Innovative medicinal chemistry strategies for enhancing drug solubility.

Drug candidates with poor solubility have been recognized as the cause of many drug development failures, owing to the fact that low solubility is unfavorable for physicochemical, pharmacokinetic (PK) and pharmacodynamic (PD) properties. Given the imperative role of solubility during drug development, we herein summarize various strategies for solubility optimizations from a medicinal chemistry perspective, including introduction of polar group, salt formation, structural simplification, disruption of molecular planarity and symmetry, optimizations on the solvent exposed region as well as prodrug design. In addition, methods for solubility assessment and prediction are reviewed. Besides, we have deeply discussed the strategies for solubility improvement. This paper is expected to be beneficial for the development of drug-like molecules with good solubility.

Benzophenone-4 inhibition in marine diatoms: Physiological and molecular perspectives.

Benzophenone-4 (BP-4), a widely utilized organic ultraviolet (UV) filter, is recognized as a pseudo-persistent contaminant in aquatic environments. To elucidate the effects and mechanisms of BP-4 on marine diatoms, an investigation was conducted on the growth rate, photosynthetic pigment content, photosynthetic parameters, antioxidant enzyme activity, malondialdehyde (MDA) levels, cellular structure, and transcriptome profile of the model species, Phaeodactylum tricornutum. The results showed a pronounced inhibition of algal growth upon exposure to BP-4, with a 144 h-EC50 value of 201 mg·L-1. In addition, BP-4 exposure resulted in a significant reduction in biomass, disruption of cell membrane integrity, and increased MDA accumulation, with levels escalating 3.57-fold at 125 mg·L-1 of BP-4. In the BP-4-treated samples, 1556 differentially expressed genes (DEGs) were identified, of which 985 were upregulated and 571 were downregulated. Gene ontology and KEGG pathway enrichment analysis revealed that the carbon fixation and carbon metabolism processes in P. tricornatum were disrupted in response to BP-4 exposure, along with excessive reactive oxygen species (ROS) production. The upregulation of genes associated with photosynthetic pigment (chlorophyll and carotenoids) synthesis, phospholipid synthesis, ribosome biogenesis, and translation-related pathways may be regarded as a component of P. tricornatum's tolerance mechanism towards BP-4. These results provide preliminary insights into the toxicity and tolerance mechanisms of BP-4 on P. tricornatum. They will contribute to a better understanding of the ecotoxicological impacts of BP-4 on the marine ecosystem and provide valuable information for elimination of BP-4 in aquatic environment by bioremediation.

A Self-Catalytic NO/O2 Gas-Releasing Nanozyme for Radiotherapy Sensitization through Vascular Normalization and Hypoxia Relief.

Radiotherapy (RT), essential for treating various cancers, faces challenges from tumor hypoxia, which induces radioresistance. A tumor-targeted "prosthetic-Arginine" coassembled nanozyme system, engineered to catalytically generate nitric oxide (NO) and oxygen (O2) in the tumor microenvironment (TME), overcoming hypoxia and enhancing radiosensitivity is presented. This system integrates the prosthetic heme of nitric oxide synthase (NOS) and catalase (CAT) with NO-donating Fmoc-protected Arginine and Ru3+ ions, creating HRRu nanozymes that merge NOS and CAT functionalities. Surface modification with human heavy chain ferritin (HFn) improves the targeting ability of nanozymes (HRRu-HFn) to tumor tissues. In the TME, strategic arginine incorporation within the nanozyme allows autonomous O2 and NO release, triggered by endogenous hydrogen peroxide, elevating NO and O2 levels to normalize vasculature and improve blood perfusion, thus mitigating hypoxia. Employing the intrinsic O2-transporting ability of heme, HRRu-HFn nanozymes also deliver O2 directly to the tumor site. Utilizing esophageal squamous cell carcinoma as a tumor model, the studies reveal that the synergistic functions of NO and O2 production, alongside targeted delivery, enable the HRRu-HFn nanozymes to combat tumor hypoxia and potentiate radiotherapy. This HRRu-HFn nanozyme based approach holds the potential to reduce the radiation dose required and minimize side effects associated with conventional radiotherapy.

PegIFN alpha-2a reduces relapse in HBeAg-negative patients after nucleo(s)tide analogue cessation: A randomized-controlled trial.

BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse. However, the effect of pegylated interferon alpha-2a (PegIFN-α-2a) on virological relapse after NUC cessation is unknown. Therefore, this study aimed to evaluate the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96. METHODS: In this multicentre randomized controlled clinical trial, 180 non-cirrhotic HBeAg-negative chronic hepatitis B patients on continuous NUC therapy for ≥ 2.5 years with HBV DNA levels < 60 IU/mL were randomized to discontinue NUC (n=90) or receive 48 weeks of PegIFN-α-2a treatment (n=90) and followed up till 96 weeks. The primary endpoint was the virological relapse rate until week 96. RESULTS: Intention-to-treat analysis revealed patients in the interferon monotherapy group had significantly lower cumulative virological relapse rates than the NUC cessation group until week 96 (20.8% vs. 53.6%, P < 0.0001). Consistently, a significantly lower proportion of patients in the interferon monotherapy group had virological relapse than those in the NUC cessation group at 48 weeks off treatment (17.8% vs. 36.7%, P = 0.007). The virological relapse rate positively correlated with HBsAg levels in the NUC cessation group. The interferon monotherapy group had a lower cumulative clinical relapse rate (7.8% vs. 20.9%, P = 0.008) and a higher HBsAg loss rate (21.5% vs. 9.0%, P = 0.03) than the NUC cessation group. CONCLUSIONS: Switching from NUC to PegIFN-α-2a treatment for 48 weeks significantly reduces virological relapse rates and achieves higher HBsAg loss rates than NUC treatment cessation alone in HBeAg-negative chronic hepatitis B patients. IMPACT AND IMPLICATIONS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse, but an optimised scheme to reduce the virological relapse rate after NUC withdrawal is yet to be reported. This randomized controlled trial investigated the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96 in HBeAg-negative chronic hepatitis B patients. The interferon monotherapy group had a significantly lower cumulative virological relapse rate (20.8% vs. 53.6%, P < 0.0001) and higher HBsAg loss rate (21.5% vs. 9.0%, P= 0.03) than the NUC cessation group until week 96. This provides an optimized strategy for NUC cessation in HBeAg-negative patients. TRIAL REGISTRATION NUMBER: NCT02594293.

Discovery of Novel Imidazo[1,2-a]pyridine-Based HDAC6 Inhibitors as an Anticarcinogen with a Cardioprotective Effect.

Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.

Targeted discovery of clerodane diterpenoids from Tinospora sinensis as immunomodulatory agents.

Under the guidance of MS/MS-based molecular networking, five new clerodane diterpenoid glucosides, tinosinesides R-V (1-5), along with 15 known diterpenoids (6-20), were isolated from the stems of Tinospora sinensis. Compound 1 represents the first example of diterpenoid bearing a thio sugar and compound 5 is the first 18,19-dinor-clerodane with cis-fused A/B ring. The structures of the new compounds were elucidated by spectroscopic means, and their absolute configurations were established on the basis of time-dependent density functional theory (TD-DFT) based electronic circular dichroism (ECD) calculation and chemical methods. Selected compounds were evaluated for their immunomodulatory effect and several compounds could enhance the proliferation of B lymphocytes. Preliminary mechanistic studies disclosed that 3 could promote B cell generation and inhibit B cell differentiation.

PTBP1 knockdown impairs autophagy flux and inhibits gastric cancer progression through TXNIP-mediated oxidative stress.

BACKGROUND: Gastric cancer (GC) is a prevalent malignant tumor, and the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) has been identified as a crucial factor in various tumor types. Moreover, abnormal autophagy levels have been shown to significantly impact tumorigenesis and progression. Despite this, the precise regulatory mechanism of PTBP1 in autophagy regulation in GC remains poorly understood. METHODS: To assess the expression of PTBP1 in GC, we employed a comprehensive approach utilizing western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and bioinformatics analysis. To further identify the downstream target genes that bind to PTBP1 in GC cells, we utilized RNA immunoprecipitation coupled with sequencing (si-PTBP1 RNA-seq). To evaluate the impact of PTBP1 on gastric carcinogenesis, we conducted CCK-8 assays, colony formation assays, and GC xenograft mouse model assays. Additionally, we utilized a transmission electron microscope, immunofluorescence, flow cytometry, western blot, RT-qPCR, and GC xenograft mouse model experiments to elucidate the specific mechanism underlying PTBP1's regulation of autophagy in GC. RESULTS: Our findings indicated that PTBP1 was significantly overexpressed in GC tissues compared with adjacent normal tissues. Silencing PTBP1 resulted in abnormal accumulation of autophagosomes, thereby inhibiting GC cell viability both in vitro and in vivo. Mechanistically, interference with PTBP1 promoted the stability of thioredoxin-interacting protein (TXNIP) mRNA, leading to increased TXNIP-mediated oxidative stress. Consequently, this impaired lysosomal function, ultimately resulting in blockage of autophagic flux. Furthermore, our results suggested that interference with PTBP1 enhanced the antitumor effects of chloroquine, both in vitro and in vivo. CONCLUSION: PTBP1 knockdown impairs GC progression by directly binding to TXNIP mRNA and promoting its expression. Based on these results, PTBP1 emerges as a promising therapeutic target for GC.

Bioimaging and prospects of night pearls-based persistence phosphors in cancer diagnostics.

Inorganic persistent phosphors feature great potential for cancer diagnosis due to the long luminescence lifetime, low background scattering, and minimal autofluorescence. With the prominent advantages of near-infrared light, such as deep penetration, high resolution, low autofluorescence, and tissue absorption, persistent phosphors can be used for deep bioimaging. We focus on highlighting inorganic persistent phosphors, emphasizing the synthesis methods and applications in cancer diagnostics. Typical synthetic methods such as the high-temperature solid state, thermal decomposition, hydrothermal/solvothermal, and template methods are proposed to obtain small-size phosphors for biological organisms. The luminescence mechanisms of inorganic persistent phosphors with different excitation are discussed and effective matrixes including galliumate, germanium, aluminate, and fluoride are explored. Finally, the current directions where inorganic persistent phosphors can continue to be optimized and how to further overcome the challenges in cancer diagnosis are summarized.

Five-Year Outcomes of Bioresorbable Stent Therapy for Coronary Heart Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: The efficacy of bioresorbable vascular scaffolds (BVS) compared to metallic stents for the treatment of coronary heart disease remains controversial. The analysis of clinical outcomes at five years following the initial treatment has yet to be reviewed. This study sought to assess the five-year outcomes in randomized controlled trials of BVS in the treatment of coronary heart disease using a systematic review and meta-analysis. Methods: A systematic database search was conducted from their inception to June 30th, 2023 using various Medical Subject Headings (MeSH) terms including: "Coronary Disease", "Bioresorbable stent", "Randomized controlled trials". Results: After a rigorous selection process, a total of five high-quality articles were finally included in this study. Each trial demonstrated a low risk of bias. After 5 years, bioresorbable stents showed outcomes similar to conventional metal stents in terms of cardiac mortality. However, they were inferior in terms of lesion revascularization rates, in-stent thrombosis rates, target lesion failure, target vessel failure, and myocardial infarction. Conclusions: While bioresorbable stents are comparable to metallic stents in terms of cardiac mortality rates, they exhibit significant drawbacks that warrant clinical consideration.

A comprehensive review on DCN1 protein, inhibitors and their therapeutic applications.

DCN1, a critical co-E3 ligase in the neddylation process, mediates the activation of Cullin-RING Ligases (CRLs) by selectively catalyzing cullin neddylation, further regulating the activity of substrate proteins. It has been identified as an important target for human diseases, including cancers, fibrotic diseases, and cardiovascular disorders. This work aims to provide a perspective for the discovery of novel DCN1 inhibitors by the analysis of biological roles, protein structures, structure-activity relationships and design strategy disclosed in recent years. Additionally, we will discuss the current status, challenges and opportunities in hope of offering insights into the development of DCN1 inhibitors for human diseases.

Targeting histone methylation and demethylation for non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, facing increasing challenges in terms of prevention and treatment. The methylation of lysine and arginine residues on histone proteins is dynamically controlled by histone methyltransferases (HMTs) and histone demethylases (HDMs), regulating chromatin structure and gene transcription. Mutations, genetic translocations, and altered gene expression involving HMTs and HDMs are frequently observed in NAFLD. HMTs and HDMs are receiving increasing attention in regulating NALFD. Targeting specific HMTs and HDMs for drug development is becoming a new strategy for treating NAFLD. This review provides a comprehensive summary of the regulatory mechanism of histone methylation/demethylation in NAFLD. Additionally, we discuss the potential applications of HMTs and HDMs inhibitors in preventing NAFLD, which may provide a scientific basis for the treatment of NAFLD.

Associations between different coffee types, neurodegenerative diseases, and related mortality: findings from a large prospective cohort study.

BACKGROUND: Observational studies have suggested associations between amount of coffee consumption and decreased risk of neurodegenerative diseases. However, these studies do not consider differences among coffee types, including sweetened, unsweetened, caffeinated, and decaffeinated varieties. OBJECTIVES: This study aims to identify associations between the consumption of various coffee types (sugar-sweetened, artificially sweetened, unsweetened, caffeinated, and decaffeinated) and risks of Alzheimer's disease and related dementias (ADRD) and Parkinson's disease (PD), along with related mortality. METHODS: This prospective study included 204,847 participants (44.7% males) from the UK Biobank. Cox proportional hazards models were used to assess the associations of coffee type with neurodegenerative outcome. On the basis of coffee consumption, participants were divided into 5 groups: non-coffee consumers, >0-1 cup/d, ≥1-2 cups/d, ≥2-3 cups/d, and ≥3 cups/d. RESULTS: Over a median follow-up of 9 y, the study documented 1696 cases of ADRD, 1093 cases of PD, and 419 neurodegenerative-related deaths. In the multivariate analysis, compared with non-coffee consumers, those with the highest intake of unsweetened and caffeinated coffee (≥3 cups/d) showed hazard ratios (95% confidence intervals) of 0.75 (0.62, 0.91) for ADRD, 0.71 (0.56, 0.91) for PD, and 0.67 (0.44, 1.01) for neurodegenerative-related death. However, no significant associations were noted in either decaffeinated or sugar/artificially sweetened coffee groups (P > 0.05). CONCLUSIONS: Higher intake of caffeinated coffee, particularly the unsweetened variety, was associated with reduced risks of ADRD and PD. No such associations were observed for sugar-sweetened or artificially sweetened coffee.

Causal relationship between the gut microbiota, immune cells, and coronary heart disease: a mediated Mendelian randomization analysis.

Background: Recent studies have shown that the gut microbiota (GM), immune cells, and coronary heart disease (CHD) are closely related, but the causal nature of these relationships is largely unknown. This study aimed to investigate this causal relationship and reveal the effect of GM and immune cells on the risk of developing CHD using mediated Mendelian randomization (MR) analysis. Methods: First, we searched for data related to GM, immune cells, and CHD through published genome-wide association studies (GWAS). We filtered the single nucleotide polymorphisms (SNPs) associated with GM and immune cells and then performed the first MR analysis to identify disease-associated intestinal bacteria and disease-associated immune cells. Subsequently, three MR analyses were conducted: from disease-associated GM to disease-associated immune cells, from disease-associated immune cells to CHD, and from disease-associated GM to CHD. Each MR analysis was conducted using inverse variance weighting (IVW), MR-Egger regression, weighted median, weighted models, and simple models. Results: A total of six GM and 25 immune cells were found to be associated with CHD. In the MR analysis using the inverse variance weighting (IVW) method, g__Desulfovibrio.s__Desulfovibrio_piger was associated with EM DN (CD4-CD8-) %T cells (P < 0.05 and OR > 1), EM DN (CD4-CD8-) %T cells was associated with CHD (P < 0.05 and OR < 1), and g__Desulfovibrio.s__Desulfovibrio_piger was associated with CHD (P < 0.05 and OR < 1). Conclusion: An increase in the abundance of g__Desulfovibrio.s__Desulfovibrio_piger leads to an increase in the amount of EM DN (CD4-CD8-) %T cells, and an increase in the amount of EM DN (CD4-CD8-) %T cells reduces the risk of developing CHD. Our study provides some references for reducing the incidence of CHD by regulating GM and immune cells.

Wave propagation in a light-temperature neural network under adaptive local energy balance.

External electric and mechanical stimuli can induce shape deformation in excitable media because of its intrinsic flexible property. When the signals propagation in the media is described by a neural network, creation of heterogeneity or defect is considered as the effect of shape deformation due to accumulation or release of energy in the media. In this paper, a temperature-light sensitive neuron model is developed from a nonlinear circuit composed of a phototube and a thermistor, and the physical energy is kept in capacitive and inductive terms. Furthermore, the Hamilton energy for this function neuron is obtained in theoretical way. A regular neural network is built on a square array by activating electric synapse between adjacent neurons, and a few of neurons in local area is excited by noisy disturbance, which induces local energy diversity, and continuous coupling enables energy propagation and diffusion. Initially, the Hamilton energy function for a temperature-light sensitive neuron can be obtained. Then, the finite neurons are applied noise to obtain energy diversity to explore the energy spread between neurons in the network. For keeping local energy balance, one intrinsic parameter is regulated adaptively until energy diversity in this local area is decreased greatly. Regular pattern formation indicates that local energy balance creates heterogeneity or defects and a few of neurons show continuous parameter shift for keeping energy balance in a local area, which supports gradient energy distribution for propagating waves in the network.

Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy.

BACKGROUND: Breast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized. METHODS: A substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B. RESULTS: We synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice. CONCLUSIONS: Our findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer.

Small molecule targeted therapies for endometrial cancer: progress, challenges, and opportunities.

Endometrial cancer (EC) is a common malignancy among women worldwide, and its recurrence makes it a common cause of cancer-related death. Surgery and external radiation, chemotherapy, or a combination of strategies are the cornerstone of therapy for EC patients. However, adjuvant treatment strategies face certain drawbacks, such as resistance to chemotherapeutic drugs; therefore, it is imperative to explore innovative therapeutic strategies to improve the prognosis of EC. With the development of pathology and pathophysiology, several biological targets associated with EC have been identified, including PI3K/Akt/mTOR, PARP, GSK-3ß, STAT-3, and VEGF. In this review, we summarize the progress of small molecule targeted therapies in terms of both basic research and clinical trials and provide cases of small molecules combined with fluorescence properties in the clinical applications of integrated diagnosis and treatment. We hope that this review will facilitate the further understanding of the regulatory mechanism governing the dysregulation of oncogenic signaling in EC and provide insights into the possible future directions of targeted therapeutic regimens for EC treatment by developing new agents with fluorescence properties for the clinical applications of integrated diagnosis and treatment.

An overview of cyclopropenone derivatives as promising bioactive molecules.

Cyclopropenone is a valuable electrophilic reagent that can react with electrophilic reagents, nucleophilic reagents, free radicals, organic metals, etc. Furthermore, cyclopropenone derivatives have shown significant biological activity in various diseases, such as triple-negative breast cancer (TNBC), melanoma, and alopecia areata (AA). The cyclopropenone analogue diphenylcyclopropenone (DPCP) has been approved for the treatment of AA. Given the potential therapeutic benefits of cyclopropenone derivatives, this review aims to systematically summarize the structures, synthesis routes, and potential pharmacological functions of cyclopropenone analogues in the hope of offering novel insights for further rational design of more drugs based on the cyclopropenone skeleton for the treatment of human diseases.

A novel protein FNDC3B-267aa encoded by circ0003692 inhibits gastric cancer metastasis via promoting proteasomal degradation of c-Myc.

BACKGROUND: Gastric cancer (GC) ranks fifth in global cancer incidence and third in mortality rate among all cancer types. Circular RNAs (circRNAs) have been extensively demonstrated to regulate multiple malignant biological behaviors in GC. Emerging evidence suggests that several circRNAs derived from FNDC3B play pivotal roles in cancer. However, the role of circFNDC3B in GC remains elusive. METHODS: We initially screened circFNDC3B with translation potential via bioinformatics algorithm prediction. Subsequently, Sanger sequencing, qRT-PCR, RNase R, RNA-FISH and nuclear-cytoplasmic fractionation assays were explored to assess the identification and localization of circ0003692, a circRNA derived from FNDC3B. qRT-PCR and ISH were performed to quantify expression of circ0003692 in human GC tissues and adjacent normal tissues. The protein-encoding ability of circ0003692 was investigated through dual-luciferase reporter assay and LC/MS. The biological behavior of circ0003692 in GC was confirmed via in vivo and in vitro experiments. Additionally, Co-IP and rescue experiments were performed to elucidate the interaction between the encoded protein and c-Myc. RESULTS: We found that circ0003692 was significantly downregulated in GC tissues. Circ0003692 had the potential to encode a novel protein FNDC3B-267aa, which was downregulated in GC cells. We verified that FNDC3B-267aa, rather than circ0003692, inhibited GC migration in vitro and in vivo. Mechanistically, FNDC3B-267aa directly interacted with c-Myc and promoted proteasomal degradation of c-Myc, resulting in the downregulation of c-Myc-Snail/Slug axis. CONCLUSIONS: Our study revealed that the novel protein FNDC3B-267aa encoded by circ0003692 suppressed GC metastasis through binding to c-Myc and enhancing proteasome-mediated degradation of c-Myc. The study offers the potential applications of circ0003692 or FNDC3B-267aa as therapeutic targets for GC.

Frequent Misdiagnosis of Scabies as Eczema in China: A Descriptive Study of 23 Cases.

Objective: To outline the clinical manifestations observed in patients with scabies misdiagnosed as generalized eczema, analyse the factors contributing to these misdiagnoses and explore potential reasons for the resurgence of scabies. Patients and Methods: A retrospective analysis was performed to investigate the patients with scabies misdiagnosed as generalized eczema. Results: We included 23 patients, with twelve (52.17%) being male and eleven (47.83%) female. The illness duration ranged from 0.5 to 7 months. Among all patients, 12 (52.17%) were residents of nursing homes, 5 (21.74%) were staff members of these facilities, 4 (17.39%) were caregivers of long-term hospitalized relatives, 1 (4.35%) was a construction worker, and 1 (4.35%) had a history of tourism. The rash predominantly affected the trunk and extremities, 12 patients (52.17%) are each involved the perineum and fingers webbings. The presentations included erythema, papules, and nodules. The main complaint of all patients was nocturnal itch. Under direct microscopy, 5 patients (21.74%) tested positive for scabies mites, and 3 (13.04%) showed histopathological features consistent with scabies. All patients were initially misdiagnosed with generalized eczema. Conclusion: Over half of all patients diagnosed with scabies either resided or worked in long-term care facilities. The lack of awareness of scabies among medical staff in long-term care facilities readily led to frequent misdiagnosis. Comprehensive measures should be implemented urgently to strengthen disease management.

A neuron model with nonlinear membranes.

One-layer membrane separates the gradient field in and out of the cell, while some two-layer membranes filled with excitable media/material are important to regulate the energy flow when ions are propagated and diffused. The intracellular and extracellular media can be effectively separated by the membrane. It is important to clarify and describe the biophysical function and then the capacitive property can be reproduced in equivalent neural circuit. Here, we suggest the cell membrane has certain thickness and becomes flexible under external stimuli, therefore, it is considered as a kind of nonlinear media. To mimic the physical property of the two-layer cell membrane, a nonlinear resistor is used to connect two linear circuits, which is used to describe the electrical characteristic of two sides of the cell membrane, respectively. The combination of two linear circuits via a nonlinear resistor can describe the energy characteristic and firing mode in the flexible membrane of biophysical neurons. Circuit equations are defined and converted into equivalent nonlinear oscillator like a neuron. The voltage difference for the two capacitors can be consistent with the membrane potential for the neuron. The Hamilton energy function for this neuron can be mapped from the field energy in the electronic components, and it is also derived by using Helmholtz's theorem. The neuron can show similar spiking and bursting firing patterns, and uncertain diversity in membrane potentials is effective to support continuous firing patterns and mode transition under external stimulus. Furthermore, noisy disturbance is applied to induce coherence resonance. The results indicate that the lower coefficient variability and higher average energy level supports periodic firing in the neuron under coherence resonance. Therefore, this neuron model with nonlinear membranes (or two-layer form) is more suitable for identifying the biophysical property of biological neuron.