the intricacies of the HIF-1α/HO-1 signaling pathway.