Apelin Receptor Homodimerisation Inhibits Hippocampal Neuronal Autophagy via G Protein-Dependent Signalling in Vascular Dementia.

Vascular dementia (VD), a progressive vascular cognitive impairment, is characterised by the presence of cerebral hypoperfusion, increased blood-brain barrier permeability, and white matter lesions. Although current treatment strategies primarily focus on risk factors such as hypertension, diabetes, and heart disease, efficient and targeted therapies are lacking and the underlying mechanisms of VD remain unclear. We previously discovered that Apelin receptors (APJ), which are G protein-coupled receptors (GPCRs), can homodimerize and generate signals that are distinct from those of APJ monomers in VD rats. Apelin-13 reduces the level of APJ homodimers and leads to the proliferation of endogenous neural stem cells in the hippocampal dentate gyrus area, suggesting that it has a neuroprotective role. In this study, we established a rat and cellular oxygen-glucose deprivation/reoxygenation VD model to investigate the impact of APJ homodimerisation on autophagy. We found that APJ homodimers protect against VD by inhibiting autophagy through the Gαq and PI3K/Akt/mTOR pathways upon Gαi signalling, both in vivo and in vitro. This discovery provides a promising therapeutic target for chronic cerebral ischaemia-reperfusion diseases and an experimental foundation for the development of drugs that target APJ homodimers.

MAL2 reprograms lipid metabolism in intrahepatic cholangiocarcinoma via EGFR/SREBP-1 pathway based on single-cell RNA sequencing.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq, we discovered that the tetra-transmembrane protein mal, T cell differentiation protein 2 (MAL2), exhibited specific enrichment in ICC cancer cells and was strongly associated with a poor prognosis. The inhibition of MAL2 effectively suppressed cell proliferation, invasion, and migration. Transcriptomics and metabolomics analyses suggested that MAL2 promoted lipid accumulation in ICC by stabilizing EGFR membrane localization and activated the PI3K/AKT/SREBP-1 axis. Molecular docking and Co-IP proved that MAL2 interacted directly with EGFR. Based on constructed ICC organoids, the downregulation of MAL2 enhanced apoptosis and sensitized ICC cells to cisplatin. Lastly, we conducted a virtual screen to identify sarizotan, a small molecule inhibitor of MAL2, and successfully validated its ability to inhibit MAL2 function. Our findings highlight the tumorigenic role of MAL2 and its involvement in cisplatin sensitivity, suggesting the potential for novel combination therapeutic strategies in ICC.

Effects of artificial light with different spectral compositions on refractive development and matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2 expression in the sclerae of juvenile guinea pigs.

Artificial light can affect eyeball development and increase myopia rate. Matrix metalloproteinase 2 (MMP-2) degrades the extracellular matrix, and induces its remodeling, while tissue inhibitor of matrix MMP-2 (TIMP-2) inhibits active MMP-2. The present study aimed to look into how refractive development and the expression of MMP-2 and TIMP-2 in the guinea pigs' remodeled sclerae are affected by artificial light with varying spectral compositions. Three weeks old guinea pigs were randomly assigned to groups exposed to five different types of light: natural light, LED light with a low color temperature, three full spectrum artificial lights, i.e. E light (continuous spectrum in the range of ~390-780 nm), G light (a blue peak at 450 nm and a small valley 480 nm) and F light (continuous spectrum and wavelength of 400 nm below filtered). A-scan ultrasonography was used to measure the axial lengths of their eyes, every two weeks throughout the experiment. Following twelve weeks of exposure to light, the sclerae were observed by optical and transmission electron microscopy. Immunohistochemistry, Western blot and RT-qPCR were used to detect the MMP-2 and TIMP-2 protein and mRNA expression levels in the sclerae. After four, six, eight, ten, and twelve weeks of illumination, the guinea pigs in the LED and G light groups had axial lengths that were considerably longer than the animals in the natural light group while the guinea pigs in the E and F light groups had considerably shorter axial lengths than those in the LED group. Following twelve weeks of exposure to light, the expression of the scleral MMP-2 protein and mRNA were, from low to high, N group, E group, F group, G group, LED group; however, the expression of the scleral TIMP-2 protein and mRNA were, from high to low, N group, E group, F group, G group, LED group. The comparison between groups was statistically significant (p<0.01). Continuous, peaks-free or valleys-free artificial light with full-spectrum preserves remodeling of scleral extracellular matrix in guinea pigs by downregulating MMP-2 and upregulating TIMP-2, controlling eye axis elongation, and inhibiting the onset and progression of myopia.

The Transformation of Neck Unicentric Castleman's Disease to Follicular Dendritic Cell Sarcoma.

A patient with a large neck mass underwent appropriate imaging, routine blood tests, and serological evaluations. The medical history revealed the patient had undergone a lymphadenectomy in the same region 8 years ago, and the pathological diagnosis was the hyaline-vascular subtype of unicentric Castleman's disease (UCD). The incisional biopsy and subsequent histopathological and immunohistochemical examination revealed the diagnosis of follicular dendritic cell sarcoma, consistent with the malignant transformation of UCD. UCD is uncommon and the malignant transformation of UCD is extremely rare in the head and neck region. Regional lymph node resection of one or more adjacent regions is the preferred treatment choice. Appropriate treatment procedures for UCD and regular follow-up are essential for a good prognosis. Laryngoscope, 2024.

Immunomodulation of adipose-derived mesenchymal stem cells on peripheral blood mononuclear cells in colorectal cancer patients with COVID-19.

BACKGROUND: Accumulating evidence has shown that adipose tissue-derived mesenchymal stem cells (ADSCs) are an effective therapeutic approach for managing coronavirus disease 2019 (COVID-19); however, further elucidation is required to determine their underlying immunomodulatory effect on the mRNA expression of T helper cell-related transcription factors (TFs) and cytokine release in peripheral blood mononuclear cells (PBMCs). AIM: To investigate the impact of ADSCs on the mRNA expression of TFs and cytokine release in PBMCs from colorectal cancer (CRC) patients with severe COVID-19 (CRC+ patients). METHODS: PBMCs from CRC+ patients (PBMCs-C+) and age-matched CRC patients (PBMCs-C) were stimulated and cultured in the presence/absence of ADSCs. The mRNA levels of T-box TF TBX21 (T-bet), GATA binding protein 3 (GATA-3), RAR-related orphan receptor C (RORC), and forkhead box P3 (FoxP3) in the PBMCs were determined by reverse transcriptase-polymerase chain reaction. Culture supernatants were evaluated for levels of interferon gamma (IFN-γ), interleukin 4 (IL-4), IL-17A, and transforming growth factor beta 1 (TGF-ß1) using an enzyme-linked immunosorbent assay. RESULTS: Compared with PBMCs-C, PBMCs-C+ exhibited higher mRNA levels of T-bet and RORC, and increased levels of IFN-γ and IL-17A. Additionally, a significant decrease in FoxP3 mRNA and TGF-ß1, as well as an increase in T-bet/GATA-3, RORC/FoxP3, IFN-γ/IL-4, and IL-17A/TGF-ß1 ratios were observed in PBMCs-C+. Furthermore, ADSCs significantly induced a functional regulatory T cell (Treg) subset, as evidenced by an increase in FoxP3 mRNA and TGF-ß1 release levels. This was accompanied by a significant decrease in the mRNA levels of T-bet and RORC, release of IFN-γ and IL-17A, and T-bet/GATA-3, RORC/FoxP3, IFN-γ/IL-4, and IL-17A/TGF-ß1 ratios, compared with the PBMCs-C+alone. CONCLUSION: The present in vitro studies showed that ADSCs contributed to the immunosuppressive effects on PBMCs-C+, favoring Treg responses. Thus, ADSC-based cell therapy could be a beneficial approach for patients with severe COVID-19 who fail to respond to conventional therapies.

Effect of Auxin on Cadmium Toxicity-Induced Growth Inhibition in Solanum lycopersicum.

Auxins play crucial regulatory roles in plants coping with cadmium (Cd) stress. However, the regulatory mechanism by which auxins alleviate Cd toxicity in tomato seedlings remains unclear. Here, we demonstrate that exposure to Cd stress leads to dynamic changes in the auxin response in tomato roots, characterized by an initial increase followed by a subsequent weakening. Under Cd stress, tomato seedlings show primary root- and hypocotyl-growth inhibition, accompanied by the accumulation of Cd and reactive oxygen species (ROS) in the roots. The exogenous application of 1-naphthylacetic acid (NAA) does not mitigate the inhibitory effect of Cd toxicity on primary root growth, but it does significantly enhance lateral root development under Cd stress. Auxin transport inhibitors, such as 1-N-naphthylphthalamic acid (NPA) and 2,3,5-triiodobenoic acid (TIBA), aggravate the growth inhibition of primary roots caused by Cd stress. Additionally, lateral root development was inhibited by NPA. However, applying auxin synthesis inhibitors L-kynurenine (kyn) and yucasin alleviated the tomato root growth inhibition caused by Cd stress; between them, the effect of yucasin was more pronounced. Yucasin mitigates Cd toxicity in tomato seedlings by reducing Cd2+ absorption and auxin accumulation, strengthening ROS scavenging, and reducing cell death in roots. These observations suggest that yucasin potentially mitigates Cd toxicity and improves the tolerance of tomato seedlings to Cd stress.

Epidemiological Features of Hepatitis C in China From 2015 to 2021: Insights From National Surveillance Data.

The COVID-19 pandemic overwhelmed national health care systems, not least in the context of hepatitis elimination. This study investigates the effects of the pandemic response on the incidence rate, mortality rate, and case fatality rate (CFR) for hepatitis C virus (HCV) cases in China. We extracted the number of hepatitis C cases and HCV-related deaths by month and year for 2015 to 2021 in China and applied two proportional tests to analyze changes in the average yearly incidence rates, mortality rates, and CFRs for 2015 to 2020. We used the autoregressive integrated moving average model to predict these three rates for 2020 based on 2015 to 2019 HCV data. The incidence of hepatitis C decreased by 7.11% and 1.42% (P < .001) in 2020 and 2021, respectively, compared with 2015 to 2019, while it increased by 6.13% (P < .001) in 2021 relative to 2020. The monthly observed incidence in 2020 was significantly lower (-26.07%) than predicted. Meanwhile, no differences in mortality rate or CFR were observed between 2021, 2020, and 2015 to 2019. Our findings suggest that nonpharmaceutical interventions and behavioral changes to mitigate COVID-19 could have reduced hepatitis C incidence and accelerated China's implementation of a plan to eliminate HCV infection.

Respiratory pathogenic microbial infections: a narrative review.

Respiratory infectious diseases have long been recognised as a substantial global healthcare burden and are one of the leading causes of death worldwide, particularly in vulnerable individuals. In the post COVID-19 era, there has been a surge in the prevalence of influenza virus A and other multiple known viruses causing cold compared with during the same period in the previous three years, which coincided with countries easing COVID-19 restrictions worldwide. This article aims to review community-acquired respiratory illnesses covering a broad spectrum of viruses, bacteria, and atypical microorganisms and focuses on the cluster prevalence of multiple known respiratory pathogens in China, thereby providing effective prevention and control measures.

Nuclear receptor NURR1 functions to promote stemness and epithelial-mesenchymal transition in prostate cancer via its targeting of Wnt/ß-catenin signaling pathway.

Dysregulated activation of Wnt/ß-catenin signaling pathway is a frequent or common event during advanced progression of multiple cancers. With this signaling activation, it enhances their tumorigenic growth and facilitates metastasis and therapy resistance. Advances show that this signaling pathway can play dual regulatory roles in the control of cellular processes epithelial-mesenchymal transition (EMT) and cancer stemness in cancer progression. Aberrant activation of Wnt/ß-catenin signaling pathway is shown to be common in prostate cancer and also castration-resistant prostate cancer (CRPC). However, the transcriptional regulators of this pathway in prostate cancer are still not well characterized. NURR1 (NR4A2) is an orphan nuclear receptor and plays an important role in the development of dopaminergic neurons. Previously, we have shown that NURR1 exhibits an upregulation in isolated prostate cancer stem-like cells (PCSCs) and a xenograft model of CRPC. In this study, we further confirmed that NURR1 exhibited an upregulation in prostate cancer and also enhanced expression in prostate cancer cell lines. Functional and molecular analyses showed that NURR1 could act to promote both in vitro (cancer stemness and EMT) and also in vivo oncogenic growth of prostate cancer cells (metastasis and castration resistance) via its direct transactivation of CTNNB1 (ß-catenin) and activation of ß-catenin to mediate the activation of Wnt/ß-catenin signaling pathway. Moreover, we also demonstrated that NURR1 activity in prostate cancer cells could be modulated by small molecules, implicating that NURR1 could be a potential therapeutic target for advanced prostate cancer management.

Telocinobufagin, a PLK1 suppressor that inhibits tumor growth and metastasis by modulating CDC25c and CTCF in HNSCC cells.

BACKGROUND: The high metastasis and mortality rates of head and neck squamous cell carcinoma (HNSCC) urgently require new treatment targets and drugs. A steroidal component of ChanSu, telocinobufagin (TBG), was verified to have anti-cancer effects in various tumors, but its activity and mechanism in anti-HNSCC were still unknown. PURPOSE: This study tried to demonstrate the anti-tumor effect of TBG on HNSCC and verify its potential mechanism. METHODS: The effect of TBG on cell proliferation and metastasis were performed and the TBG changed genes were detected by RNA-seq analysis in HNSCC cells. The GSEA and PPI analysis were used to identify the pathways targeted for TBG-regulated genes. Meanwhile, the mechanism of TBG on anti-proliferative and anti-metastasis were investigated in vitro and in vivo. RESULTS: The in vitro and in vivo experiments confirmed that TBG has favorable anti-tumor effects by induced G2/M phase arrest and suppressed metastasis in HNSCC cells. Further RNA-seq analysis demonstrated the genes regulated by TBG were enriched at the G2/M checkpoint and PLK1 signaling pathway. Then, the bioinformatic analysis of clinical data found that high expressed PLK1 were closely associated with poor overall survival in HNSCC patients. Furthermore, PLK1 directly and indirectly modulated G2/M phase and metastasis (by regulated CTCF) in HNSCC cells, simultaneously. TBG significantly inhibited the protein levels of PLK1 in both phosphorylated and non-phosphorylated forms and then, in one way, inactivated PLK1 failed to activate G2/M phase-related proteins (including CDK1, CDC25c, and cyclin B1). In another way, be inhibited PLK1 unable promote the nuclear translocation of CTCF and thus suppressed HNSC cell metastasis. In contrast, the anti-proliferative and anti-metastasis effects of TBG on HNSCC cell were vanished when cells high-expressed PLK1. CONCLUSION: The present study verified that PLK1 mediated TBG induced anti-tumor effect by modulated G2/M phase and metastasis in HNSCC cells.

Algorithmic and sensor-based research on Chinese children's and adolescents' screen use behavior and light environment.

Background: Myopia poses a global health concern and is influenced by both genetic and environmental factors. The incidence of myopia tends to increase during infectious outbreaks, such as the COVID-19 pandemic. This study examined the screen-time behaviors among Chinese children and adolescents and investigated the efficacy of artificial intelligence (AI)-based alerts in modifying screen-time practices. Methods: A cross-sectional analysis was performed using data from 6,716 children and adolescents with AI-enhanced tablets that monitored and recorded their behavior and environmental light during screen time. Results: The median daily screen time of all participants was 58.82 min. Among all age groups, elementary-school students had the longest median daily screen time, which was 87.25 min and exceeded 4 h per week. Children younger than 2 years engaged with tablets for a median of 41.84 min per day. Learning accounted for 54.88% of participants' screen time, and 51.03% (3,390/6,643) of the participants used tablets for 1 h at an average distance <50 cm. The distance and posture alarms were triggered 807,355 and 509,199 times, respectively. In the study, 70.65% of the participants used the tablet under an illuminance of <300 lux during the day and 61.11% under an illuminance of <100 lux at night. The ambient light of 85.19% of the participants exceeded 4,000 K color temperature during night. Most incorrect viewing habits (65.49% in viewing distance; 86.48% in viewing posture) were rectified swiftly following AI notifications (all p < 0.05). Conclusion: Young children are increasingly using digital screens, with school-age children and adolescents showing longer screen time than preschoolers. The study highlighted inadequate lighting conditions during screen use. AI alerts proved effective in prompting users to correct their screen-related behavior promptly.

Targeting JMJD1C to selectively disrupt tumor Treg cell fitness enhances antitumor immunity.

Regulatory T (Treg) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving Treg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral Treg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral Treg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor Treg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor Treg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral Treg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor Treg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor Treg cells without affecting systemic immune homeostasis.

Early regional changes in retina and choroid of chicks following monocular hemifield form deprivation.

To investigate regional changes in the chick retina and choroid after hemifield form deprivation (HFD). Ten chicks were randomly and equally divided into a temporal retinal deprivation (TRD) and nasal retinal deprivation (NRD) group. HFD was induced with half-lateral translucent plastic goggles in the right eye; the left eye was kept untreated. Swept-source optical coherence tomography (SS-OCT) images obtained at 0, 3, and 72 hours (h) were analyzed using customized software. After 72 h of TRD, the retinal thickness (RT) of the treated eyes was significantly less than that of the fellow eyes in the temporal (P = 0.034) rather than the nasal (P = 0.083) region. In the NRD group, the RT of the treated eyes was thinner in both the nasal and temporal regions than that of the fellow eyes (P < 0.01). The RT alterations were more pronounced in the temporal (Δ = -16.86 ± 7.14 µm) than in the nasal (Δ = -13.44 ± 4.83 µm) region after 72-h TRD (P = 0.036), whereas the opposite was observed in the NRD group (P = 0.008). The choroidal thickness (ChT) of the treated eyes was less in both the nasal and temporal regions than that of the fellow eyes in both groups after 72-h treatment (P < 0.01). The ChT alterations were more pronounced in the temporal (Δ = -2.48 ± 8.95 µm) than in the nasal (Δ = 23.65 ± 13.58 µm) region after 72-h TRD (P = 0.021), whereas the NRD group showed the opposite effect (P = 0.019). HFD in chicks can lead to retinal and choroidal thinning in the corresponding regions.

Enhancing dye degradation using a novel cobalt metal-organic framework as a peroxymonosulfate activator.

Among transition metals, cobalt ions exhibit superior catalytic activity in the peroxymonosulfate (PMS) degradation of pollutants. However, practical application is hindered by their high rate of ion leaching and the propensity for particle reunion issues. In this study, a novel cobalt metal-organic framework catalyst, denoted as CUST-565 ([Co3(BTB)2(BIPY)2]·4.5H2O·DMA), was synthesized via a one-step solvothermal method. The obtained crystal was employed as a catalyst to activate PMS for degrading two pollutants, methyl orange (MO) and rhodamine B (RhB), in wastewater. The catalyst demonstrated efficacy in PMS, achieving 97% degradation of MO and 98% degradation of RhB within 30 min at an initial concentration of 20.0 mg L-1. Additionally, various factors affecting dye degradation, including PMS dosage, catalyst dosage, temperature, initial pH, and coexisting anions, were investigated. Radical quenching experiments confirmed the presence of sulfate radicals (SO4˙-), hydroxyl radicals (HO˙), superoxide radicals (O2˙-), and singlet oxygen (1O2) in the system. After four cycles, CUST-565 retained its ability to catalytically degrade approximately 80% of the pollutants. These observed stability and reusability properties, corroborated by a series of characterization analyses before and after use, suggest that CUST-565 exhibits reliable performance. This work contributes to the development of cobalt-PMS catalysts for efficiently degrading dyes in wastewater.

Chemical components and against alzheimer's disease effects of the calyxes of Physalis alkekengi L. var. franchetii (Mast.) Makino.

Physalis alkekengi L. var. franchetii (Mast.) Makino (PA), a traditional Chinese medicine, is utilised for treating dermatitis, sore throat, dysuria, and cough. This research aimed to identify the main constituents in the four extracted portions from the calyces of PA (PAC) utilising ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The Alzheimer's disease (AD) mice model was induced by D-galactose (D-gal) combined with aluminium chloride (AlCl3). Subsequent investigation into the underlying mechanisms involved behavioural and histopathological observations. The results demonstrated that four extracted portions of PAC (PACE) significantly enhanced memory and learning abilities in the Morris water maze. The concentrations of Aß, tau and p-tau in brain tissue exhibited a significant decrease relative to the model group. Moreover, the four PACE treatment groups increased the glutathione (GSH) and superoxide dismutase (SOD) levels, while concurrently reducing malondialdehyde (MDA), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) levels. In summary, the current study demonstrates that the four PACE formulations exhibit beneficial anti-AD properties, with the most pronounced efficacy observed in the EA group. Additionally, PAC shows potential in mitigating neuroinflammation and oxidative damage by inhibiting the TLR4/NF-κB signalling pathway. This research lays a theoretical groundwork for the future clinical development and utilisation of PAC in treating AD.