Functional Investigation and Two-sample Mendelian Randomization Study of Inguinal Hernia Hub Genes Obtained by Bioinformatics Analysis.

BACKGROUND: Inguinal hernia in adults is a common and frequent disease in surgery, prone to occur in the elderly or in those with a weak abdominal wall. Despite its prevalence, Molecular mechanisms underlying inguinal hernia formation are unclear. OBJECTIVE: This study aims to identify potential gene markers for inguinal hernia and available drugs. METHODS: Pubmed2Ensembl text mining was used to identify genes related to "inguinal hernia" keywords. The GeneCodis system was used to specify GO biological process terms and KEGG pathways defined in the Kyoto Encyclopedia of Genes and Genomes (KEGG). The STRING tool was used to construct protein-protein interaction networks, which were then visualized using Cytoscape.CytoHubba and Molecular Complex Detection were utilized to analyze the module (MCODE). A GO and KEGG analysis of gene modules was conducted using the DAVID platform database. Hub genes are those that are concentrated in prominent modules. The druggene interaction database was also used to identify potential drugs for inguinal hernia patients based on their interactions between the hub genes. Finally, a Mendelian randomization study was conducted based on genome-wide association studies to determine whether hub genes cause inguinal hernias. RESULTS: The identification of 96 genes associated with inguinal hernia was carried out using text mining techniques. It was constructed using PPI networks with 80 nodes and 476 edges, and the sequence of the genes was performed using CytoHubba. MCODE analysis identified three gene modules. Three modules contain 37 genes clustered as hub candidate genes associated with inguinal hernia patients. The PI3K-Akt, MAPK, AGE-RAGE, and HIF-1 pathways were found to be enriched in signaling pathways. Sixteen of the 37 genes were found to be targetable by 30 existing drugs. The relationship between hub genes and inguinal hernia was examined using Mendelian randomization. The research revealed nine genes that may be connected with inguinal hernia, such as POMC, CD40LG, TFRC, VWF, LOX, IGF2, BRCA1, TNF, and HGF in the plasma. By inverse variance weighting, ALB was associated with an increased risk of inguinal hernia with an OR of 1.203 (OR [95%] = 1,04 [1.012 to 1.089], p = 0.008). CONCLUSION: We identified potential hub genes for inguinal hernia, predicted potential drugs for inguinal hernia, and reverse-validated potential genes by Mendelian randomization. This may provide further insights into asymptomatic pre-diagnostic methods and contribute to studies to understand the molecular mechanisms of risk genes associated with inguinal hernia.

Probabilistic human health risk assessment of PCDD/Fs near municipal solid-waste incinerator using Monte Carlo analysis coupled with triangular fuzzy numbers.

PCDD/Fs are dioxins produced by waste incineration and pose risks to human health. We aimed to detail the health risks of airborne and soil PCDD/Fs near a municipal solid-waste incinerator (MSWI) for the surrounding population and develop a new model that improves upon existing methods. Thus, we conducted field sampling and then investigated a MSWI in the Pearl River Delta (2016-2018). Our results showed that the carcinogenic and non-carcinogenic risk values of PCDD/Fs exposed to residents in nearby areas were acceptable, with hazard index (HI) values lower than 1.0 and a total carcinogenic risk lower than 1.0E-6. Notably, the results raised concerns regarding higher non-carcinogenic risks in children than in adults. Comparative analysis of the frequency accumulation diagram, accumulated probability risk, and the absolute value of error (δ) between the 95% confidence interval (CI) and the 90% CI of the Monte Carlo stochastic simulation-triangular fuzzy number (MCSS-TFN) and the MCSS model, respectively, demonstrated that the MCSS-TFN exhibited less uncertainty than the MCSS model, regardless of the health risk value of PCDD/Fs in ambient air or in soil. This observation underscores the superiority of the MCSS-TFN model over other models in assessing the health risks associated with PCDD/Fs in situations with limited data. Our new method overcomes the limited dataset size and high uncertainty in assessing the health risks of dioxin substances, providing a more comprehensive understanding of their associated health risks than MCSS models.

Osteocyte mitochondria regulate angiogenesis of transcortical vessels.

Transcortical vessels (TCVs) provide effective communication between bone marrow vascular system and external circulation. Although osteocytes are in close contact with them, it is not clear whether osteocytes regulate the homeostasis of TCVs. Here, we show that osteocytes maintain the normal network of TCVs by transferring mitochondria to the endothelial cells of TCV. Partial ablation of osteocytes causes TCV regression. Inhibition of mitochondrial transfer by conditional knockout of Rhot1 in osteocytes also leads to regression of the TCV network. By contrast, acquisition of osteocyte mitochondria by endothelial cells efficiently restores endothelial dysfunction. Administration of osteocyte mitochondria resultes in acceleration of the angiogenesis and healing of the cortical bone defect. Our results provide new insights into osteocyte-TCV interactions and inspire the potential application of mitochondrial therapy for bone-related diseases.

PTCH1 mutation as a potential predictive biomarker for immune checkpoint inhibitors in gastrointestinal cancer.

Immune checkpoint inhibitors (ICIs) have become prominent therapies for gastrointestinal cancer (GC). However, it is urgent to screen patients who can benefit from ICIs. Protein patched homolog 1 (PTCH1) is a frequently altered gene in GC. We attempt to explore the association between PTCH1 mutation and immunotherapy efficacy. The MSKCC cohort (n = 236) with GC (esophageal, gastric and colorectal cancers) patients receiving ICIs was used for discovery and the Peking University Cancer Hospital (PUCH) GC cohort (n = 92) was used for validation. Overall survival (OS) and tumor mutational burden (TMB) of the PTCH1 mutant-type (PTCH1-MUT) and PTCH1 wild-type (PTCH1-WT) groups were compared. Furthermore, GC data were collected from TCGA to assess the potential mechanisms. In the MSKCC cohort, PTCH1-MUT group showed significantly better OS (P = 0.017) and higher TMB. Multivariate analysis showed that PTCH1 mutation was associated with better OS. In the PUCH cohort, PTCH1-MUT group showed significantly longer OS (P = 0.036) and PFS, and higher DCB and TMB. Immune cell infiltration analysis revealed that PTCH1-MUT group had significantly higher distributions of CD8 T cells, CD4 T cells, NK cells, mast cells, and M1 cells. The PTCH1-MUT group showed significantly higher expression of most immune- related genes. GSEA showed that the PTCH1-MUT group had enriched INF-γ response, INF-α response, glycolysis, and reactive oxygen species pathway gene sets. PTCH1 mutation may represent a potential biomarker for predicting ICIs response in GC. Nevertheless, prospective cohort studies should be performed to further validate our results.

Fate of sulfamethoxazole in wetland sediment under controlled redox conditions.

Redox condition is an important controlling factor for contaminant removal in constructed wetlands; however, the redox-sensitivity of antibiotic removal in wetland sediments under controlled conditions with specific electron acceptors remains unclear. Here, using a 14C radioactive tracer, we explored fate of sulfamethoxazole (SMX) in a wetland sediment slurry under oxic, nitrate-reducing, iron-reducing, and methanogenic conditions. In the sterile treatment, unlike the comparable SMX dissipation from the water phase under four redox conditions, non-extractable residues (NERs) of SMX was highest formed in the sediment under oxic condition, mainly in sequestered and ester/amide-linked forms. Microorganisms markedly promoted SMX transformation in the slurry. The dissipation rate of SMX and its transformation products (TPs) followed the order: oxic ≈ iron-reducing > methanogenic >> nitrate-reducing conditions, being consistent with the dynamics of microbial community in the sediment, where microbial diversity was greater and networks connectivity linking dominant bacteria to SMX transformation were more complex under oxic and iron-reducing conditions. Kinetic modeling indicated that the transformation trend of SMX and its TPs into the endpoint pool NERs depended on the redox conditions. Addition of wetland plant exudates and sediment dissolved organic matter at environmental concentrations affected neither the abiotic nor the biotic transformation of SMX. Overall, the iron-reducing condition was proven the most favorable and eco-friendly for SMX transformation, as it resulted in a high rate of SMX dissipation from water without an increase in toxicity and subsequent formation of significant stable NERs in sediment. Our study comprehensively revealed the abiotic and biotic transformation processes of SMX under controlled redox conditions and demonstrated iron-reducing condition allowing optimal removal of SMX in constructed wetlands.

miR-196b-5p regulates inflammatory process and migration via targeting Nras in trabecular meshwork cells.

Glaucoma, an insidious ophthalmic pathology, is typified by an aberrant surge in intraocular pressure (IOP) which culminates in the degeneration of retinal ganglion cells and optical neuropathy. The mitigation of IOP stands as the principal therapeutic strategy to forestall vision loss. The trabecular meshwork's (TM) integrity and functionality are pivotal in modulating aqueous humor egress. Despite their potential significance in glaucomatous pathophysiology, the implications of microRNAs (miRNAs) on TM functionality remain largely enigmatic. Transcriptomic sequencing was employed to delineate the miRNA expression paradigm within the limbal region of rodent glaucoma models, aiming to elucidate miRNA-mediated mechanisms within the glaucomatous milieu. Analytical scrutiny of the sequencing data disclosed 174 miRNAs with altered expression profiles, partitioned into 86 miRNAs with augmented expression and 88 with diminished expression. Notably, miRNAs such as hsa-miR-196b-5p were identified as having substantial expression discrepancies with concomitant statistical robustness, suggesting a potential contributory role in glaucomatous progression. Subsequent in vitro assays affirmed that miR-196b-5p augments the inflammatory cascade within immortalized human TM (iHTM) and glaucoma-induced human TM (GTM3) cells, concurrently attenuating cellular proliferation, motility, and cytoskeletal architecture. Additionally, miR-196b-5p implicates itself in the regulation of IOP and inflammatory processes in rodent models. At a mechanistic level, miR-196b-5p modulates its effects via the targeted repression of Nras (neuroblastoma RAS viral oncogene homolog). Collectively, these transcriptomic investigations furnish a comprehensive vista into the regulatory roles of miRNAs within the glaucomatous framework, and the identification of differentially expressed miRNAs alongside their targets could potentially illuminate novel molecular pathways implicated in glaucoma, thereby aiding in the development of innovative therapeutic avenues.

Schaftoside reduces inflammation in Aspergillus fumigatus keratitis through the inhibition of the TLR4/MyD88 pathway.

PURPOSE: The purpose of this research study was to investigate the impact of schaftoside on Aspergillus fumigatus (A. fumigatus) keratitis and elucidate its underlying mechanisms. METHODS: In order to establish safe experimental concentrations of schaftoside in human corneal epithelial cells (HCECs), RAW264.7 cells, and mouse models, various techniques were employed including cytotoxicity assay (CCK-8) assay, cell scratch assay, and Draize test. The therapeutic effect of schaftoside was assessed using slit-lamp biomicroscopy, clinical scores, as well as determination of neutrophil infiltration through hematoxylin and eosin (HE) staining, immunofluorescence (IF) staining, and myeloperoxidase (MPO) assay. The levels of Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), pro-inflammatory mediators interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6 were determined using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and IF techniques. RESULTS: Schaftoside at a concentration of 160 µM displayed no harmful side effects on HCECs, RAW cells, and mouse corneas, rendering it suitable for further experiments. In a murine fungal keratitis model, schaftoside mitigated the severity of fungal keratitis by inhibiting neutrophil infiltration and reducing MPO activity. Both in vitro and in vivo experiments demonstrated that schaftoside treatment suppressed the upregulation of IL-1ß, TNF-α, and IL-6 expression, while also downregulating the expressions of TLR4 as well as MyD88 at both mRNA and protein levels. CONCLUSIONS: Schaftoside demonstrated a protective effect against A. fumigatus keratitis by reducing corneal damage through inhibition of neutrophil recruitment and downstream inflammatory cytokines. The anti-inflammatory properties of schaftoside in A. fumigatus keratitis may involve modulation of the TLR4/MyD88 pathway.

Mitochondrial heterogeneity in diseases.

As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes in morphology, components and functions in response to various environmental stresses and cellular demands. Previous studies of mitochondria research have gradually evolved, from focusing on morphological change analysis to systematic multiomics, thereby revealing the mitochondrial variation between cells or within the mitochondrial population within a single cell. The phenomenon of mitochondrial variation features is defined as mitochondrial heterogeneity. Moreover, mitochondrial heterogeneity has been reported to influence a variety of physiological processes, including tissue homeostasis, tissue repair, immunoregulation, and tumor progression. Here, we comprehensively review the mitochondrial heterogeneity in different tissues under pathological states, involving variant features of mitochondrial DNA, RNA, protein and lipid components. Then, the mechanisms that contribute to mitochondrial heterogeneity are also summarized, such as the mutation of the mitochondrial genome and the import of mitochondrial proteins that result in the heterogeneity of mitochondrial DNA and protein components. Additionally, multiple perspectives are investigated to better comprehend the mysteries of mitochondrial heterogeneity between cells. Finally, we summarize the prospective mitochondrial heterogeneity-targeting therapies in terms of alleviating mitochondrial oxidative damage, reducing mitochondrial carbon stress and enhancing mitochondrial biogenesis to relieve various pathological conditions. The possibility of recent technological advances in targeted mitochondrial gene editing is also discussed.

Health risk assessment of trace metal(loid)s in agricultural soil using an integrated model combining soil-related and plants-accumulation exposures: A case study on Hainan Island, South China.

Traditional health risk assessment of trace metal(loid)s (TMs) in agricultural soil exclusively considers direct soil-related exposure and may underestimate the health risks they pose. In this study, the health risks of TMs were evaluated using an integrated model that combined soil-related and plant-accumulating exposures. A detailed investigation of common TMs (Cr, Pb, Cd, As, and Hg) coupled with probability risk analysis based on a Monte Carlo simulation was conducted on Hainan Island. Our results showed that, except for As, the non-carcinogenic risk (HI) and carcinogenic risk (CR) of the TMs were all within the acceptable ranges (HI < 1.0, and CR < 1E-06) for direct soil-related exposure to bio-accessible fractions and indirect exposure via plant accumulation (CR substantially lower than the warning threshold 1E-04). We identified crop food ingestion as the essential pathway for TM exposure and As as the critical toxic element in terms of risk control. Moreover, we determined that RfDo and SFo are the most suitable parameters for assessing As health risk severity. Our study demonstrated that the proposed integrated model combining soil-related and plant-accumulating exposures can avoid major health risk assessment deviations. The results obtained and the integrated model proposed in this study can facilitate future multi-pathway exposure research and could be the basis for determining agricultural soil quality criteria in tropical areas.

[Spatial Network of Urban Heat Environment in Beijing-Tianjin-Hebei Urban Agglomeration Based on MSPA and Circuit Theory].

Rapid urbanization has increased the complexity of the urban heat environment system, which has negative impacts on the health of the urban ecological system and the human habitat. By combining theories and technologies such as geographic information systems, remote sensing, morphological spatial pattern analysis, and circuit theory with data from MODIS land surface temperature production, urban heat island patches in the Beijing-Tianjin-Hebei urban agglomeration were quantitatively identified in terms of their spatial and temporal distribution characteristics and their spatial and temporal transfer paths. This foundation revealed the geographical network structure of the urban heat environment as well as the spatial and temporal evolution process of critical corridors. According to the findings, urban heat island patches covered 16610 km2 in 2020, accounting for 7.68% of the study area. In the Beijing-Tianjin-Hebei urban agglomeration, both the area and the number of urban heat island patches considerably increased between 2005 and 2020, going from being dominated by isolated island types of urban heat island patches in 2005 to being dominated by core types in 2020. In particular, the non-urban heat island patches, core type, and edge type of urban heat island patches in 2005 were the major ancestors of the core type and edge type urban heat island patches in 2020. In the Beijing-Tianjin-Hebei urban agglomeration, there were more urban heat environment source sites, corridor length, densities, and present densities in 2020 than there were in 2005. The sensitive corridor was found to be the predominant type of urban heat island corridor in the Beijing-Tianjin-Hebei urban agglomeration in 2020. The number of sensitive corridors increased the highest in the period from 2005-2020. As the coefficient of urban heat environment corridors increased concurrently, it was apparent that the urban heat environment corridor had a propensity to grow continuously in the Beijing-Tianjin-Hebei urban agglomeration. The active adaptation and mitigation measures of the urban heat environment were proposed, and a spatial network model of the urban heat environment was finally provided. To adapt to, mitigate, and promote urban sustainable development risks, these research findings will serve as a paradigm for the identification of the urban heat environment spatial network actively and methodically.

Modified inferior oblique anterior transposition for dissociated vertical deviation combined with superior oblique palsy: A case report.

BACKGROUND: Inferior oblique anterior transposition (IOAT) has emerged as an effective surgery in the management of dissociated vertical deviation (DVD) combined with superior oblique palsy (SOP). Traditional IOAT usually provides satisfactory primary position alignment and simultaneously restricts the superior floating phenomenon. However, it also increases the risk of the anti-elevation syndrome and narrowing of the palpebral fissure in straight-ahead gaze, especially after the unilateral operation. CASE SUMMARY: We report the outcomes of the modified unilateral IOAT in two patients with unilateral DVD combined with SOP. The anterior-nasal fibers of the inferior oblique muscle were attached at 9 mm posterior to the corneal limbus along the temporal board of the inferior rectus muscle, the other fibers were attached a further 5 mm temporal to the anterior-nasal fibers. Postoperatively, both hypertropia and floating were improved, and no obvious complications occurred. CONCLUSION: In these cases, the modified unilateral IOAT was an effective and safe surgical method for treating DVD with SOP.

Stone attenuation on computer tomography helps surgeons make decisions between miniaturized percutaneous nephrolithotomy or retrograde intrarenal surgery for lower pole stones: a retrospective study.

A retrospective study was performed on 200 patients who underwent miniaturized percutaneous nephrolithotomy (mini-PCNL) or retrograde intrarenal surgery (RIRS) for 10-20 mm sized lower pole renal calculi to investigate the relationship between computed tomography (CT) attenuation of calculi and surgical outcomes. CT was used to examine the location, size, and CT attenuation values of the calculi. Additionally, the operation time, hospital stay, hemoglobin (Hb) reduction, stone-free rate (SFR), and complication rate were also meticulously documented and subjected to comparative analysis. Complications were assessed using the Clavien-Dindo grading system. We observed no significant differences in hospitalization data and follow-up outcomes, except for a longer hospital stay and higher Hb drops in patients receiving mini-PCNL. Statistical analysis revealed an association between CT attenuation and operation time. Compared with mini-PCNL, RIRS could reduce bleeding, hospital stay, surgery time, and complications for 10-20 mm sized lower pole kidney stones with CT values < 1000 HU. RIRS resulted in longer operation time and lower stone-free rates despite shorter hospital stays and less bleeding than mini-PCNL for stones with CT values > 1000 HU. Therefore, selecting an appropriate surgical method based on CT attenuation might improve outcomes. For patients with stone attenuation values < 1000 HU, RIRS is the recommended option. When stone attenuation values > 1000 HU, the surgical method should be chosen based on the patient's individual situation.

Long non-coding RNA SNHG11 regulates the Wnt/ß-catenin signaling pathway through rho/ROCK in trabecular meshwork cells.

Trabecular meshwork (TM) cell dysfunction is the leading cause of elevated intraocular pressure (IOP) and glaucoma. The long non-coding RNA (lncRNA) small nucleolar RNA host gene 11 (SNHG11) is associated with cell proliferation and apoptosis, but its biological functions and role in glaucoma pathogenesis remain unclear. In the present study, we investigated the role of SNHG11 in TM cells using immortalized human TM and glaucomatous human TM (GTM3 ) cells and an acute ocular hypertension mouse model. SNHG11 expression was depleted using siRNA targeting SNHG11. Transwell assays, quantitative real-time PCR analysis (qRT-PCR), western blotting, and CCK-8 assay were used to evaluate cell migration, apoptosis, autophagy, and proliferation. Wnt/ß-catenin pathway activity was inferred from qRT-PCR, western blotting, immunofluorescence, and luciferase reporter and TOPFlash reporter assays. The expression of Rho kinases (ROCKs) was detected using qRT-PCR and western blotting. SNHG11 was downregulated in GTM3 cells and mice with acute ocular hypertension. In TM cells, SNHG11 knockdown inhibited cell proliferation and migration, activated autophagy, and apoptosis, repressing the Wnt/ß-catenin signaling pathway, and activated Rho/ROCK. Wnt/ß-catenin signaling pathway activity increased in TM cells treated with ROCK inhibitor. SNHG11 regulated Wnt/ß-catenin signaling through Rho/ROCK by increasing GSK-3ß expression and ß-catenin phosphorylation at Ser33/37/Thr41 while decreasing ß-catenin phosphorylation at Ser675. We demonstrate that the lncRNA SNHG11 regulates Wnt/ß-catenin signaling through Rho/ROCK via ß-catenin phosphorylation at Ser675 or GSK-3ß-mediated phosphorylation at Ser33/37/Thr41, affecting cell proliferation, migration, apoptosis, and autophagy. Through its effects on Wnt/ß-catenin signaling, SNHG11 is implicated in glaucoma pathogenesis and is a potential therapeutic target.

Fixed-Time Adaptive Neural Network Control for Nonlinear Systems With Input Saturation.

This study concentrates on the tracking control problem for nonlinear systems subject to actuator saturation. To improve the performance of the controller, we propose a fixed-time tracking control scheme, in which the upper bound of the convergence time is independent of the initial conditions. In the control scheme, first, a smooth nonlinear function is employed to approximate the saturation function so that the controller can be designed under the framework of backstepping. Then, the effect of input saturation is compensated by introducing an auxiliary system. Furthermore, a fixed-time adaptive neural network control method is given with the help of fixed-time control theory, in which the dynamic order of controllers is reduced to a certain extent since there is only one updating law in the entire control design. Through rigorous theoretical analysis, it is concluded that the proposed control scheme can guarantee that: 1) the output tracking error can converge to a small neighborhood near the origin in a fixed time and 2) all signals in the closed-loop system are bounded. Finally, a numerical example and a practical example based on the single-link manipulator are provided to verify the effectiveness of the proposed method.

Global stabilization via output feedback for a class of uncertainty nonlinear systems with time-varying delay and zero dynamics.

This paper proposes a new control strategy to deal with three different types of uncertainties for a class of time-varying delay nonlinear systems. Quite different from related celebrated works, the considered systems allow the existence of parameter uncertainties in the output function and nonlinearities, dynamic uncertainties of the unmeasurable state, and continuous external disturbances, which invokes the motivation of the paper. The objective is to construct a continuous output feedback controller by utilizing a new restructured integral function and the double-domination method. The novelty control design is the capability of tackling zero-dynamic and unknown output function simultaneously, thereby guaranteeing the state convergence of the closed-loop system. Finally, the proposed scheme is applied to a practical example and a numerical one simultaneously to demonstrate the effectiveness and the superiority.

Adaptive Event-Triggered Fast Finite-Time Stabilization of High-Order Uncertain Nonlinear Systems and Its Application in Maglev Systems.

This article is concerned with the global fast finite-time adaptive stabilization for a class of high-order uncertain nonlinear systems in the presence of serious nonlinearities and constraint communications. By renovating the technique of continuous feedback domination to the construction of a serial of integral functions with nested sign functions, this article first proposes a new event-triggered strategy consisting of a sharp triggered rule and a time-varying threshold. The strategy guarantees the existence of the solutions of the closed-loop systems and the fast finite-time convergence of original system states while reaching a compromise between the magnitude of the control and the trigger interval. Quite different from traditional methods, a simple logic is presented to avoid searching all the possible lower bounds of trigger intervals. An example of the maglev system and a numerical example are provided to demonstrate the effectiveness and superiority of the proposed strategy.

Vitreous function and intervention of it with vitrectomy and other modalities.

The vitreous body, the largest intraocular component, plays a key role in eye development, refraction, cell barrier function, oxygen metabolism and the pathogenesis of assorted diseases. Age, refraction and systemic diseases can cause vitreous metabolic abnormalities. With the continuous development of vitrectomy techniques and equipment, vitreous injections and vitrectomies have increased over the recent decades. However, the normal oxygen tension gradient in the vitreous helps to protect the lens and anterior chamber angle from oxidative stress damage, whereas the increased vitreous oxygen tension around lens and the trabecular meshwork after vitrectomy. It may lead to postoperative nuclear cataract and increase the risk for glaucoma. As a conventional procedure, scleral buckling holds several advantages over vitrectomy in selected cases. This review raises concerns regarding the function of the vitreous and encourages conducting vitreous interventions prudently if it is possible.

Tumor Microenvironment Triggered the In Situ Synthesis of an Excellent Sonosensitizer in Tumor for Sonodynamic Therapy.

An ultrasound-triggered sonodynamic therapy has shown great promise for cancer therapy. However, its clinical applications are very limited because the traditional sonosensitizers tend to suffer from very poor efficiency combined with low retention in cancer cells and low tumor selectivity. Therefore, sonosensitizers with higher effectivity, higher tumor cell retention, and higher tumor cell specificity are highly required. Herein, we constructed a Ti2C(OH)X nanosheet, which was a poor sonosensitizer but had a long circulation in the blood system. However, it was very interesting to find that the tumor microenvironment could in situ turn Ti2C(OH)X nanosheet into a novel and excellent sonosensitizer with a nanofiber structure in tumors, exhibiting excellent ability to generate reactive oxygen species (ROS) under ultrasound. Moreover, the nanofiber structure made it very difficult to get out of cancer cells, highly enhancing the retention of the sonosensitizer in the tumor, thereby enabling it to effectively and selectively kill cancer cells in vivo. Our findings demonstrate that the strategy of the tumor microenvironment triggering the in situ synthesis of an effective sonosensitizer in tumor provided a promising means to simultaneously increase the efficiency, sonosensitizer retention in cancer cells, and cancer selectivity, thereby effectively killing cancer cells but causing little damage to healthy tissues via the sonodynamic therapy.

Saikosaponin D exerts antidepressant effect by regulating Homer1-mGluR5 and mTOR signaling in a rat model of chronic unpredictable mild stress.

BACKGROUND: Many studies about depression have focused on the dysfunctional synaptic signaling in the hippocampus that drives the pathophysiology of depression. Radix Bupleuri has been used in China for over 2000 years to regulate liver-qi. Extracted from Radix Bupleuri, Saikosaponin D (SSD) is a pharmacologically active substance that has antidepressant effects. However, its underlying mechanism remains unknown. MATERIALS AND METHODS: A chronic unpredictable mild stress (CUMS) paradigm was used as a rat model of depression. SD rats were randomly assigned to a normal control (NC) group or one exposed to a CUMS paradigm. Of the latter group, rats were assigned to four subgroups: no treatment (CUMS), fluoxetine-treated (FLU), high-dose and low-dose SSD-treated (SSDH and SSDL). SSD was orally administrated of 1.50 mg/kg and 0.75 mg/kg/days for three weeks in the SSDH and SSDL groups, respectively. Fluoxetine was administrated at a dose of 2.0 mg/kg/days. SSD's antidepressant effects were assessed using the open field test, forced swim test, and sucrose preference test. Glutamate levels were quantified by ELISA. Western blot and immunochemical analyses were conducted to quantify proteins in the Homer protein homolog 1 (Homer1)-metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) pathways in the hippocampal CA1 region. To measure related gene expression, RT-qPCR was employed. RESULTS: CUMS-exposed rats treated with SSD exhibited increases in food intake, body weight, and improvements in the time spent in the central are and total distance traveled in the OFT, and less pronounced pleasure-deprivation behaviors. SSD also decreased glutamate levels in CA1. In CA1 region of CUMS-exposed rats, SSD treatment increased mGluR5 expression while decreasing Homer1 expression. SSD also increased expressions of postsynaptic density protein 95 (PSD95) and synapsin I (SYP), and the ratios of p-mTOR/mTOR, p-p70S6k/p70S6k, and p-4E-BP1/4E-BP1 in the CA1 region in CUMS-exposed rats. CONCLUSIONS: SSD treatment reduces glutamate levels in the CA1 region and promotes the expression of the synaptic proteins PSD-95 and SYP via the regulation of the Homer1-mGluR5 and downstream mTOR signaling pathways. These findings suggest that SSD could act as a natural neuroprotective agent in the prevention of depression.