Overview of mechanisms and novel therapies on rheumatoid arthritis from a cellular perspective.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation of joints in response to autoimmune disorders. Once triggered, many factors were involved in the development of RA, including both cellular factors like osteoclasts, synovial fibroblasts, T cells, B cells, and soluble factors like interleukin-1 (IL-1), IL-6, IL-17 and tumor necrosis factor-α (TNF-α), etc. The complex interplay of those factors results in such pathological abnormality as synovial hyperplasia, bone injury and multi-joint inflammation. To treat this chronic life-affecting disease, the primary drugs used in easing the patient's symptoms are disease-modifying antirheumatic drugs (DMARDs). However, these traditional drugs could cause serious side effects, such as high blood pressure and stomach ulcers. Interestingly, recent discoveries on the pathogenesis of RA have led to various new kinds of drugs or therapeutic strategies. Therefore, we present a timely review of the latest development in this field, focusing on the cellular aspects of RA pathogenesis and new therapeutic methods in clinical application. Hopefully it can provide translational guide to the pre-clinical research and treatment for the autoimmune joint disease.

Aberrant glycosylation in schizophrenia: insights into pathophysiological mechanisms and therapeutic potentials.

Schizophrenia (SCZ) is a severe neuropsychiatric disorder characterized by cognitive, affective, and social dysfunction, resulting in hallucinations, delusions, emotional blunting, and disordered thinking. In recent years, proteomics has been increasingly influential in SCZ research. Glycosylation, a key post-translational modification, can alter neuronal stability and normal signaling in the nervous system by affecting protein folding, stability, and cellular signaling. Recent research evidence suggests that abnormal glycosylation patterns exist in different brain regions in autopsy samples from SCZ patients, and that there are significant differences in various glycosylation modification types and glycosylation modifying enzymes. Therefore, this review explores the mechanisms of aberrant modifications of N-glycosylation, O-glycosylation, glycosyltransferases, and polysialic acid in the brains of SCZ patients, emphasizing their roles in neurotransmitter receptor function, synaptic plasticity, and neural adhesion. Additionally, the effects of antipsychotic drugs on glycosylation processes and the potential for glycosylation-targeted therapies are discussed. By integrating these findings, this review aims to provide a comprehensive perspective to further understand the role of aberrant glycosylation modifications in the pathophysiology of SCZ.

Beliefs about self-control.

It is increasingly recognized that successful self-control is not only determined by sheer willpower, but also by people's beliefs about self-control. While early research has provided evidence that people's implicit theories can moderate their subsequent self-control performance, recent research considers the role of metacognition in self-control more comprehensively. In this review, we present an overview of recent advances in the field, emphasizing self-control beliefs and their potential impact on self-control outcomes. We also stress lay beliefs about self-control as an overlooked topic and promising avenue for future research.

Progress in Research of Nanotherapeutics for Overcoming Multidrug Resistance in Cancer.

Chemotherapy has been widely applied in oncotherapy. However, the development of multidrug resistance (MDR) has diminished the effectiveness of anticancer drugs against tumor cells. Such resistance often results in tumor recurrence, metastasis, and patient death. Fortunately, nanoparticle-based drug delivery systems provide a promising strategy by codelivery of multiple drugs and MDR reversal agents and the skillful, flexible, smart modification of drug targets. Such systems have demonstrated the ability to bypass the ABC transporter biological efflux mechanisms due to drug resistance. Hence, how to deliver drugs and exert potential antitumor effects have been successfully explored, applied, and developed. Furthermore, to overcome multidrug resistance, nanoparticle-based systems have been developed due to their good therapeutic effect, low side effects, and high tumor metastasis inhibition. In view of this, we systematically discuss the molecular mechanisms and therapeutic strategies of MDR from nanotherapeutics. Finally, we summarize intriguing ideas and future trends for further research in overcoming MDR.

The Potential Role of Plant Polysaccharides in Treatment of Ulcerative Colitis.

Ulcerative colitis (UC) results in inflammation and ulceration of the colon and the rectum's inner lining. The application of herbal therapy in UC is increasing worldwide. As natural macromolecular compounds, polysaccharides have a significant role in the treatment of UC due to advantages of better biodegradation, good biocompatibility, immunomodulatory activity, and low reactogenicity. Therefore, polysaccharide drug formulation is becoming a potential candidate for UC treatment. In this review, we summarize the etiology and pathogenesis of UC and the therapeutic effects of polysaccharides on UC, such as regulating the expression of cytokines and tight junction proteins and modulating the balance of immune cells and intestinal microbiota. Polysaccharides can also serve as drug delivery carriers to enhance drug targeting and reduce side effects. This review provides a theoretical basis for applying natural plant polysaccharides in the prevention and treatment of UC.

ERBB3 targeting: A promising approach to overcoming cancer therapeutic resistance.

Human epidermal growth factor receptor-3 (ERBB3) is a member of the ERBB receptor tyrosine kinases (RTKs) and is expressed in many malignancies. Along with other ERBB receptors, ERBB3 is associated with regulating normal cell proliferation, apoptosis, differentiation, and survival, and has received increased research attention for its involvement in cancer therapies. ERBB3 expression or co-expression levels have been investigated as predictive factors for cancer prognosis and drug sensitivity. Additionally, the association between the elevated expression of ERBB3 and treatment failure in cancer therapy further established ERBB3-targeting therapy as a crucial therapeutic approach. This review delves into the molecular mechanisms of ERBB3-driven resistance to targeted therapeutics against ERBB2 and EGFR and other signal transduction inhibitors, endocrine therapy, chemotherapy, and radiotherapy. Using preclinical and clinical evidence, we synthesise and explicate how various aspects of aberrant ERBB3 activities-such as compensatory activation, signal crosstalk interactions, dysregulation in the endocytic pathway, mutations, ligand-independent activation, intrinsic kinase activity, and homodimerisation-can lead to resistance development and/or treatment failures. Several ERBB3-directed monoclonal antibodies, bispecific antibodies, and the emerging antibody-drug conjugate demonstrate encouraging clinical outcomes for improving therapeutic efficacy and overcoming resistance, especially when combined with other anti-cancer approaches. More research efforts are needed to identify appropriate biomarkers tailored for ERBB3-targeted therapies.

Mitochondrial targeted modification and anticancer mechanism of natural product ergosterol peroxide.

Ergosterol peroxide (EP) isolated from the edible medicinal fungus Pleurotus ferulae has a wide range of anti-tumor activity, but poor water solubility and low bioavailability limit further application. In this study, EP was structurally modified using triphenylphosphine (TPP+), which combines mitochondrial targeting, amphiphilicity, and cytotoxicity. A series of TPP+-conjugated ergosterol peroxide derivatives (TEn) with different length linker arms were synthesized. The structure-activity relationship showed that the anticancer activity of TEn gradually decreased with the elongation of the linker arm. The compound TE3 has the optimal and broadest spectrum of antitumor effects. It mainly through targeting mitochondria, inducing ROS production, disrupting mitochondrial function, and activating mitochondria apoptosis pathway to exert anti-cervical cancer activity. Among them, TPP+ only acted as a mitochondrial targeting group, while EP containing peroxide bridge structure served as an active group to induce ROS. In vivo experiments have shown that TE3 has better anti-cervical cancer activity and safety than the first-line anticancer drug cisplatin, and can activate the immune response in mice. Although TE3 exhibits some acute toxicity, it is not significant at therapeutic doses. Therefore, TE3 has the potential for further development as an anti-cervical cancer drug.

Raman spectroscopy combined with convolutional neural network for the sub-types classification of breast cancer and critical feature visualization.

PROBLEMS: Raman spectroscopy has emerged as an effective technique that can be used for noninvasive breast cancer analysis. However, the current Raman prediction models fail to cover all the molecular sub-types of breast cancer, and lack the visualization of the model. AIMS: Using Raman spectroscopy combined with convolutional neural network (CNN) to construct a prediction model for the existing known molecular sub-types of breast cancer, and selected critical peaks through visualization strategies, so as to achieve the purpose of mining specific biomarker information. METHODS: Optimizing network parameters with the help of sparrow search algorithm (SSA) for the multiple parameters in the CNN to improve the prediction performance of the model. To avoid the contingency of the results, multiple sets of data were generated through Monte Carlo sampling and used to train the model, thereby improving the credibility of the results. Based on the accurate prediction of the model, the spectral regions that contributed to the classification were visualized using Gradient-weighted Class Activation Mapping (Grad-CAM), achieving the goal of visualizing characteristic peaks. RESULTS: Compared with other algorithms, optimized CNN could obtain the highest accuracy and lowest standard error. And there was no significant difference between using full spectra and fingerprint regions (within 2 %), indicating that the fingerprint region provided the most contribution in classifying sub-types. Based on the classification results from the fingerprint region, the model performances about various sub-types were as follows: CNN (95.34 %±2.18 %)>SVM(94.90 %±1.88 %)>PLS-DA(94.52 %±2.22 %)> KNN (80.00 %±5.27 %). The critical features visualized by Grad-CAM could match well with IHC information, allowing for a more distinct differentiation of sub-types in their spatial positions. CONCLUSION: Raman spectroscopy combined with CNN could achieve accurate and rapid identification of breast cancer molecular sub-types. Proposed visualization strategy could be proved from biochemistry information and spatial location, demonstrated that the strategy might be used for the mining of biomarkers in future.

In vivo pharmacokinetics of Glycyrrhiza uralensis polysaccharides.

Glycyrrhiza uralensis polysaccharides (GUPS) are widely applied in biomedicine and functional food due to their multiple pharmacological activities and low toxicity. Despite their widespread use, the in vivo metabolic profile of GUPS remains poorly understood. To address this gap, we developed a quantitative analysis method that involves labeling GUPS with visible fluorescein (5-DTAF) and near-infrared (NIR) fluorescein (Cy7), resulting in stable conjugates with substitution degrees of 0.81% for 5-DTAF and 0.39% for Cy7. The pharmacokinetic studies showed a biphasic elimination pattern in the blood concentration-time curve following both intravenous and oral administration, consistent with a two-compartment model. Using fluorescence quantification and NIR imaging, we observed that GUPS was distributed to various tissues, exhibiting higher concentrations particularly in liver, kidney and lung. Excretion studies indicated that feces were the major excretion pathway of GUPS after oral administration (60.98%), whereas urine was the main pathway after intravenous administration (31.16%). Notably, GUPS could be absorbed rapidly by gut (Tmax 1 ± 0.61 h) and showed a biological half-time t1/2 26.4 ± 7.72 h after oral administration. Furthermore, the Caco-2 cells uptake studies illustrated that macropinocytosis and clathrin-mediated endocytosis were participated in the transport of GUPS in intestine epithelium. This comprehensive analysis of the in vivo pharmacokinetics of GUPS not only enhances our understanding of its metabolic pathways but also establishes a foundational basis for its clinical application, optimizing its therapeutic potential and safety profile.

Non-viral vectors combined delivery of siRNA and anti-cancer drugs to reverse tumor multidrug resistance.

Multidrug resistance (MDR) of tumors is one of the main reasons for the failure of chemotherapy. Multidrug resistance refers to the cross-resistance of tumor cells to multiple antitumor drugs with different structures and mechanisms of action. Current strategies to reverse multidrug resistance in tumors include MDR inhibitors and RNAi technology. siRNA is a small molecule RNA that is widely used in RNAi technology and has the characteristics of being prepared in large quantities and chemically modified. However, siRNA is susceptible to degradation in vivo. The effect of siRNA therapy alone is not ideal, so siRNA and anticancer drugs are administered in combination to reverse the MDR of tumors. Non-viral vectors are now commonly used to deliver siRNA and anticancer drugs to tumor sites. This article will review the progress of siRNA and chemotherapeutic drug delivery systems and their mechanisms for reversing multidrug resistance.

Enhanced Thermostability of Nattokinase by Computation-Based Rational Redesign of Flexible Regions.

Nattokinase is a nutrient in healthy food natto that has the function of preventing and treating blood thrombus. However, its low thermostability and fibrinolytic activity limit its application in food and pharmaceuticals. In this study, we used bioinformatics analysis to identify two loops (loop10 and loop12) in the flexible region of nattokinase rAprY. Using this basis, we screened the G131S-S161T variant, which showed a 2.38-fold increase in half-life at 55 °C, and the M3 variant, which showed a 2.01-fold increase in activity, by using a thermostability prediction algorithm. Bioinformatics analysis revealed that the enhanced thermostability of the G131S-S161T variant was due to the increased rigidity and structural shrinkage of the overall structure. Additionally, the increased rigidity of the local region surrounding the active center and its mutated sites helps maintain its normal conformation in high-temperature environments. The increased catalytic activity of the M3 variant may be due to its more efficient substrate binding mechanism. We investigated strategies to improve the thermostability and fibrinolytic activity of nattokinase, and the resulting variants show promise for industrial production and application.

Noble Metal Nanoparticle-Based Photothermal Therapy: Development and Application in Effective Cancer Therapy.

Photothermal therapy (PTT) is a promising cancer therapy modality with significant advantages such as precise targeting, convenient drug delivery, better efficacy, and minimal adverse effects. Photothermal therapy effectively absorbs the photothermal transducers in the near-infrared region (NIR), which induces the photothermal effect to work. Although PTT has a better role in tumor therapy, it also suffers from low photothermal conversion efficiency, biosafety, and incomplete tumor elimination. Therefore, the use of nanomaterials themselves as photosensitizers, the targeted modification of nanomaterials to improve targeting efficiency, or the combined use of nanomaterials with other therapies can improve the therapeutic effects and reduce side effects. Notably, noble metal nanomaterials have attracted much attention in PTT because they have strong surface plasmon resonance and an effective absorbance light at specific near-infrared wavelengths. Therefore, they can be used as excellent photosensitizers to mediate photothermal conversion and improve its efficiency. This paper provides a comprehensive review of the key role played by noble metal nanomaterials in tumor photothermal therapy. It also describes the major challenges encountered during the implementation of photothermal therapy.

Natural Antioxidants: An Effective Strategy for the Treatment of Alzheimer's Disease at the Early Stage.

The critical role of oxidative stress in Alzheimer's disease (AD) has been recognized by researchers recently, and natural antioxidants have been demonstrated to have anti-AD activity in animal models, such as Ginkgo biloba extract, soy isoflavones, lycopene, and so on. This paper summarized these natural antioxidants and points out that natural antioxidants always have multiple advantages which are help to deal with AD, such as clearing free radicals, regulating signal transduction, protecting mitochondrial function, and synaptic plasticity. Based on the available data, we have created a relatively complete pathway map of reactive oxygen species (ROS) and AD-related targets and concluded that oxidative stress caused by ROS is the core of AD pathogenesis. In the prospect, we introduced the concept of a combined therapeutic strategy, termed "Antioxidant-Promoting Synaptic Remodeling," highlighting the integration of antioxidant interventions with synaptic remodeling approaches as a novel avenue for therapeutic exploration.

Application of Nanomaterial-Based Sonodynamic Therapy in Tumor Therapy.

Sonodynamic therapy (SDT) has attracted significant attention in recent years as it is an innovative approach to tumor treatment. It involves the utilization of sound waves or ultrasound (US) to activate acoustic sensitizers, enabling targeted drug release for precise tumor treatment. This review aims to provide a comprehensive overview of SDT, encompassing its underlying principles and therapeutic mechanisms, the applications of nanomaterials, and potential synergies with combination therapies. The review begins by introducing the fundamental principle of SDT and delving into the intricate mechanisms through which it facilitates tumor treatment. A detailed analysis is presented, outlining how SDT effectively destroys tumor cells by modulating drug release mechanisms. Subsequently, this review explores the diverse range of nanomaterials utilized in SDT applications and highlights their specific contributions to enhancing treatment outcomes. Furthermore, the potential to combine SDT with other therapeutic modalities such as photothermal therapy (PTT) and chemotherapy is discussed. These combined approaches aim to synergistically improve therapeutic efficacy while mitigating side effects. In conclusion, SDT emerges as a promising frontier in tumor treatment that offers personalized and effective treatment options with the potential to revolutionize patient care. As research progresses, SDT is poised to play a pivotal role in shaping the future landscape of oncology by providing patients with a broader spectrum of efficacious and tailored treatment options.

Diagnosis of benign and malignant peripheral lung lesions based on a feature model constructed by the random forest algorithm for grayscale and contrast-enhanced ultrasound.

Rationale and objectives: To construct a predictive model for benign and malignant peripheral pulmonary lesions (PPLs) using a random forest algorithm based on grayscale ultrasound and ultrasound contrast, and to evaluate its diagnostic value. Materials and methods: We selected 254 patients with PPLs detected using chest lung computed tomography between October 2021 and July 2023, including 161 malignant and 93 benign lesions. Relevant variables for judging benign and malignant PPLs were screened using logistic regression analysis. A model was constructed using the random forest algorithm, and the test set was verified. Correlations between these relevant variables and the diagnosis of benign and malignant PPLs were evaluated. Results: Age, lesion shape, size, angle between the lesion border and chest wall, boundary clarity, edge regularity, air bronchogram, vascular signs, enhancement patterns, enhancement intensity, homogeneity of enhancement, number of non-enhancing regions, non-enhancing region type, arrival time (AT) of the lesion, lesion-lung AT difference, AT difference ratio, and time to peak were the relevant variables for judging benign and malignant PPLs. Consequently, a model and receiver operating characteristic curve were constructed with an AUC of 0.92 and an accuracy of 88.2%. The test set results showed that the model had good predictive ability. The index with the highest correlation for judging benign and malignant PPLs was the AT difference ratio. Other important factors were lesion size, patient age, and lesion morphology. Conclusion: The random forest algorithm model constructed based on clinical data and ultrasound imaging features has clinical application value for predicting benign and malignant PPLs.

HAuCl4-mediated green synthesis of highly stable Au NPs from natural active polysaccharides: Synthetic mechanism and antioxidant property.

Polysaccharide-functionalized gold nanoparticles (Polysaccharide-Au NPs) with high stability were successfully prepared by a straightforward method. Notably, the Au (III) ion acts as a strong Lewis acid to facilitate glycosidic bond breaking. Subsequently, the polysaccharide conformation was transformed to an open-chain form, exposing highly reduced aldehyde or ketone groups that reduce Au (III) to Au (0) crystal species, further growing into Au NPs. As-prepared Au NPs displayed excellent stability over a longer storage period (more than 70 days), a wide range of temperatures (25-60 °C), and pH range (3-11), varying concentrations (0-200 mM) and types of salt ions (Na+, K+, Ca2+, Mg2+), and glutathione solutions (5 mM). More interestingly, polysaccharide-Au NPs retained the antioxidant activity of polysaccharides and reduced oxidative damage at the cellular level through decreased reactive oxygen species (ROS) production. The intracellular levels of ROS pretreated with polysaccharide and polysaccharide-Au NPs were decreased 53.12-75.85 % compared to the H2O2 group, respectively. Therefore, the green synthesized Au NPs from natural active polysaccharides exhibit potential applications in biomedical fields.

Research Progress of Plant-Derived Natural Products against Drug-Resistant Cancer.

As one of the malignant diseases globally, cancer seriously endangers human physical and mental health because of its high morbidity and mortality. Conventional cancer treatment strategies, such as surgical resection and chemoradiotherapy, are effective at the early stage of cancer but have limited efficacy for advanced cancer. Along with cancer progress and treatment, resistance develops gradually within the population of tumor cells. As a consequence, drug resistance become the major cause that leads to disease progression and poor clinical prognosis in some patients. The mechanisms of cancer drug resistance are quite complex and involve various molecular and cellular mechanisms. Therefore, exploring the mechanisms and finding specific targets are becoming imperative to overcome drug resistance. In recent years, plant-derived natural products have been evaluated as potential therapeutic candidates against cancer with drug resistance due to low side effects and high anticancer efficacy. A growing number of studies have shown that natural products can achieve superior antitumor effects through multiple signaling pathways. The mechanisms include regulation of multiple drug resistance (MDR)-related genes, inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, induction of autophagy, and blockade of the cell cycle. This paper reviews the molecular and cellular mechanisms of cancer drug resistance, as well as the therapeutic effects and mechanisms of plant-derived natural products against cancer drug resistance. It provides references for developing therapeutic medication for drug-resistant cancer treatment with high efficacy and low side effects.

Enhanced Cathode Performance: The Heterostructure Construction of LiCoO2@Co3O4@Li6.4La3Zr1.4Ta0.6O12.

In this study, the heterostructure cathode material LiCoO2@Co3O4@Li6.4La3Zr1.4Ta0.6O12 was prepared by coating Li6.4La3Zr1.4Ta0.6O12 on the surface of LiCoO2 through a one-step solid-phase synthesis. The morphology, structure, electrical state, and elemental contents of both pristine and modified materials were assessed through a range of characterization techniques. Theoretical calculations revealed that the LCO@LLZTO material possessed a reduced diffusion barrier compared to LiCoO2, thereby facilitating the movement of Li ions. Electrochemical tests indicated that the capacity retention rate of the modified cathode composites stood at 70.43% following 300 cycles at a 2C rate. This high rate occurred because the Li6.4La3Zr1.4Ta0.6O12 film on the surface enhanced the migration of Li+, and the spinel phase of Co3O4 had better interfacial stability to alleviate the generation of microcracks by inhibiting the phase change from the layered phase to the rock-salt phase, which considerably improved the electrochemical properties.

Research Progress of Polysaccharide-Gold Nanocomplexes in Drug Delivery.

Clinical drug administration aims to deliver drugs efficiently and safely to target tissues, organs, and cells, with the objective of enabling their therapeutic effects. Currently, the main approach to enhance a drug's effectiveness is ensuring its efficient delivery to the intended site. Due to the fact that there are still various drawbacks of traditional drug delivery methods, such as high toxicity and side effects, insufficient drug specificity, poor targeting, and poor pharmacokinetic performance, nanocarriers have emerged as a promising alternative. Nanocarriers possess significant advantages in drug delivery due to their size tunability and surface modifiability. Moreover, nano-drug delivery systems have demonstrated strong potential in terms of prolonging drug circulation time, improving bioavailability, increasing drug retention at the tumor site, decreasing drug resistance, as well as reducing the undesirable side effects of anticancer drugs. Numerous studies have focused on utilizing polysaccharides as nanodelivery carriers, developing delivery systems based on polysaccharides, or exploiting polysaccharides as tumor-targeting ligands to enhance the precision of nanoparticle delivery. These types of investigations have become commonplace in the academic literature. This review aims to elucidate the preparation methods and principles of polysaccharide gold nanocarriers. It also provides an overview of the factors that affect the loading of polysaccharide gold nanocarriers with different kinds of drugs. Additionally, it outlines the strategies employed by polysaccharide gold nanocarriers to improve the delivery efficiency of various drugs. The objective is to provide a reference for further development of research on polysaccharide gold nanodelivery systems.