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Abstract Background Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance. Methods MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro. Results Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner. Conclusion Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.

BackgroundFatty Liver Disease (FLD) progresses from steatosis to steatohepatitis and, if left untreated, can lead to irreversible conditions such as cirrhosis and hepatocarcinoma. The etiology of FLD remains unclear, but factors such as overconsumption, poor diet, obesity, and diabetes contribute to its development. Palmitic acid (PA) plays a significant role in FLD progression by inducing apoptosis, inflammation, oxidative stress, and endoplasmic reticulum (ER) stress in hepatocytes. Cordyceps militaris (CM), a fungus with various biological activities, including antioxidant properties is examined both in vitro and in vivo to assess its effectiveness in mitigating PA-induced hepatocyte apoptosis and preventing FLD progression.PurposeThis study aims to investigate the potential and mechanism of CM in combating FLD, particularly in inhibiting hepatocyte apoptosis.MethodsIn vitro studies utilized Clone9 hepatocytes treated with PA to simulate FLD conditions. The effects of CM ethyl acetate extract (EAECM) on apoptosis, mitochondrial function, ER stress, inflammation, and oxidative stress were evaluated. In vivo experiments involved FVB mice fed a NASH diet containing high levels of PA to induce FLD, with powdered CM administered orally to assess its impact on body weight, fasting blood glucose level, liver health, fibrosis, and markers of ER stress, inflammation, and oxidative stress.ResultsEAECM demonstrated protective effects against PA-induced apoptosis, mitochondrial dysfunction, ER stress, inflammation, and oxidative stress in vitro. In vivo, powdered CM supplementation attenuated body weight gain, improved fasting blood glucose level, prevented hepatomegaly, reduced serum triglycerides, and inhibited liver fibrosis. Furthermore, powdered CM treatment mitigated ER stress, inflammation, and oxidative stress in the liver of mice receiving a NASH diet.ConclusionC. militaris holds promise as a therapeutic agent for FLD, as evidenced by its ability to alleviate PA-induced hepatocytes damage and hinder FLD progression in mice. Further research is warranted to identify the active compounds responsible for its beneficial effects and to explore its potential clinical applications in treating FLD.

Abstract In this study, in situ, Si‐doped heteroepitaxial Ga2O3 layers are grown on c‐plane sapphire by metalorganic chemical vapor deposition. The X‐ray diffraction peaks of the doped Ga2O3 epilayers shows ß‐phase of Ga2O3 ,and full width at half maximum of Ga2O3 crystallinity is decreased at a Tetraethoxysilane (TEOS) molar flow rate of 2.23 × 10−7 mol min−1 but increased with higher flow rates. The dopant concentrations of Ga2O3 grown at 825 °C with TEOS molar flows of 2.23 × 10−7, 4.47 × 10−7, and 6.69 × 10−7 mol min−1 are measured to be 5.5 × 1019, 1.1 × 1020, and 1.4 × 1020 atom cm−3, respectively, using secondary ion mass spectra and Hall measurements reveal n‐type nature with carrier concentrations of 6.5 × 1017, 3.2 × 1018, and 3.9 × 1018 atom/cm3 , respectively. To increase Si dopant activation, Ga2O3 growth temperature is raised to 875 °C. The result suggests a higher growth temperature can contribute to a greater probability of Si substitution on Ga lattice sites, which further reduces the resistivity of Ga2O3 epilayer. Moreover, results are compared with theoretical Density Functional Theory studies.

Colorectal cancer (CRC) remains the third most prevalent type of cancer worldwide contributing to an estimated 10 % of all cancer cases. CPT-11 is one of the first-line drugs for CRC treatment. Unfortunately, the development of drug resistance significantly exacerbates the adverse impact of CRC. Consequent tumor recurrences and metastasis, years after treatment are the frequently reported incidences. MicroRNAs (miRNA) are short non-coding RNA with the functionality of gene suppression. The insulin-like growth factor type 1 receptor (IGF1R) is a tyrosine kinase receptor frequently upregulated in cancers and is associated with cell survival and drug resistance. MiRNAs are frequently reported to be dysregulated in cancers including CRC. Evidence suggests that dysregulated miRNAs have direct consequences on the biological processes of their target genes. We previously demonstrated that miRNA-376a-3p is upregulated in CPT-11responsive, CRC cells upon treatment with CPT-11. We therefore aimed to investigate the involvement of miRNA-376a-3p in CPT-11 resistance and its probable association with IGF1R-mediated cancer cell survival. Our experimental approach used knockdown and overexpression experiments supplemented with western blot, RT-qPCR, flow cytometry, MTT, and migration assays to achieve our aim. Our data reveals the mechanism through which IGF1R and miRNA-376a-3p perpetrate and attenuate CPT-11 resistance respectively. MiRNA-376a-3p overexpression negatively regulated the IGF1R-induced cell survival, PI3K/AKT pathway, and reversed the epithelial-mesenchymal transition, hence sensitizing resistant cells to CPT-11. Our findings suggests that the miRNA-376a-3p/IGF1R axis holds promise as a potential target to sensitize CRC to CPT-11 in cases of drug resistance.

Abstract Although irradiated induced-pluripotent stem cells (iPSCs) as a prophylactic cancer vaccine elicit an antitumor immune response, the therapeutic efficacy of iPSC-based cancer vaccines is not promising due to their insufficient antigenicity and the immunosuppressive tumor microenvironment. Here, we found that neoantigen-engineered iPSC cancer vaccines can trigger neoantigen-specific T cell responses to eradicate cancer cells and increase the therapeutic efficacy of RT in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). We generated neoantigen-augmented iPSCs (NA-iPSCs) by engineering AAV2 vector carrying murine neoantigens and evaluated their therapeutic efficacy in combination with radiotherapy. After administration of NA-iPSC cancer vaccine and radiotherapy, we found that ~60% of tumor-bearing mice achieved a complete response in microsatellite-stable CRC model. Furthermore, splenocytes from mice treated with NA-iPSC plus RT produced high levels of IFNγ secretion in response to neoantigens and had a greater cytotoxicity to cancer cells, suggesting that the NA-iPSC vaccine combined with radiotherapy elicited a superior neoantigen-specific T-cell response to eradicate cancer cells. The superior therapeutic efficacy of NA-iPSCs engineered by mouse TNBC neoantigens was also observed in the syngeneic immunocompetent TNBC mouse model. We found that the risk of spontaneous lung and liver metastasis was dramatically decreased by NA-iPSCs plus RT in the TNBC animal model. Altogether, these results indicated that autologous iPSC cancer vaccines engineered by neoantigens can elicit a high neoantigen-specific T-cell response, promote tumor regression, and reduce the risk of distant metastasis in combination with local radiotherapy.

The largescale blackfish, Girella punctata (Gray, 1835), inhabits rocky substrates in the coastal waters of Japan and northeastern Taiwan. Despite its commercial significance, there is limited knowledge regarding its reproductive biology due to the sparse occurrence of broodstocks in its natural environment. This study investigated the reproductive performance and embryonic development of G. punctata, assesses its feeding preferences through controlled feeding trials, and evaluates the impact of various feed types on its growth performance. In total, 124 wild-caught G. punctata were reared for 3–4 years, and their reproductive performance was assessed in 2015 and 2016. Their egg production increased with a sudden water temperature change from 17 ℃ in 2015–22 ℃ and 2016. The total and daily average egg production weights were 3589.22 and 40.79 g, respectively, whereas the total and daily average fertilized egg production weights were 1630.72 and 18.59 g, respectively; moreover, the hatching rate was 42.61 %. During embryonic development, the eggs hatched 45 h post fertilization at 19 ℃. Newly hatched larvae were 2.26 ± 0.04 mm in length with a yolk sac of 1.09 ± 0.02 mm in length. The yolk sac was almost completely absorbed 3 days post hatch (dph), when the larvae grew to a length of 3.42 ± 0.06 mm. We found that fish meal with 40 % protein was the optimal G. punctata fish diet. The weight gain in juveniles fed Cladophora fascicularis ranged from 47 % to 52 %, which was significantly higher than that in those fed Hypnea charoides (p < 0.05). The present study provided a practical guideline on the conditions required for successful fertilization and early development of G. punctata embryos and other larval stages. This information should help ensure greater survival and a higher proportion of healthy G. punctata larvae for mariculture applications.

Exosomes are nano-sized extracellular vesicles produced by almost all mammalian cells. They play an important role in cell-to-cell communication by transferring biologically active molecules from the cell of origin to the recipient cells. Ionizing radiation influences exosome production and molecular cargo loading. In cancer management, ionizing radiation is a form of treatment that exerts its cancer cytotoxicity by induction of DNA damage and other alterations to the targeted tissue cells. However, normal bystander non-targeted cells may exhibit the effects of ionizing radiation, a phenomenon called radiation-induced bystander effect (RIBE). The mutual communication between the two groups of cells (targeted and non-targeted) via radiation-influenced exosomes enables the exchange of radiosensitive molecules. This facilitates indirect radiation exposure, leading, among other effects, to epigenetic remodeling and subsequent adaptation to radiation. This review discusses the role exosomes play in epigenetically induced radiotherapy resistance through the mediation of RIBE.

Although advancements in n- and p-doping of gallium oxide (Ga2O3) are underway, the realization of functional pn diodes remains elusive. Here, we present the successful fabrication of a Ga2O3 pn diode utilizing ion implantation technology. The Ga2O3 epilayers were grown on c-plane sapphire substrates by metalorganic chemical vapor deposition (MOCVD). P-type conductivity Ga2O3 epilayer, confirmed by Hall effect analysis, was achieved by phosphorus (P) ion implantation followed with a rapid thermal annealing (RTA) process. This p-Ga2O3 epilayer reveals a significant reduction in resistivity ( 3kT/q) and remained very low at 2✕10−8 A, as the diode operated at 150oC. The behavior could be due to Ga2O3 being a wide bandgap material.

Stem cells exhibit pluripotency and self-renewal abilities. Adipose-derived mesenchymal stem cells can potentially be used to reconstruct various tissues. They possess significant versatility and alleviate various aging-related diseases. Unfortunately, aging leads to senescence, apoptosis, and a decline in regenerative capacity in adipose-derived mesenchymal stem cells. These changes necessitate a strategy to mitigate the effects of aging on stem cells. Ohwia caudata (O. caudata) has therapeutic effects against several illnesses. However, studies on whether O. caudata has therapeutic effects against aging are lacking. In this study, we aimed to identify potential therapeutic anti-aging effects in the crude aqueous extract of O. caudata on adipose-derived mesenchymal stem cells. Using 0.1 μM doxorubicin, we induced aging in human adipose-derived mesenchymal stem cells (hADMSCs) and evaluated whether various concentrations of O. caudata aqueous extract exhibit anti-aging effects on them. The O. caudata extract exhibited significant antioxidant effects on hADMSCs without any toxicity. Furthermore, after treatment with the O. caudata aqueous extract, the levels of mitochondrial superoxide, DNA double-strand breaks, and telomere shortening were reduced in the hADMSCs subjected to doxorubicin-induced aging. The extract also suppressed doxorubicin-induced aging by upregulating klotho and downregulating p21 in hADMSCs. These findings indicated that the O. caudata extract exhibited anti-aging properties that modulated hADMSC homeostasis. Therefore, it could be a potential candidate for restoring the self-renewal ability and multipotency of aging hADMSCs.

Background Cancer-intrinsic type I interferon (IFN-I) production triggered by radiotherapy (RT) is mainly dependent on cytosolic double-stranded DNA (dsDNA)-mediated cGAS/STING signaling and increases cancer immunogenicity and enhances the antitumor immune response to increase therapeutic efficacy. However, cGAS/STING deficiency in colorectal cancer (CRC) may suppress the RT-induced antitumor immunity. Therefore, we aimed to evaluate the importance of the dsRNA-mediated antitumor immune response induced by RT in patients with CRC.Methods Cytosolic dsRNA level and its sensors were evaluated via cell-based assays (co-culture assay, confocal microscopy, pharmacological inhibition and immunofluorescent staining) and in vivo experiments. Biopsies and surgical tissues from patients with CRC who received preoperative chemoradiotherapy (neoCRT) were collected for multiplex cytokine assays, immunohistochemical analysis and SNP genotyping. We also generated a cancer-specific adenovirus-associated virus (AAV)-IFNβ1 construct to evaluate its therapeutic efficacy in combination with RT, and the immune profiles were analyzed by flow cytometry and RNA-seq.Results Our studies revealed that RT stimulates the autonomous release of dsRNA from cancer cells to activate TLR3-mediated IFN-I signatures to facilitate antitumor immune responses. Patients harboring a dysfunctional TLR3 variant had reduced serum levels of IFN-I-related cytokines and intratumoral CD8+ immune cells and shorter disease-free survival following neoCRT treatment. The engineered cancer-targeted construct AAV-IFNβ1 significantly improved the response to RT, leading to systematic eradication of distant tumors and prolonged survival in defective TLR3 preclinical models.Conclusion Our results support that increasing cancer-intrinsic IFNβ1 expression is an immunotherapeutic strategy that enhances the RT-induced antitumor immune response in locally patients with advanced CRC with dysfunctional TLR3.

Abstract ATP and its receptor P2RX7 exert a pivotal effect on antitumor immunity during chemotherapy-induced immunogenic cell death (ICD). Here, we demonstrated that TNFα-mediated PANX1 cleavage was essential for ATP release in response to chemotherapy in colorectal cancer (CRC). TNFα promoted PANX1 cleavage via a caspase 8/3-dependent pathway to enhance cancer cell immunogenicity, leading to dendritic cell maturation and T-cell activation. Blockade of the ATP receptor P2RX7 by the systemic administration of small molecules significantly attenuated the therapeutic efficacy of chemotherapy and decreased the infiltration of immune cells. In contrast, administration of an ATP mimic markedly increased the therapeutic efficacy of chemotherapy and enhanced the infiltration of immune cells in vivo. High PANX1 expression was positively correlated with the recruitment of DCs and T cells within the tumor microenvironment and was associated with favorable survival outcomes in CRC patients who received adjuvant chemotherapy. Furthermore, a loss-of-function P2RX7 mutation was associated with reduced infiltration of CD8+ immune cells and poor survival outcomes in patients. Taken together, these results reveal that TNFα-mediated PANX1 cleavage promotes ATP-P2RX7 signaling and is a key determinant of chemotherapy-induced antitumor immunity.

Traditional Chinese medicine (TCM) has gained considerable attention over the past few years for its multicomponent, multitarget, and multi-pathway approach to treating different diseases. Studies have shown that TCMs as adjuvant therapy along with conventional treatment may benefit in safely treating various disorders. However, investigations on finding effective herbal combinations are ongoing. A novel TCM formula, “Jing Si Herbal Tea (JSHT),” has been reported recently for their health-promoting effects in improving overall body and mental health. JSHT is a combination of eight herbs recognized in Chinese herbal pharmacopoeia for their anti-viral, anti-aging, and anti-cancer properties as well as protective effects against cardiovascular, metabolic, neural, digestive, and genitourinary diseases. Thus, to better understand the beneficial effects of the ingredients of JSHT on health, this review intends to summarize the preclinical and clinical studies of the ingredients of JSHT on human health and diseases, and possible therapeutic effects with the related mode of actions and future prospects for their application in complementary therapies.

Abstract Regional lymph node metastasis is an important predictor for survival outcome and an indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer. Even with advances in adjuvant chemotherapeutic regimens, 5-year distant metastasis and survival rates are still unsatisfactory. Here, we evaluate the clinical significance of polymorphisms in receptors for HMGB1, which is the hallmark of chemotherapy-induced immunogenic cell death, in patients with stage II–III colon carcinoma (COAD). We found that high cytosolic HMGB1 is elicited in stage III COAD patients who received adjuvant chemotherapy. Patients with the TLR1-N248S polymorphism (rs4833095), which causes loss-of-function in HMGB1-mediated TLR1–TLR2 signaling, may influence the therapeutic efficacy of adjuvant chemotherapy, leading to a high risk of distant metastasis within 5 years [HR = 1.694, 95% CI = 1.063–2.698, p = 0.027], suggesting that TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. We found that defective TLR1 impaired TLR1/2 signaling during dendritic cell (DC) maturation for the antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired their maturation ability by HMGB1 and reduced the secretion of IFNγ from T cells to eradicate tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. In contrast, administration of a TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered a high density of tumor-infiltrating immune cells. We also observed that fewer tumor-infiltrating cytotoxic T lymphocytes were located within the tumor microenvironment in patients bearing the TLR1-N248S polymorphism. Overall, our results suggest that dysfunctional TLR1 may reduce the therapeutic response to adjuvant chemotherapy by impairing HMGB1-mediated DC maturation and attenuating the antitumor immune response in locally advanced colon carcinoma patients.

The health of the host is significantly influenced by the gut microbiota. Penaeus vannamei (white shrimp) is one of the most profitable aquaculture species globally. Synbiotics are typically used as a beneficial diet supplement for raising aquaculture species’ growth capacities and enhancing immunity against pathogenicity. However, the effects of synbiotics on the white shrimp intestinal microbiota remain poorly understood. In the present study, we targeted the V3–V4 region of 16S rRNA genes to analyze the effects of synbiotics on white shrimp gut microbiota. Dietary synbiotics, having Lactobacillus acidophilus, and Moringa oleifera leaf extract were added to the white shrimps’ feed in various proportions in the present study. In total, 490 operational taxonomic units yielding 23 phyla, 41 classes, 94 orders, 151 families, and 250 genera of microorganisms were obtained. The diet containing L. acidophilus at 1 × 107 CFU/g and M. oleifera at 2.5 g/kg led to an increase in the relative abundance of beneficial microorganisms through a significant decrease in the α diversity. Moreover, it upregulated several physiological pathways such as carbohydrate metabolism, signal transduction, lipid metabolism, nucleotide metabolism, amino acid metabolism, and environmental adaptation, which led to the upregulation of the AMPK, MAPK, P13K-Akt, lysosome, peroxisome, and ferroptosis signaling pathways; this enhanced growth and immunity in white shrimp. Whether a single species or a combination of different microorganisms improves growth and immunity remains unclear till now. Nevertheless, our results will facilitate further in-depth investigation into beneficial microbial communities for upliftment of white shrimp aquaculture.

Cardiac fibrosis is a prevalent pathological complication observed in individuals with diabetes. Diallyl trisulfide (DATS), a bioactive compound found in garlic oil, has been reported to exhibit anti-inflammatory and anti-apoptotic effects in various cardiovascular diseases. However, its potential impact on cardiac fibrosis, particularly in the context of diabetes, remains unknown. In the neonatal rat ventricular fibroblasts (NRVFs) model, our results demonstrated that DATS effectively attenuated advanced glycation end products (AGEs)-induced activation of Nuclear factor kappa B (NF-κB) and Smad2/3 signaling pathways, leading to a reduction in the downstream secretion of pro-inflammatory cytokines and collagen synthesis. In the in vivo study using echocardiographic assessment, administration of DATS significantly ameliorated cardiac dysfunction induced by streptozotocin (STZ). Taken together, our findings highlight the potential of DATS as a promising therapeutic agent for mitigating cardiac fibrosis associated with diabetes, emphasizing its potential clinical relevance in the prevention and management of diabetic cardiomyopathy.

Alpha-synuclein (α-syn) and amyloid-beta peptide (Aβ) accumulation cause neurodegenerative diseases. The accumulation of neurotoxins, like Aβ, tau, and α-syn is related to aging therefore studying aging mediated neurodegenerative disease is important. In this study, we used A53T tg mice in this mice behavioral and motor abnormalities could be promoted by Aβ and α-syn interaction, and we decided to prevent this interaction and their associated accumulation in the SN brain region in the A53T tg mice by Hericium erinaceus treatment. Three-month-old A53T mice were separated into three groups A53T, A53T+ low dose alcohol extracted mycelium (3.2 mg/30 g BW/day), and A53T+ high dose alcohol extracted mycelium (6.4 mg/30 g BW/day). Age-matched normal mice were used as a control. Our results confirmed that Hericium erinaceus mycelia extract prevented the formation of Aβ-mediated α-syn accumulation in the SN brain region of A53T tg mice by activating SIRT-1/ERK-1/2 mediated autophagy. We confirmed that SIRT-1/ERK-1/2 mediated autophagy via Hericium erinaceus treatment prevents Aβ and α-syn accumulation and regulates dopamine neuron survival. Our study makes significant contribution because we reported for the first time that Hericium erinaceus mycelia prevents the formation and accumulation of Aβ and α-syn in A53T tg mice by regulating SIRT-1/ERK-1/2 mediated autophagy.

Background: Effects of the major ginsenoside Rg1 on mammalian longevity and physical vitality are rarely reported. Purpose: To examine longevity, tumor, and spontaneous locomotor activity in rats consuming Rg1. Methods: A total of 138 Wistar rats were randomized into 2 groups: control (N = 69) and Rg1 (N = 69). Rg1 (0.1 mg/kg per day) were orally supplemented from 6 months of age until natural death. Spontaneous mobility was measured by video-tracking together with body composition (dual energy x-ray absorptiometry) and inflammation markers at 5, 14, 21, and 28 months of age. Results: No significant differences in longevity (control: 706 days; Rg1: 651 days, p = 0.77) and tumor incidence (control: 19%; Rg1: 12%, p = 0.24) were observed between the two groups. Movement distance in the control group declined significantly by ∼60% at 21 months of age, together with decreased TNF-α (p = 0.01) and increased IL-10 (p = 0.02). However, the movement distance in the Rg1 group was maintained ∼50% above the control groups (p = 0.01) at 21 months of age with greater magnitudes of TNF-α decreases and IL-10 increases. Glucose, insulin, and body composition (bone, muscle and fat percentages) were similar for both groups during the entire observation period. Conclusion: The results of the study suggest a delay age-dependent decline in physical vitality during late life by lifelong Rg1 consumption. This improvement is associated with inflammatory modulation. Significant effects of Rg1 on longevity and tumorigenesis were not observed.

Abstract Astaxanthin (AST), a super antioxidant with coloring and medical properties, renders it a beneficial feed additive for shrimp. This study conducted a white shrimp feeding trial of 3S, 3’S isoform AST, which was derived from metabolic-engineered Kluyveromyces marxianus fermented broth (TB) and its extract (TE) compared to sources from two chemically synthetic ASTs (Carophyll Pink [CP] and Lucantin Pink [LP]), which contain 3S, 3’S, 3R, 3’S (3S, 3’R) and 3R, 3’R isoforms ratio of 1:2:1. The effects on red coloration, immune parameters and resistance to Vibrio infection were evaluated. Four AST sources were incorporated into the diets at concentrations of 0 (control), 100 mg kg−1 (TB100, TE100, CP100, and LP100), and 200 mg kg−1 (TB200, TE200, CP200, and LP200). Results revealed that in week 4, shrimps that received AST-supplemented feeds, especially TB100, TB200, and TE200, significantly increased redness (a*) values. Immune responses including phagocytosis activity, superoxide-anion production, phenoloxidase activity, and immune-related genes were examined on days 0, 1, 2, 4, 7, 14, 21, and 28. Generally, shrimps that received AST-supplemented feeds exhibited higher immune responses on days 7 and 14 than the control feed. Gene expression levels of superoxide dismutase and glutathione peroxidase were significantly upregulated on days 7 and 14 in shrimps that received AST-supplemented feeds, while genes of penaeidins, antilipopolysaccharide factor, and lysozyme were upregulated on days 4, 7, and 14, especially received TB200 and TE200. Furthermore, shrimps that received TB100, TE100, CP100, and LP100 7 days were then challenged with Vibrio parahaemolyticus and the result demonstrated higher survival rates especially TB100 at 168 h than the control feed. In conclusion, incorporating AST into the diets enhanced shrimp red coloration, immune parameters, and resistance against V. parahaemolyticus infection. The K. marxianus-derived AST exhibited higher performance than did chemical AST to be a potential feed additive in shrimp aquaculture.

Abstract Patients with mutations of WDR4, a substrate adaptor of the CUL4 E3 ligase complex, develop cerebellar atrophy and gait phenotypes. However, the underlying mechanisms remain unexplored. Here, we identify a crucial role of Wdr4 in cerebellar development. Wdr4 deficiency in granule neuron progenitors (GNPs) not only reduces foliation and the sizes of external and internal granular layers but also compromises Purkinje neuron organization and the size of the molecular layer, leading to locomotion defects. Mechanistically, Wdr4 supports the proliferation of GNPs by preventing their cell cycle exit. This effect is mediated by Wdr4-induced ubiquitination and degradation of Arhgap17, thereby activating Rac1 to facilitate cell cycle progression. Disease-associated Wdr4 variants, however, cannot provide GNP cell cycle maintenance. Our study identifies Wdr4 as a previously unappreciated participant in cerebellar development and locomotion, providing potential insights into treatment strategies for diseases with WDR4 mutations, such as primordial dwarfism and Galloway-Mowat syndrome.

Objectives: This study retrospectively evaluated the effectiveness of percutaneous pulley release by our newly designed needle knife in terms of cure, relapse, and complication rates. Materials and Methods: Two hundred and fifty-seven patients were allocated into male and female groups between October 2014 and September 2021. We included patients >15 years of age with a trigger finger (TF) (types II–VI). The primary outcome was the absence of a TF and pain-free movement. In contrast, the secondary outcome included second-time surgery and the number of complications such as infection and admission for antibiotics. Results: One hundred patients were male, and 157 patients were female. Males and females had mean ages of 62.45 ± 11.76 and 61.50 ± 8.57 years, respectively. The operative time was significantly longer in males than in females (7.88 ± 6.02 vs. 6.52 ± 3.74 min in males and females, respectively, P = 0.027). However, the percentages of diabetes mellitus and gout were the same in both groups. For the percutaneous methods with our needle knife, remission of the trigger was achieved in all cases. In addition, seven patients received revision and three patients with complications. After needle surgery, topical and joint pain scores were improved in both groups (from 5.09 ± 1.31 to 0.80 ± 1.56). Conclusion: The percutaneous methods with our needle knife displayed effectiveness. The cure rate was high, and the relapse rate was low. Further large-scale clinical trials comparing percutaneous needle to open surgery for releasing the TF will be needed to confirm our results.

Lung cancer is the most common malignant cancer worldwide. Combination therapies are urgently needed to increase patient survival. Calycosin is a phytoestrogen isoflavone that has been reported previously to inhibit tumor cell growth, although its effects on lung cancer remain unclear. The aim of this study was to investigate the effects of calycosin on cell proliferation and apoptosis of gemcitabine-resistant lung cancer cells. Using calycosin to treat human lung cancer cells (CL1-0) and gemcitabine-resistant lung cancer cells (CL1-0 GEMR) and examine the effects on the cells. Cultured human lung cancer cells (CL1-0) and gemcitabine-resistant lung cancer cells (CL1-0 GEMR) were treated with increasing concentrations of calycosin. Cell viability and apoptosis were studied by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, flow cytometry, and TUNEL assays. Western blots were used to measure the expression levels of proliferation-related proteins and cancer stem cell proteins in CL1-0 GEMR cells. The results showed that calycosin treatment inhibited cell proliferation, decreased cell migration ability, and suppressed cancer stem cell properties in CL1-0 GEMR cells. Interestingly, in CL1-0 GEMR cells, calycosin treatment not only increased LDOC1 but also decreased GNL3L/NFκB protein levels and mRNA levels, in concentration-dependent manners. We speculate that calycosin inhibited cell proliferation of the gemcitabine-resistant cell line through regulating the LDOC1/GNL3L/NFκB pathway.

Background/Purpose: Endodontic microsurgery (EMS) is a reliable treatment for teeth with non-healing apical periodontitis. This study evaluated the outcome of EMS with mineral trioxide aggregate as the retrograde filling material and identified potential prognostic factors associated with the EMS outcome. Methods: Consecutive clinical and radiographic records of EMS performed in a teaching hospital from 2013 to 2017 were reviewed. Cases of root fracture, cemental tear, re-surgery, and incomplete records were excluded. After selection, 268 EMS-treated teeth with the follow-up period more than one year were included. Surgical outcome as success or failure was evaluated according to Molven's criteria. For analysis of potential prognostic factors, multivariate logistic regression was performed followed by bivariate chi-square tests. Stratified analysis was performed to understand the interactions between two prognostic factors. Results: The overall EMS success rate was 89.9% in this study. Tooth type (anteriors vs. molars, odds ratio (OR) = 6.83, P = 0.001, anteriors vs. premolars, OR = 4.27, P = 0.010) and endodontic-periodontal (endo-perio) communicating defects (with vs. without, OR = 4.92, P = 0.005) both had a significant influence on the EMS outcome. The negative impact of endo-perio communicating defects was closely associated with tooth type. Premolars with endo-perio communicating defects had significantly higher rates of failure. Conclusion: The EMS outcome is significantly affected by the tooth type and endo-perio communicating defect. The presence of endo-perio communicating defects has a greater negative influence on the success rate for premolars than for anteriors and molars.

Purpose: 8-Hydroxy-2′-deoxyguanosine (8-OHdG) is a byproduct of DNA oxidation resulting from free radical attacks. Paradoxically, treatment with 8-OHdG accelerates tissue healing. The aim of this study is to quantify the 8-OHdG response after a single session of exercise in both trained and untrained adults.Methods: A systematic review and meta-analysis of exercise intervention studies measuring changes in blood 8-OHdG following resistance exercise and aerobic exercise were conducted. The literature search included Web of Science, PubMed, BASE, and Scopus, with publications up to February 2023 included. Subgroup analysis of training status was also conducted.Results: Sixteen studies involving 431 participants met the eligibility criteria. Resistance exercise showed a medium effect on increasing circulating 8-OHdG levels (SMD = 0.66, p < 0.001), which was similar for both trained and untrained participants. However, studies on aerobic exercise presented mixed results. For trained participants, a small effect of aerobic exercise on increasing circulating 8-OHdG levels was observed (SMD = 0.42; p < 0.001). In contrast, for untrained participants, a large effect of decreasing circulating 8-OHdG levels was observed, mostly after long-duration aerobic exercise (SMD = −1.16; p < 0.05). Similar to resistance exercise, high-intensity aerobic exercise (5–45 min, ≥75% VO2max) significantly increased circulating 8-OHdG levels, primarily in trained participants.Conclusion: Pooled results from the studies confirm an increase in circulating 8-OHdG levels after resistance exercise. However, further studies are needed to fully confirm the circulating 8-OHdG response to aerobic exercise. Increases in 8-OHdG after high-intensity aerobic exercise are observed only in trained individuals, implicating its role in training adaptation.Systematic Review Registration: [https://Systematicreview.gov/], identifier [CRD42022324180]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused 403 million cases of coronavirus disease (COVID-19) and resulted in more than 5.7 million deaths worldwide. Extensive research has identified several potential drug treatments for COVID-19. However, the development of new compounds or therapies is necessary to prevent the emergence of drug resistance in SARS-CoV-2. In this study, a novel compound based on hexaacetotetraaquadihydroxochromium(III)diiron(III) nitrate, which contains small amounts of chromium (III), was synthesised and evaluated for its effectiveness against multiple variants of COVID-19 using both in vitro and in vivo models. This innovative compound demonstrated interference with the interaction between the spike protein of SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2). Furthermore, in vitro experiments showed that this compound downregulated the expression of ACE2 and transmembrane serine protease 2 (TMPRSS2). It also exhibited a reduction in the activity of 3-chymotrypsin-like protease (3CL) and RNA-dependent RNA polymerase (RdRp). Pretreatment with this small chromium (III)-based compound resulted in reduced ACE2-rich cell infection by various variants of SARS-CoV-2 spike protein-pseudotyped lentivirus. Finally, the compound effectively inhibited viral infection by multiple variants of SARS-CoV-2 spike protein-pseudotyped lentivirus in both the abdominal and thoracic regions of mice. In conclusion, this compound lowers the likelihood of SARS-CoV-2 entry into cells, inhibits viral maturation and replication in vitro, and reduces infection levels of multiple variants of SARS-CoV-2 spike protein-pseudotyped lentivirus in the abdomen and thorax following pretreatment. Small chromium (III)-based compounds have the potential to restrict the progression of SARS-CoV-2 infections.

In this work, we have fabricated a highly sensitive direct irradiating X-ray photodetector (DXPD) based on Zinc Gallium Oxide (ZnGa2O4) epilayers with a metal-semiconductor-metal structure. The ZnGa2O4 epilayers were grown on a c-plane sapphire substrate by metalorganic chemical vapor deposition (MOCVD). To test the DXPD's capabilities, we subjected it to a synchrotron hard X-ray source with an energy of 10 keV, and measured incident radiation flux ranging from 5.7✕107 to 4.6 ✕1011 counts/sec. The effect of changing the applied bias voltage on the time response of the DXPD was investigated. The sensitivity of hard XPDs was compared using gallium oxide (β-Ga2O3) epilayer grown by MOCVD. The results showed that ZnGa2O4 DXPD had approximately 104 times greater sensitivity than the β-Ga2O3 based XPD. ZnGa2O4 based detectors also exhibited remarkable sensitivity of 2.87 × 109 μC Gyair−1cm−2 for the incident flux of 5.7✕107 counts/sec at 15 V. Additionally, the sensitivity was examined in terms of applied bias and dose rate. Based on these observations, it can be concluded that ZnGa2O4 epilayers grown by MOCVD hold immense potential for use in high-performance hard XPDs.

The habitats of giant clams are undergoing environmental changes, and giant clam populations are declining. The present study was conducted to facilitate clam conservation. We conducted three 18-week trials to investigate the effects of nutrient, temperature, and salinity on the growth performance and survival rates (SRs) of juvenile Tridacna noae, adult Tridacna crocea, and subadult Tridacna derasa, respectively. Regarding nutrient sources, no significant differences were observed in shell length gain, specific growth rate, or SR between clams fed with Chaetoceros muelleri or commercial feed (hw nanotip) and those in a control group (juvenile phototrophs). Regarding temperature, clams cultivated at 27 °C exhibited significantly better growth performance and SR than did those cultivated at 19 °C or 31 °C (p < 0.05). By week 6, all clams in the 19 °C and 31 °C groups had died, indicating that suboptimal growth temperatures have severe adverse effects. Regarding salinity, clams cultivated at 34‰ exhibited significantly higher length gains and specific growth rates than did those cultivated at 20‰ or 25‰ (p < 0.05). SR was not significantly affected by salinity. Understanding how environmental factors affect giant clam populations may help researchers devise effective clam conservation strategies.

Abstract Radiotherapy (RT) mainly elicits antitumor immunity via the cGAS/STING axis for type I interferon (IFN) production. However, dysregulation of cGAS/STING constrains radiotherapy-induced antitumor immunity and type I IFN-dependent cell death and is associated with shorter survival of patients with colorectal cancer (CRC). Due to their tumor tropism, mesenchymal stem cells (MSCs) have shown the potential to deliver therapeutic genes for cancer therapy. Here, we showed that MSCs enhance the sensitivity to RT by inducing TRAIL-dependent cell death and remodel the tumor microenvironment by recruiting CD8+ immune cells to upregulate PD-L1 in the tumor. By engineering MSCs to express CRC-specific soluble TRAIL via adenovirus-associated virus 2 (AAV2), we found that the therapeutic activity of MSC-sTRAIL was superior to that of MSCs alone when combined with RT. Combined treatment with MSC-sTRAIL and RT significantly reduced cell viability and increased apoptosis by inducing TRAIL-dependent cell death in STING-deficient colorectal cancer cells. MSC-sTRAIL directly triggered TRAIL-dependent cell death to overcome the deficiency of the cGAS/STING axis. Moreover, these combination treatments of MSC-sTRAIL and RT significantly remodeled the tumor microenvironment, which was more suitable for anti-PD-L1 immunotherapy. Taken together, this therapeutic strategy represents a novel targeted treatment option for patients with colorectal cancer, especially cGAS/STING-deficient patients.

Systematically study of in-plane intrinsic defects and edge atoms is important to guide the design of low-dimensional photocatalysts. Here the authors investigate photocatalytic CO2 reduction to CH4 over reconstructed edge atoms of monolayer semiconducting WSe2.

Diabetic retinopathy (DR) is a major cause of vision loss in diabetic patients. Hyperglycemia-induced oxidative stress and the accumulation of inflammatory factors result in blood-retinal barrier dysfunction and the pathogenesis of DR. Scoparia dulcis L. extract (SDE), a traditional Chinese medicine, has been recently recognized for its various pharmacological effects, including anti-diabetic, anti-hyperlipidemia, anti-inflammatory, and anti-oxidative activities. However, there is no relevant research on the protective effect of SDE in DR. In this study, we treated high glucose (50 mM) in human retinal epithelial cells (ARPE-19) with different concentrations of SDE and analyzed cell viability, apoptosis, and ROS production. Moreover, we analyzed the expression of Akt, Nrf2, catalase, and HO-1, which showed that SDE dose-dependently reduced ROS production and attenuated ARPE-19 cell apoptosis in a high-glucose environment. Briefly, we demonstrated that SDE exhibited an anti-oxidative and anti-inflammatory ability in protecting retinal cells from high-glucose (HG) treatment. Moreover, we also investigated the involvement of the Akt/Nrf2/HO-1 pathway in SDE-mediated protective effects. The results suggest SDE as a nutritional supplement that could benefit patients with DR.

Microsatellite instability (MSI), caused by deficiency of the DNA mismatch repair system, has been associated with improved response to immune checkpoint blockade (ICB). Here the authors show that inactivation of protein phosphatase 2A induces a MSI status, promoting cytotoxic T cell infiltration and response to ICB in pre-clinical cancer models.

Diallyl trisulfide (DATS), an organosulfide compound derived from garlic, is renowned for its potent antioxidant properties, particularly in countering the generation of reactive oxygen species (ROS). It has also gained recognition as a potential agent for preventing heart-related conditions. Doxorubicin (Dox), a commonly used chemotherapeutic drug, is known to induce severe cardiac complications by promoting ROS production. Therefore, it was imperative to investigate whether DATS possesses cardioprotective capabilities against Dox-induced cardiac apoptosis and elucidate the underlying mechanisms. In this study, we observed that the intracellular ROS levels and cardiac apoptosis were heightened in H9c2 cells exposed to Dox (1 μM). However, treatment with 10 μM DATS effectively mitigated the Dox-induced ROS generation and apoptotic signaling, concurrently activating the PI3K/Akt pathway. Notably, the anti-apoptotic effects of DATS were attenuated when PI3K siRNA and the LY294002 PI3K inhibitor were employed. Furthermore, the TUNEL assay results demonstrated a significant reduction in Dox-induced apoptosis with DATS treatment. In summary, our findings indicate that DATS can activate the PI3K/Akt pathway, reducing ROS production in cardiac cells exposed to Dox, and subsequently rescue cardiac cells from apoptosis.

Multiple studies show increased severity of SARS-CoV2-infection in patients with comorbidities such as hypertension and diabetes. In this study, we have prepared two herbal-based formulations, a pleiotropic herbal drink (Jin Si Herbal Tea, JHT) and a nasal drop (Jin Si nasal drop, JND), to provide preventive care against SARS-CoV2 infection. The effect of JHT and JND was determined in SARS-CoV2-S-pseudotyped lentivirus-infected bronchial and colorectal cell lines and in SKH-1 mouse models. For preliminary studies, ACE2 receptor abundant bronchial (Calu-3) and colorectal cells (Caco-2) were used to determine the effect of JHT and JND on the host entry of various variants of SARS-CoV2-S-pseudotyped lentivirus. A series of experiments were performed to understand the infection rate in SKH-1 mice (6 weeks old, n = 9), find the effective dosage of JHT and JND, and determine the combination effect of JHT and JND on the entry and adhesion of various variant SARS-CoV2-S-pseudotyped lentiviruses, which included highly transmissible delta and gamma mutants. Furthermore, the effect of combined JHT and JND was determined on diabetes-induced SKH-1 mice against the comorbidity-associated intense viral entry and accumulation. In addition, the effect of combined JHT and JND administration on viral transmission from infected SKH-1 mice to uninfected cage mate mice was determined. The results showed that both JHT and JND were effective in alleviating the viral entry and accumulation in the thorax and the abdominal area. While JHT showed a dose-dependent decrease in the viral load, JND showed early inhibition of viral entry from day 1 of the infection. Combined administration of 48.66 mg of JHT and 20 µL of JND showed rapid reduction in the viral entry and reduced the viral load (97–99%) in the infected mice within 3 days of treatment. Moreover, 16.22 mg of JHT and 20 µL JND reduced the viral infection in STZ-induced diabetic SKH-1 mice. Interestingly, combined JHT and JND also inhibited viral transmission among cage mates. The results, therefore, showed that combined administration of JHT and JND is a novel and an efficient strategy to potentially prevent SARS-CoV2 infection.

Constipation is correlated with diminished cognitive function, revealing a possible rectum-brain connection. In this counter-balanced crossover trial, 13 elite triathletes underwent a Stroop test to assess cognitive function and executive control. The Stroop test was conducted both with and without magnesium oxide intake, with a 1-week washout period between sessions. Oxygenation and blood distribution during the cognitive challenge were measured using Near-Infrared Spectroscopy (NIRS). Measurements were taken in both the prefrontal brain and the sub-navel region, where the highest glucose uptake was detected under the 18F-fluorodeoxyglucose Positron Emission Tomography (PET) scan. A significant reduction in completion time for the Stroop test was observed after defecation compared to the non-defecated condition (non-defecation: [27.1 ± 1.1] s; non-magnesium defecation: [24.4 ± 0.9] s; magnesium defecation: [23.4 ± 0.8] s, p < 0.05). Stroop test performance was improved in all (100%, 13/13) of the participants after magnesium-induced defecation and most (69%, 9/13) of the participants after non-magnesium-induced defecation. While no alterations in oxygenation and blood distribution were observed in the prefrontal brain during the Stroop test, decreased oxygenation levels were observed in the sub-navel region under both defecated conditions, without significant changes in blood distribution (p < 0.05). This data suggests an acute increase in oxygen consumption at this specific region. The result of this study suggests an unexplored causal link between the state of the rectum and cognitive performance. Magnesium supplementation to improved rectal emptying presents a novel application for optimizing cognitive function in athletes navigating intricate racing conditions. [ABSTRACT FROM AUTHOR]

This contribution presents the occurrence of epibiotic species associated with Neocaridina davidi shrimp collected in the wild, aquaculture ponds, and aquaria. A total of 900 shrimp are imported from Taiwan, three-quarters of which host at least one of the recorded epibionts. Among those epibionts, two species new to science are discovered, Cladogonium kumaki sp. nov. and Monodiscus kumaki sp. nov., while the other two, Holtodrilus truncatus and Scutariella japonica, are redescribed. The largest number of epibionts is found in shrimp collected from aquaculture ponds and the lowest in individuals from aquaria. Epibiont occurrence differs across designated microhabitats. The epibionts may be introduced alongside their host outside their native range, and their presence may affect shrimp breeding rates. Thus, more control over them should be provided. Their spread can be limited by removal from the host during molting or manually, as well as by using interspecies interactions.

Introduction: Insulin-like growth factor-I receptor (IGF1R) mediated survival signaling is a crucial mechanism for cellular endurance and a potential indicator of recuperation in deteriorating hearts. Objective: This study evaluates the impact of long-term exercise training in enhancing cardiac survival mechanism in D-galactose-induced toxicity associated aging rats. Methods: Forty-eight male SD-rats were segregated into 4 groups (n=9) and were named as control, exercise training groups, aging group and aging group with exercise training. Aging was induced by intraperitoneal (IP) D-galactose (150 mL/kg) injection for 8 weeks and for exercise training, the rats were left to swim in warm water for 60 min every day and 5 times/week. Western blotting of proteins from the left ventricles was performed to identify the modulations in the survival signaling. Tissue sections were analyzed to determine the extent of fibrosis and apoptosis. Results: Western-blot analysis performed on the excised left ventricles (LV) showed that proteins of the cardiac survival pathway including IGF1R and Akt and the pro-survival Bcl-2 showed significant decrease in the aging group, whereas the levels were restored in the aging rats subjected to exercise training. In addition, aging groups showed increased interstitial space and collagen accumulation. Further, TUNEL assay showed higher number of apoptotic cells in the LV of aging group, which was correlated with increase in the proteins involved in FAS-FADD-dependent apoptosis. However, these aging associated effects were ameliorated upon exercise training in the D-galactose-induced aging rats that showed elevated IGF1R/Akt signaling. Conclusion: The results suggest that IGFIR survival signaling cascadeis elevated in following long-term exercise training and thereby provide cardio-protective benefits in D-galactose induced aging rats.

Malachite green (MG) residue in aquatic environments can adversely affect food chains. To solve this problem, many adsorbents have been developed to remove MG from aqueous solutions. These adsorbents exhibit benefits in different aspects such as low cost, nontoxicity, and environment friendliness. Zeolite, oyster shell powder (OSP), humic acid (HA), and Chloride dioxide (ClO2) are widely used agents for water purification, indicating their potential to remove MG from both freshwater and seawater. Liquid chromatography tandem mass spectrometry was performed as a valid analytical method for measuring MG and its metabolite leucomalachite green (LMG). The analysis examined linearity, specificity, accuracy, precision, and limit of quantification. We found that three agents—zeolite, OSP, and HA—have high affinity for MG and LMG in both freshwater and seawater because of their physicochemical properties; ClO2 exhibited even greater efficiency for MG and LMG degradation due to its oxidation capacity. The MG removal efficiency of zeolite, OSP and HA in freshwater was 100%, 87.52%, and 100%, respectively. In the MG-containing seawater, the removal efficiency of zeolite, OSP and HA was 95.24%, 6.57%, and 89.36%, respectively. The LMG removal efficiency of zeolite, OSP and HA in freshwater was 100%, 53.56%, and 100%, while in seawater, the LMG removal efficiency of zeolite, OSP and HA was 100%, 62.70%, and 84.65%, respectively. ClO2 treatments in both freshwater and seawater expressed 100% removal efficiency. The adsorption capacity of three water agents in MG-containing freshwater decreased in the order: zeolite = HA > OSP; in MG-containing seawater: zeolite > HA > OSP. Whereas the adsorption capacity of three water agents in LMG-containing freshwater decreased in the order: zeolite = HA > OSP; in LMG-containing seawater: zeolite > HA > OSP. In this study, four water treatment agents are reported to remove MG and LMG from freshwater and seawater, indicating their potential for reducing the amount of hazardous MG and LMG residue in aquatic environments.

Hot compress modalities are used to ameliorate pain despite prevalent confusion about which modality should be used and when. Most recommendations for hot compresses are based on empirical experience, with limited evidence to support its efficacy. To obtain insight into the nerve transmission mechanism of hot compresses and to identify the nerve injury marker proteins specifically associated with sciatic nerve pain, we established a rat model of chronic constriction injury (CCI) and performed mechanical allodynia, electrophysiology, and histopathological analysis. All CCI rats exhibited geometric representation of the affected hind paw, which indicated a hyper-impact on both mechanical gait and asymmetry of gait on day 28. The CCI model after 28 days of surgery significantly reduced compound muscle action potential (CMAP) amplitude, but also significantly reduced latency. Administration of hot compress for 3 weeks (heated at 40–42°C, cycle of 40 min, and rest for 20 min, three cycles each time, three times per week) significantly increased the paw withdrawal thresholds in response to stimulation by Von Frey fibers and reversed the CCI-induced reduced sciatic functional index (SFI) scores. Hot compress treatment in the CCI model improved CMAP amplitude and latency. The S100 protein expression level in the CCI+Hot compression group was 1.5-fold higher than in the CCI group; it dramatically reduced inflammation, such as tumor necrosis factor alpha and CD68 expression in nerve injury sites. Synaptophysin (Syn) expression in the CCI+Hot compression group was less than threefold in the CCI group at both nerve injury sites and brain (somatosensory cortex and hippocampus). This finding indicates that local nerve damage and inflammation cause significant alterations in the sensorimotor strip, and hot compress treatment could significantly ameliorate sciatic nerve pain by attenuating Syn and inflammatory factors from local pathological nerves to the brain. This study determines the potential efficacy and safety of hot compress, and may have important implications for its widespread use in sciatic nerve pain treatment.

Deep brain stimulation of the bilateral subthalamic nucleus (STN) is a therapeutic option for patients with Parkinson’s disease (PD) in whom medical therapies have been ineffective. This retrospective cohort study analyzed the motor function of 27 patients with advanced PD, from the First Affiliated Hospital of Guangzhou Medical University, China, who received deep brain stimulation of the bilateral subthalamic nucleus and evaluated its therapeutic effects. The 10-year follow-up data of patients was analyzed in Qingyuan People’s Hospital, Sixth Affiliated Hospital of Guangzhou Medical University, China. The follow-up data were divided into two categories based on patients during levodopa treatment (on-medication) and without levodopa treatment (off-medication). Compared with baseline, the motor function of on-medication PD patients improved after deep brain stimulation of the bilateral subthalamic nucleus. Even 2 years later, the motor function of off-medication PD patients had improved. On-medication PD patients exhibited better therapeutic effects over the 5 years than off-medication PD patients. On-medication patients’ akinesia, speech, postural stability, gait, and cognitive function worsened only after 5 years. These results suggest that the motor function of patients with advanced PD benefitted from treatment with deep brain stimulation of the bilateral subthalamic nucleus over a period up to 5 years. The overall therapeutic effects were more pronounced when levodopa treatment was combined with deep brain stimulation of the bilateral subthalamic nucleus. This study was approved by Institutional Review Board of Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, China (approval No. QPH-IRB-A0140) on January 11, 2018.

Abstract Colorectal cancer (CRC) is the leading cause of cancer-related mortality worldwide. Although the role of tumor programmed cell death 1 ligand 1 (PD-L1) in suppressing antitumor immunity has been validated in various malignances, the impact of PD-L2 (PD-L2/PDCD1LG2) within tumors remains elusive. Here, we examined tumor PD-L2 expression by immunohistochemical analysis and assessed its association with clinicopathological characteristics and the infiltration of intratumoral T lymphocytes in colon carcinoma patients (n = 1264). We found that tumor PD-L2 status was correlated with perineural invasion (PNI) and associated with survival outcome in colon carcinoma patients. The level of tumor PD-L2 was positively associated with tumor PD-L1 expression but inversely associated with the density of CD8+ tumor-infiltrating lymphocytes (TILs). Patients with elevated tumor PD-L2 levels had a favorable 5-year overall survival (OS) compared to patients with low PD-L2 levels (57% vs 40%, p

Abstract Naturally occurring tumor in animals receiving high minerals from deep oceans (DOM: hardness 600 mg/L) from 6 months of age until natural death was firstly assessed in 200 Sprague Dawley rats, randomized into four groups: Control (C), DOM (D), Fructose (F), and Fructose + DOM (FD). Fructose drink contained 11% fructose. Tumor incidence (necropsy at death) in the D group was ~40% lower than that in the C group (P

There is an increasing interest in generating retinal pigment epithelial (RPE) cells from stem cells for treating degenerative eye diseases. However, whether human umbilical cord mesenchymal stem cells (HUCMSCs) can differentiate into RPE-like cells in a co-culture system has not been fully understood. In this study, induction of HUCMSC differentiation into RPE-like cells was performed by co-culturing HUCMSCs and a human RPE-like cell line (ARPE19) in a transwell system and then analyzed for biomarkers using quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining technique. Moreover, the functional characterization of induced cells was carried out by examining their phagocytic and neurotrophic factor–secreting activities. Our results showed that mRNA expressions of RPE-specific markers—MITF, OTX2, RPE65, PEDF, PME17, and CRALBP—and protein markers—RPE65, CRALBP, and ZO-1—were significantly increased in HUCMSC-derived RPE-like cells. Functional characteristic studies showed that these induced cells were capable of engulfing photoreceptor outer segments and secreting brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF), which are typical functions of RPE-like cells. Overall, the study findings indicate that the morphology and proliferation of HUCMSCs can be maintained in a serum-free medium, and differentiation into RPE-like cells can be induced by simply co-culturing HUCMSCs with ARPE19 cells. Thus, the study provides fundamental information regarding the clinical-scale generation of RPE-like cells from HUCMSCs.

Despite multidisciplinary therapy, the prognosis is poor for esophageal squamous cell carcinoma (ESCC). In the locally advanced stage, neoadjuvant chemoradiotherapy (nCRT) followed by surgery could provide survival benefits to some patients. Here, we aimed to identify for tumor therapy response a biomarker based on RNA sequencing. We collected endoscopic biopsies of 32 ESCC patients, who were divided according to nCRT response, into two groups: the complete response group (n = 13) and the non-complete response group (n = 19). RNA-sequencing data showed that 464 genes were differentially expressed. Increased in non-complete response group, 4 genes increased expressions were AGR2 (anterior gradient 2), GADD45B (growth arrest and DNA damage inducible beta), PPP1R15A (protein phosphatase 1 regulatory subunit 15A) and LRG1 (leucine rich alpha-2-glycoprotein 1). The areas under the curve (AUC) of the AGR2 gene was 0.671 according to read counts of RNA-seq and therapy response of nCRT. In vitro study showed that apoptosis cell was significantly increased in the AGR2-knockdown TE-2 cell line treated with cisplatin and 5-Fluorouracil (5-FU), when compared with si-control. Results suggest that in ESCC, the AGR2 gene is a promising and predictive gene marker for the response to anti-tumor therapy.

Stem cell therapy has been explored for the treatment of cerebral stroke. Several types of stem cells have been investigated to ensure the safety and efficacy in clinical trials. Cryopreserved umbilical cord blood (UCB) mononuclear cells (MNCs) obtained from healthy donors have a more stabilized quality, thereby ensuring a successful therapy. A phase I study was conducted on patients aged 45–80 years who sustained acute ischemic stroke. An UCB unit was obtained from a public cord blood bank based on ABO/Rh blood type, HLA matching score (6/6), and cell dose (total MNC count of 0.5–5 × 10 7 cells/kg). In addition, to facilitate blood brain barrier penetration of UCB, 4 doses of 100 mL mannitol was administered intravenously after 30 min after UCB transplantation and every 4 h thereafter. The primary outcomes were the number of disease (GVHD) within 100 days after transfusion. The secondary outcomes were changes in the National Institutes of Health Stroke Scale (NIHSS), Barthel index, and Berg Balance Scale scores. A 46-year-old male patient with identical ABO/Rh blood type, HLA matching score of 6/6, and MNC count of 2.63 × 10 8 cells/kg was enrolled. The patient did not present with serious AEs or GVHD during the 12-month study period. The patient’s NIHSS score decreased from 9 to 1. Moreover, the Berg Balance Scale score increased from 0 to 48 and the Barthel index score from 0 to 90. This preliminary study showed that an adult patient with hemiplegia due to ischemic stroke completely recovered within 12 months after receiving allogeneic UCB therapy.

Purpose: This study aimed to assess the requirement of protein in pre-exercise carbohydrate drinks for optimal endurance performance at high intensity and post-exercise fatigue recovery.Methods: Endurance performance at 85% V.⁢O2peak of young men (age 20 ± 0.9 years, V.⁢2peak 49.3 ± 0.3 L/min) was measured for two consecutive days using cycling time to exhaustion and total work exerted 2 h after three isocaloric supplementations: RICE (50 g, protein: 1.8 g), n = 7; SOY + RICE (50 g, protein: 4.8 g), n = 7; and WHEY + RICE (50 g, protein: 9.2 g), n = 7.Results: Endurance performance was similar for the three supplemented conditions. Nevertheless, maximal cycling time and total exerted work from Day 1 to Day 2 were improved in the WHEY + RICE (+21%, p = 0.05) and SOY-RICE (+16%, p = 0.10) supplemented conditions, not the RICE supplemented condition. Increases in plasma interleukin-6 (IL-6) were observed 1 h after exercise regardless of supplemented conditions. Plasma creatine kinase remained unchanged after exercise for all three supplemented conditions. Increases in ferric reducing antioxidant power (FRAP) after exercise were small and similar for the three supplemented conditions.Conclusion: Adding protein into carbohydrate drinks provides no immediate benefit in endurance performance and antioxidant capacity yet enhances fatigue recovery for the next day. Soy-containing carbohydrate drink, despite 50% less protein content, shows similar fatigue recovery efficacy to the whey protein-containing carbohydrate drink. These results suggest the importance of dietary nitrogen sources in fatigue recovery after exercise.

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Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide. Accumulating evidences have highlighted the importance of exosomes and non-coding RNAs (ncRNAs) in cardiac physiology and pathology. It is in general consensus that exosomes and ncRNAs play a crucial role in the maintenance of normal cellular function; and interestingly it is envisaged that their potential as prospective therapeutic candidates and biomarkers are increasing rapidly. Considering all these aspects, this review provides a comprehensive overview of the recent understanding of exosomes and ncRNAs in CVDs. We provide a great deal of discussion regarding their role in the cardiovascular system, together with providing a glimpse of ideas regarding strategies exploited to harness their potential as a therapeutic intervention and prospective biomarker against CVDs. Thus, it could be envisaged that a thorough understanding of the intricacies related to exosomes and ncRNA would seemingly allow their full exploration and may lead clinical settings to become a reality in near future.

Danshen (Salvia miltiorrhiza) is a traditional Chinese medicine (TCM) and is frequently used to treat various diseases, such as cardiovascular disease, cancers, liver disease, and nervous system disease. Recent studies have shown that Danshen and its active compounds exhibit prominent protective, anti-inflammatory, antioxidative or antiplatelet properties. The present article reviews the different aspects, such as sources, uses, bioavailability, and medical applications, of Danshen. It is a compilation of all the relevant literature available in this regard in a very concise form to make the readers understand its chemical properties, metabolism, health benefits and other effects. This includes studies that have been done thus far in relation to the therapeutic effects of Danshen in a variety of diseases, such as diabetes, neurological disorders, and even cancer. This article also provides a scientific rationale for understanding the traditional use of Danshen in various diseases.

Abstract Recent studies indicate that umbilical cord stem cells are cytoprotective against several disorders. One critical limitation in using stem cells is reduction in their viability under stressful conditions, such as diabetes. However, the molecular intricacies responsible for diabetic conditions are not fully elucidated. In this study, we found that high glucose (HG) conditions induced loss of chaperone homeostasis, stabilized PTEN, triggered the downstream signaling cascade, and induced apoptosis and oxidative stress in Wharton's jelly derived mesenchymal stem cells (WJMSCs). Increased Carboxyl terminus of Hsc70 interacting protein (CHIP) expression promoted phosphatase and tensin homolog (PTEN) degradation via the ubiquitin‐proteasome system and shortened its half‐life during HG stress. Docking studies confirmed the interaction of CHIP with PTEN and FOXO3a with the Bim promoter region. Further, it was found that the chaperone system is involved in CHIP‐mediated PTEN proteasomal degradation. CHIP depletion stabilizes PTEN whereas PTEN inhibition showed an inverse effect. CHIP overactivation suppressed the binding of FOXO3a with bim. Coculturing CHIP overexpressed WJMSCs suppressed HG‐induced apoptosis and oxidative stress in embryo derived cardiac cell lines. CHIP overexpressing and PTEN silenced WJMSCs ameliorated diabetic effects in streptozotocin (STZ) induced diabetic rats and further improved their body weight and heart weight, and rescued from hyperglycemia‐induced cardiac injury. Considering these, the current study suggests that CHIP confers resistance to apoptosis and acts as a potentiation factor in WJMSCs to provide protection from degenerative effects of diabetes.

Abstract Background Diabetic patients are highly vulnerable to hypoxic injury, which is associated with hypoxia induced BNIP3 expression that subsequently activate apoptosis. Our previous research show that Tetramethylpyrazine (TMP), a food flavoring agent, represses the hypoxia induced BNIP3 expression attenuate myocardial apoptosis. In this study, we evaluate the effect of TMP to provide protection against hypoxia aggravated high-glucose associated cellular apoptosis. Methods The cytoprotective effect of TMP against high glucose induced cellular damages was determined on embryo derived H9c2 cardiomyoblast cells that were subjected to 5% hypoxia for 24 h and subjected to different duration of 33 mM high glucose challenge. Further, the involvement of HIF-1α and BNIP3 in cellular damage and the mechanism of protection of TMP were determined by overexpression and silencing HIF-1α and BNIP3 protein expression. Results The results show that hypoxic effects on cell viability aggravates with high glucose challenge and this augmentative effect is mediated through BNIP3 in H9c2 cardiomyoblast cells. However, TMP administration effectively reversed the augmented HIF-1α levels and BNIP3 elevation. TMP improved the survival of H9c2 cells and effectively suppressed apoptosis in H9c2 cells. Further comparison on the effects of TMP on H9c2 cells challenged with high glucose and those challenged with hypoxia show that TMP precisely regulated the hypoxic intensified apoptotic effects in high-glucose condition. Conclusion The results clearly show that flavoring agent-TMP attenuates cytotoxicity amplified by hypoxia challenge in high glucose condition by destabilizing HIF-1α.