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Hepatocellular carcinoma (HCC) accounts for the most common form of primary liver cancer cases and constitutes a major health problem worldwide. The diagnosis of HCC is still challenging due to the low sensitivity and specificity of the serum α-fetoprotein (AFP) diagnostic method. Extracellular vesicles (EVs) are heterogeneous populations of phospholipid bilayer-enclosed vesicles that can be found in many biological fluids, and have great potential as circulating biomarkers for biomarker discovery and disease diagnosis. Protein glycosylation plays crucial roles in many biological processes and aberrant glycosylation is a hallmark of cancer. Herein, we performed a comprehensive glycoproteomic profiling of urinary EVs at the intact N-glycopeptide level to screen potential biomarkers for the diagnosis of HCC. With the control of the spectrum-level false discovery rate ≤1%, 756 intact N-glycopeptides with 154 N-glycosites, 158 peptide backbones, and 107 N-glycoproteins were identified. Out of 756 intact N-glycopeptides, 344 differentially expressed intact N-glycopeptides (DEGPs) were identified, corresponding to 308 upregulated and 36 downregulated N-glycopeptides, respectively. Compared to normal control (NC), the glycoproteins LG3BP, PIGR and KNG1 are upregulated in HCC-derived EVs, while ASPP2 is downregulated. The findings demonstrated that specific site-specific glycoforms in these glycoproteins from urinary EVs could be potential and efficient non-invasive candidate biomarkers for HCC diagnosis. [ABSTRACT FROM AUTHOR]

The long-term overuse of fertilizers negatively affects soil chemical properties and health, causing unsustainable agricultural development. Although many studies have focused on the effects of long-term fertilization on soil properties, few comparative and comprehensive studies have been conducted on fertilization management over the past 35 years in China. This meta-analysis (2058 data) evaluated the effects of the fertilizer, climate, crop types, cultivation duration and soil texture on the soil chemical properties of Chinese croplands. NPKM (NPK fertilizers + manure) led to the highest increase in pH (−0.1), soil organic carbon (SOC) (+67%), total nitrogen (TN) (+63%), alkali-hydrolysable nitrogen (AN) (+70%), total phosphorus (TP) (+149%) and available potassium (AK) (+281%) compared to the unfertilized control, while the sole nitrogen fertilizer (N) led to the lowest increase. The SOC (+115%) and TN (+84%) showed the highest increase under the influence of NPKM in an arid region. The increase in the chemical properties was higher in unflooded crops, with the maximum increase in the wheat–maize rotation, compared to rice, under NPKM. The SOC and TN increased faster under the influence of organic fertilizers (manure or straw) compared to mineral fertilization. Fertilizers produced faster effects on the change in the SOC and TN in sandy loam compared to the control. Fertilizers showed the highest and lowest effects on change in pH, organic C to total N ratio (C/N), TP and TK in clay loam with the cultivation duration. NPKM greatly increased the C/N compared to NPK in an arid region by 1.74 times and in wheat by 1.86 times. Reaching the same SOC increase, the lowest TN increase was observed in wheat, and the lowest increase in TP and AK was observed in rice, compared to the other crops. These results suggest that organic fertilizers (manure or straw) play important roles in improving soil fertility and in acidification. NPKM greatly increased the potential for soil C sequestration in wheat and in the arid region. The small increases in TP and TK can increase the SOC in rice and in the humid region. Therefore, considering the crop types and climatic conditions, reduced fertilization and the combination of mineral fertilizers with manure may be the best ways to avoid agricultural soil deterioration and increase soil carbon sequestration. [ABSTRACT FROM AUTHOR]

Lung cancer, the leading cause of cancer-related deaths, presents significant challenges to patients due to its poor prognosis. Recent research has increasingly implicated circular RNAs in the development and progression of lung cancer. These circular RNAs have been found to impact various aspects of tumor behavior, including proliferation, metastasis, cell cycle regulation, apoptosis, cancer stem cells, therapy response, and the tumor microenvironment. One of the key mechanisms by which circular RNAs exert their influence is through their ability to act as miRNA sponges, sequestering microRNAs and preventing them from targeting other RNA molecules. Accumulating evidence suggests that circular RNAs can function as competing endogenous RNAs, affecting the expression of target mRNAs by sequestering microRNAs. Dysregulation of competing endogenous RNAs networks involving circular RNAs, microRNAs, and mRNAs leads to the aberrant expression of oncogenes and tumor suppressors involved in lung cancer pathogenesis. Understanding the dynamic interplay and molecular mechanisms among circular RNAs, microRNAs, and mRNAs holds great promise for advancing early diagnosis, personalized therapeutic interventions, and improved patient outcomes in lung cancer. Therefore, this study aims to provide an in-depth exploration of the executive roles of circular RNAs/microRNAs/ mRNAs interactions in lung cancer pathogenesis and their potential utility for diagnosing lung cancer, predicting patient prognosis, and guiding targeted therapies. By offering a comprehensive overview of the dysregulation of the axes as driving factors in lung cancer, we aim to pave the way for their translation into clinical practice in the future. [ABSTRACT FROM AUTHOR]

Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, have emerged as critical mediators in the communication between the human microbiota and its host. As the first responder to the inflammatory site, neutrophils play an important role in protecting the host against bacterial infections. Recent investigations revealed that SCFAs generated from microbiota influence various neutrophil activities, including activation, migration, and generation of mediators of inflammatory processes. SCFAs have also been demonstrated to exhibit potential therapeutic benefits in a variety of disorders related to neutrophil dysfunction, including inflammatory bowel disease, viral infectious disorders, and cancer. This study aims to examine the molecular processes behind the complicated link between SCFAs and neutrophils, as well as their influence on neutrophil-driven inflammatory disorders. In addition, we will also provide an in-depth review of current research on the diagnostic and therapeutic value of SCFAs as possible biomarkers for neutrophil-related diseases. [ABSTRACT FROM AUTHOR]

Recent studies have shown that the non-enzymatic function of CD73 plays a key role in tumor progression, but this function of CD73 in pancreatic cancer cells has not been studied. Furthermore, little is known about the mechanism involved in CD73 regulation in tumors. Here, we found that CD73 expression was upregulated in pancreatic ductal adenocarcinoma (PDAC) and that its expression correlated with poor prognosis. CD73 knockdown inhibited cell growth and induced G1 phase arrest via the AKT/ERK/cyclin D signaling pathway. We also found that tumor necrosis factor receptor (TNFR) 2 was involved in CD73-induced AKT and ERK signaling pathway activation in PDAC. Further, miR-30a-5p overexpression significantly increased the cytotoxic effect of gemcitabine in pancreatic cancer by directly targeting CD73 messenger RNA (mRNA), suggesting that regulation of the miR-30a-5p/CD73 axis may play an important role in the development of gemcitabine resistance in pancreatic cancer. In summary, this regulatory network of CD73 appears to represent a new molecular mechanism underlying PDAC progression, and the mechanistic interaction between miR-30a-5p, CD73, and TNFR2 may provide new insights into therapeutic strategies for pancreatic cancer. Key messages: CD73 was upregulated in PDAC and correlated with poor prognosis. CD73 knockdown inhibited cell growth and induced G1 phase arrest. TNFR2 was involved in CD73-induced AKT and ERK signaling pathway. miR-30a-5p targeted CD73 and increased the sensitivity to gemcitabine. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies, and its global morbidity and mortality are increasing. Previous studies confirmed that miR-342 was involved in the development and progression of malignant tumors. However, the relationship between miR-342 and Wnt/ β -catenin signaling pathway in HCC remains unknown. MATERIALS AND METHODS: Cell viability was detected by MTT assay. Immunofluorescence staining was used to detect Brdu-positive cells and Western blot was used to detect the apoptotic proteins. Furthermore, linear correlation analysis was used to investigate the possible relationship between miR-342 and the downstream genes of Wnt/ β -catenin signaling pathway in the progression of HCC. RESULTS: Over-expression of miR-342 significantly reduced cell proliferation and obviously increased apoptosis in HCC, while silencing of miR-342 showed an opposite effect on HCC cell proliferation and apoptosis. In addition, we found that the CXCL12 was the target gene of miR-342. This study also demonstrated that miR-342 up-regulation suppressed Wnt/ β -catenin signaling pathway by inhibiting CXCL12 expression. CONCLUSION: Up-regulation of miR-342 inhibited cell proliferation and induced cell apoptosis in HCC by inhibiting Wnt/ β -catenin signaling pathway, suggesting that miR-342 might act as a promising tumor gene therapeutic target for HCC patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate a novel and convenient method of chemical treatment to modify the hydrophilicity of titanium surfaces. Sand-blasted and acid-etched (SLA) titanium surfaces and machined titanium surfaces were treated with sodium bicarbonate (NaHCO3) solution. The wetting behavior of both kinds of surfaces was measured by water contact angle (WCA) test. The surface microstructure was assessed with scanning electron microscopy (SEM) and three-dimensional (3D) optical microscopy. The elemental compositions of the surfaces were analyzed by X-ray photoelectron spectroscopy (XPS). The protein adsorption analysis was performed with fibronectin. Results showed that, after 1 M NaHCO3 treatment, the hydrophilicity of both SLA and machined surfaces was enhanced. No significant microstructural change presented on titanium surfaces after NaHCO3 treatment. The deprotonation and ion exchange activities might cause the enhanced hydrophilicity of titanium surfaces. The increased protein adsorption of NaHCO3-treated SLA surfaces might indicate their improved tissue-integration in clinical use. [ABSTRACT FROM AUTHOR]

With fast development of industry and agriculture in last two decades, land use changed greatly on specific soil types of intrinsic low quality with C loss potential and necessitates avoiding. Although researchers studied the effect of land-use changes on soil carbon storage, that on some soil types had rarely been reported, which led to relatively more C loss. We explored the impact of land-use changes and soil types on soil organic carbon (SOC) sequestration in the top 30 cm in the Tarim River Basin (the second largest inland river in the world) from 2000 to 2020. The land-use images with a one-kilometer spatial resolution and soil data from the Harmonized World Soil Database were analysed. The groundwater levels were monitored by 11 wells along the river from 2012 to 2017. Land-use changes were dominated by increases in the areas of cultivated land (1843–4099 km2) and woodland (5055–5433 km2) and decreases in grassland area (19076–12634 km2). The increase in cultivated land area was acquired from grassland (54%), woodland (32%) and unused land (14%), which was dominated by Phaeozems, Solonchaks and Fluvisols (84%). The converted land use to woodland was dominated by Fluvisols, Phaeozems, Arenosols and Solonchaks (98%). The converted land use from grassland to other land-use types was dominated by Arenosols, Fluvisols and Phaeozems (85%). The SOC was reduced by 9.83 Tg (+8.04 in cultivated land, +0.06 in woodland, −17.93 in grassland). The SOC stock change efficiency (SOCE kg C m−2) was SOC change divided by area change. The increase in SOC (Tg) of cultivated land was 5.04 from grassland (SOCE 3.76) and 2.9 from woodland (SOCE 3.68). The SOC of woodland increased by 8.66 Tg at cost of losing grassland (SOCE 3.35). Moreover, land-use changes affected local ecological environment. The cultivated land along the river increased 298 km2, and the desertification advanced towards oasis by decreasing 950 km2 of grassland in transition zone. The average groundwater table increased in the upstream (−3.12 to −2.33 m) and midstream regions (−1.84 to −1.71 m) monthly from 2012 to 2017 and in the downstream region (−7 to −2.84 m) annually from 2009 to 2017. This was attributed to expanded cultivated land and salt-washing cultivation on Solonchaks. In conclusion, the land-use conversion from grassland to woodland and cultivated land, mainly for Fluvisols, Phaeozems and Solonchaks, caused negative SOC storage, especially in riverbanks and oasis-desert transition zones facing climate change. [Display omitted] • The cultivated land and groundwater table increased with decreased grassland. • The Tarim River Basin was a SOC source with 9.83 Tg loss (2000–2020). • The grassland to woodland and cultivated land caused negative SOC storage. • The SOCE (SOC/area) of grassland to woodland was the lowest. • Soils under land-use changes were mainly from Phaeozem, Solonchak, Fluvisol, Arenosol. [ABSTRACT FROM AUTHOR]

Over-fertilization has a significant impact on soil microbial properties and its ecological environment. However, the effects of long-term fertilization on microbial properties on a large scale are still vague. This meta-analysis collected 6211 data points from 109 long-term experimental sites in China to evaluate the effects of fertilizer type and fertilization duration, as well as soil and climate conditions, on the effect sizes on various microbial properties and indices. The organic fertilizers combined with straw (NPKS) and manure (NPKM) had the highest effect sizes, while the chemical fertilizers N (sole N fertilizer) and NPK (NPK fertilizer) had the lowest. When compared with the control, NPKM treatment had the highest effect size, while N treatment had the lowest effect size on MBN (111% vs. 19%), PLFA (110% vs. −7%), fungi (88% vs. 43%), Actinomycetes (97% vs. 44%), urease (77% vs. 25%), catalase (15% vs. −11%), and phosphatase (58% vs. 4%). NPKM treatment had the highest while NPK treatment had the lowest effect size on bacteria (123% vs. 33%). NPKS treatment had the highest while N treatment had the lowest effect sizes on MBC (77% vs. 8%) and invertase (59% vs. 0.2%). NPKS treatment had the highest while NPK treatment had the lowest effect size on the Shannon index (5% vs. 1%). The effect sizes of NPKM treatment were the highest predominantly in arid regions because of the naturally low organic carbon in soils of these regions. The effect sizes on various microbial properties were also highly dependent on soil texture. In coarse-textured soils the effect sizes on MBC and MBN peaked sooner compared with those of clayey or silty soils, although various enzymes were most active in silty soils during the first 10 years of fertilization. Effect sizes on microbial properties were generally higher under NPKM and NPKS treatments than under NPK or N treatments, with considerable effects due to climate conditions. The optimal field fertilizer regime could be determined based on the effects of fertilizer type on soil microorganisms under various climate conditions and soil textures. This will contribute to the microbial biodiversity and soil health of agricultural land. Such controls should be used for adaptation of fertilization strategies to global changes. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is one of the most important and growing diseases globally and the leading cause of cardiovascular mortality in these patients. Taurine is an amino acid that has pleiotropic protective properties on some diseases. This study aimed to investigate the potential role of taurine in the treatment of diabetes-induced nephropathy. To achieve the aim of the present study, a comprehensive systematic search based on PRISMA guidelines has been conducted up to August 2021. A total of 382 articles were found in the electronic databases based on search keywords. After doing the screening, 14 articles were included in the present systematic review. The dated demonstrated elevation of oxidative stress, inflammatory and apoptotic pathways, and changes in other molecules' function plays an essential role in diabetes-induced renal tissue damage. Due to its multiple protective effects, taurine significantly prevented the activation of the pathways mentioned above and altered the function of molecules involved in these pathways, resulting in alleviating diabetic nephropathy. According to the obtained results, it was found that taurine can mitigate diabetes-induced nephropathy, mainly through its anti-oxidant activity, which is an essential factor in activating inflammation and apoptosis pathways. [ABSTRACT FROM AUTHOR]

• Small myofibrillar structural proteins degradation initiated fish softening. • More giant myofibrillar structural proteins degraded during later storage. • Desmin and titin contributed more to softening comparatively. Softening is always a problem in fish preservation. This study was aimed to investigate the role of myofibrillar structural proteins degradation in fish softening. The changes of myofibrillar structural proteins, muscle ultrastructure, myofibril fragmentation, and shear force were studied. The results indicated that during the superchilled preservation of grass carp (Ctenopharyngodon idella), small (low-molecular-weight) myofibrillar structural proteins like desmin and troponin-T initiated textural deterioration, leading to Z-disk weakening and actin loosening. In contrast, giant (high-molecular-weight) myofibrillar structural proteins like titin and nebulin were degraded in more amount in the later storage, contributing to Z-disk and M-band disassembly and vague of light and dark regions (I and A bands). Compared to each other, desmin and titin played more important part in softening. All these changes were involved in the increase of muscle fibril segments and the sharp decrease of shear force. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic metabolic disorder marked by hyperglycemia and systemic complications, including hepatic dysfunction, significantly contributing to disease progression and morbidity. This article reviews recent advances in gene-based therapeutic strategies targeting hepatic complications in diabetes, offering a promising approach for precision medicine by addressing underlying molecular mechanisms. Traditional treatments for hepatic complications in diabetes often manage symptoms rather than molecular causes, showing limited efficacy. Gene-based therapies are poised to correct dysfunctional pathways and restore hepatic function. Fundamental gene therapy approaches include gene silencing via small interfering RNAs (siRNAs) to target hepatic glucose production, lipid metabolism, and inflammation. Viral vectors can restore insulin sensitivity and reduce oxidative stress in diabetic livers. Genome editing, especially CRISPR-Cas9, allows the precise modification of disease-associated genes, offering immense potential for hepatic complication treatment. Strategies using CRISPR-Cas9 to enhance insulin receptor expression and modulate aberrant lipid regulatory genes are explored. Safety challenges in gene-based therapies, such as off-target effects and immune responses, are discussed. Advances in nanoparticle-based delivery systems and targeted gene editing techniques offer solutions to enhance specificity and minimize adverse effects. In conclusion, gene-based therapeutic approaches are a transformative direction in managing hepatic complications in diabetes. Further research is needed to optimize efficacy, safety, and long-term outcomes. Nevertheless, these innovative strategies promise to improve the lives of individuals with diabetes by addressing hepatic dysfunction's genetic root causes. • Gene-based therapies offer precise solutions for hepatic complications in diabetes by targeting molecular causes. • SiRNAs and viral vectors promise to manage hepatic issues by addressing glucose production and insulin sensitivity. • CRISPR-Cas9 allows precise modification of disease-associated genes for hepatic complication treatment. • The article discusses safety challenges, including off-target effects and immune responses, in gene-based therapies. • Nano-delivery and gene editing advancements target hepatic complications and minimizing adverse effects. [ABSTRACT FROM AUTHOR]

Interleukin-35 (IL-35) is a newly identified inhibitory cytokine. It has recently been found to play an extremely important role in chronic hepatitis B disease, which makes it likely to be a target for new therapies for hepatitis B malady. IL-35 modulates a variety of immune mechanisms to cause persistent viral infections, such as affecting the ratio of helper T cells, reducing the activity of cytotoxic T cells, hindering the antigen presentation capacity for dendritic cells, and increasing the transcription level of hepatitis B virus. On the other hand, IL-35 can control the inflammation caused by hepatitis B liver injury. Therefore, to seek a breakthrough in curing hepatitis B disease, the contradictory part of IL-35 in the occurrence and development of this sickness is worthy of further discussion and research. This article will systematically review the biological effects of IL-35 and the specific mechanisms affecting the disease. [ABSTRACT FROM AUTHOR]

Background: Interleukin (IL)-35 regulates imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, leading to an important modulator in autoimmune disorder, cancer, and infectious diseases. Our previous study revealed an immunosuppressive activity of IL-35 in chronic hepatitis B virus (HBV) infection. Thus, the aim of the current study was to investigate the role of regulatory function of IL-35 to viral specific Tregs/Th17 cells balance in chronic HBV infection. Methods: A total of 44 HLA-A2 restricted chronic HBV infected patients, including 21 of chronic hepatitis B (CHB) and 23 of asymptomatic HBV carriers (ASC) were enrolled. Purified CD4+ T cells or CD4+CD25+CD127dim/− Tregs were stimulated with recombinant IL-35. HBV core antigen specific Tregs and Th17 cells were determined by flow cytometry. FoxP3 and RORγt mRNA was measured by real-time PCR. Cytokines production (IL-10 and IL-17) was investigated by ELISA. Results: Peripheral viral specific Tregs was comparable between CHB and ASC. However, increased percentage of viral specific Th17 cells was found in CHB, leading to the reduction of Tregs/Th17 ratio in CHB patients. IL-35 stimulation elevated viral specific Tregs, but not Th17 cells frequency, in both CHB and ASC, resulting in the elevation of Tregs/Th17 ratio in both groups. This process was accompanied by increased expression of FoxP3 mRNA and IL-10 production, and decreased IL-17 secretion and STAT3 phosphorylation in purified CD4+ T cells. Moreover, IL-35 stimulation inhibited viral specific Th17-like phenotype differentiation from Tregs in CHB patients. Effective anti-HBV therapy did not affect viral specific Tregs/Th17 cells frequency or IL-35 expression in CHB patients, however, reduced responsiveness of CD4+ T cells or Tregs to IL-35 stimulation in vitro. Conclusion: Our findings indicated that IL-35 regulation to viral specific Tregs/Th17 balance may contribute to viral persistence in chronic HBV infection. [ABSTRACT FROM AUTHOR]

Purpose: The increased risk of colorectal cancer (CRC) associated with long-term use of proton pump inhibitors (PPIs) has attracted considerable attention; however, the conclusions of studies evaluating this correlation are inconsistent or even controversial. Therefore, we conducted a systematic review and meta-analysis to determine the association of PPI use with the risk of CRC. Methods: A systematic literature search was conducted in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials to identify relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for the associations between PPI use and the risk of CRC were estimated with a fixed-effects or random-effects model. Results: We identified and included 9 observational studies (3 cohort studies and 6 case-control studies) comprising 1,036,438 participants. Overall, there was no statistically significant association between PPI use and the risk of CRC (pooled OR 1.26, 95% CI: 0.90–1.73; p = 0.166) when PPI exposure was assessed as a binary variable. However, a weak association between long-term use of PPIs and CRC was demonstrated (pooled OR 1.19, 95% CI: 1.09–1.31; p < 0.001) when the cumulative duration of PPI exposure was confined to > 5 years. Conclusions: Although the present meta-analysis suggests a weak association between long-term use (> 5 years) of PPIs and CRC, there is not enough statistical power to refute or confirm an association between the use of PPIs and CRC. More high-quality prospective cohort studies are needed to assess this correlation. [ABSTRACT FROM AUTHOR]

Liver cancer is a disease with high mortality; it is often diagnosed at intermediate and advanced stages and has a high recurrence rate. ROS restriction and adequate energy supply play significant roles in liver cancer. SLC25A11, a member of the malate-aspartate shuttle (MAS), regulates electroneutral exchange between 2-oxoglutarate and other dicarboxylates. It transports glutathione (GSH) from the cytoplasm into mitochondria to maintain GSH levels to limit ROS production. Moreover, SLC25A11 is essential for ATP generation in cancers as it regulates NADH transportation from the cytoplasm to mitochondria. The purpose of this research was to investigate the prognostic value of SLC25A11 in liver cancer. The Cancer Genome Atlas database was used to analyze the levels of SLC25A11 in liver cancer. Fisher's exact and chi-square tests were used to evaluate the relationship between SLC25A11 expression and clinical characteristics. Finally, we explored the value of SLC25A11 in prognosis by Cox analysis and Kaplan-Meier curves. Our results revealed that SLC25A11 was downregulated in liver cancer compared to normal controls. Low expression of SLC25A11 was associated with clinical stage, vital status, histologic grade, overall survival (OS) and relapse-free survival (RFS). Liver cancer patients with low SLC25A11 expression had shorter OS and RFS than patients with high SLC25A11 expression. Multivariate analysis showed that the expression of SLC25A11 was an independent predictor of RFS and OS. In conclusion, this study identified that SLC25A11 serves as a new prognostic marker for liver cancer. [ABSTRACT FROM AUTHOR]

The management and treatment of disease are achieved via the use of pharmacologically active substances or drugs. Drugs do not, however, have an intrinsic ability to be effective; rather, how well they work depends on how they are administered or supplied. Treatment of a variety of biological illnesses, such as autoimmune disorders, cancer, and bacterial infections, requires effective drug delivery. Drug absorption, distribution, metabolism, duration of therapeutic impact, pharmacokinetics, excretion, and toxicity can all be impacted by drug administration. Improved chemistry and materials are required for the delivery of therapeutic concentration of novel treatments to the specified targets within the body, as well as for the necessary duration of time. This requirement is accompanied by the development of new therapeutics. Formulating a medication as a DDS is a promising strategy for directly addressing numerous typical barriers to adherence, such as frequent dosage, such as frequent dosage, side effects, and a delayed beginning of the action. In the current review, we give a compendium of drug delivery and controlled release and subsequently highlight some of the newest developments in the realm, with a particular emphasis on cutting-edge methods for targeted therapy. In each instance, we outline the obstacles to efficient drug administration as well as the chemical and material developments that are allowing the sector to overcome these obstacles and have a positive clinical impact. [Display omitted] • Drug delivery systems (DDSs) can improve therapeutic efficacy of drugs with reduced side effects. • Drug stability, release, and tissue/cell-specific targeting are challenging to anticipate. • Injectable materials localize the drug to the site of action, reducing off-target toxicity and improving clinical impact. • Intratumoral implantation reduced off-target effects and maximize therapeutic benefit. • Systemic RNA treats genetic disease by finding abnormal body regions and restoring their essential functions. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer stem cells (CSCs) promote pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and chemoresistance. Cyclin-dependent kinase 1 (CDK1) plays an important role in tumor initiation in other tumors, but the function of CDK1 in PDAC remains unclear. Fisetin is a bioactive flavonoid with anti-tumor properties in multiple tumors, while its function in CSCs remains elusive. Results: In this study, we demonstrated that CDK1 was correlated with prognosis and was highly expressed in pancreatic cancer tissue and gemcitabine-resistant cells. Silencing CDK1 impaired tumor stemness and reduced a subset of CSCs. We found that fisetin blocked the kinase pocket domain of CDK1 and inhibited pancreatic CSC characteristics. Using acetylation proteomics analysis and phosphorylation array assay, we confirmed that fisetin reduced CDK1 expression and increased CDK1 acetylation at lysine 33 (K33), which resulted in the suppression of CDK1 phosphorylation. Silencing CDK1 or STAT3 suppressed tumor stemness properties, while overexpressing CDK1 or STAT3 showed the opposite effect. Mutation or acetylation of CDK1 at K33 weakened STAT3 phosphorylation at Y705, impairing the expression of stem-related genes and pancreatic cancer stemness. In addition, lack of histone deacetylase 3 (HDAC3), which deacetylates CDK1, contributed to weakening STAT3 phosphorylation by regulating the post-translational modification of CDK1, thereby decreasing the stemness of PDAC. Moreover, our results revealed that fisetin enhanced the effect of gemcitabine through eliminating a subpopulation of pancreatic CSCs by inhibiting the CDK1–STAT3 axis in vitro and in vivo. Conclusion: Our findings highlight the role of post-translational modifications of CDK1–STAT3 signaling in maintaining cancer stemness of PDAC, and indicated that targeting the CDK1–STAT3 axis with inhibitors such as fisetin is a potential therapeutic strategy to diminish drug resistance and eliminate PDAC. [ABSTRACT FROM AUTHOR]

DNA damage repair is a major barrier for chemotherapy efficacy of pancreatic ductal adenocarcinoma (PDAC), including the efficacy of platinum-based and gemcitabine/nab-paclitaxel treatments. N6-methyladenosine modifications (m6A) have recently been reported to play a role in homologous recombination (HR) repair of DNA double strand breaks (DSBs); however, the mechanism of action remains unknown. Our previous work indicated that fisetin may be a promising anti-tumour agent that induces DNA damage. In this study, we reported that fisetin induced DSBs and suppressed HR repair through m6A modification in PDAC cells. The m6A writer ZC3H13 and PHF10, which is a subunit of the PBAF chromatin remodelling complex, were identified as the main molecules affected by fisetin treatment. To our knowledge, it's the first time that PHF10 was found and involved in the DNA damage response. PHF10 loss-of-function resulted in elevated recruitment of γH2AX, RAD51, and 53BP1 to DSB sites and decreased HR repair efficiency. Moreover, ZC3H13 knockdown downregulated the m6A methylation of PHF10 and decreased PHF10 translation in a YTHDF1-dependent manner. In conclusion, our study demonstrates that fisetin enhanced DSBs via ZC3Hl3-mediated m6A modification of PHF10, which may provide insight into novel therapeutic approaches for PDAC. [ABSTRACT FROM AUTHOR]

Fish texture is important for consumers and degradation of myofibrillar structural proteins could cause softening. However, the role of endogenous proteases in degrading was not clear. In this study, protease inhibitors (Ac-DEVD-CHO, E−64 and EDTA-2Na) were used to distinguish the role of endogenous caspase-3, cathepsin B and L, and calpain. Results showed that caspase-3 and calpain had relatively high activity at initial ice-storage and decreased quickly afterwards, while cathepsins increased firstly and then fluctuated. Titin, nebulin and troponin-T were partially degraded by caspase-3 firstly. However subsequently, only titin and troponin-T were affected by cathepsins and calpain. Desmin showed a different degradation pattern. It was influenced by calpain significantly but not by caspase-3. Less than 2.5% of desmin remained after storage. Myofibril fragmentation index and shear force indicated that caspase-3-induced degradation occurred at initial ice-storage, while cathepsins had the greatest importance in texture softening during the whole storage. • Role of endogenous caspase-3, cathepsins and calpain were specified in ice storage. • Caspase-3 initiated degradation of titin, nebulin and troponin-T in fish. • Calpain mainly degraded desmin and desmin remained lower than 2.5% finally. • Cathepsins contributed the most for the fish softening during whole ice storage. [ABSTRACT FROM AUTHOR]

• NKB cells was down-regulated in HCC. • NKB cells promoted cytotoxicity of CD8+ T cells via IL-18 secretion. • IL-35 down-regulated NKB cell percentage and IL-18 production. • IL-35 suppressed NKB cell-mediated CD8+ T cell cytotoxicity in HCC. Natural killer-like B (NKB) cells are newly identified lymphocyte subset, which present immunomodulatory property in infectious diseases through secretion of interleukin-18 (IL-18). However, the role of NKB cells function and its regulation in hepatocellular carcinoma (HCC) is not elucidated. Seventy-two HCC patients and twenty-five controls were enrolled. Peripheral and liver-infiltrating CD3-CD19+CD56+NKp46+ cells were investigated by flow cytometry. Serum IL-35 and NKB cell-secreting cytokine level was measured by ELISA. The regulatory activity of IL-35 to peripheral and liver-infiltrating NKB cells was assessed in direct co-culture system between CD8+ T cells and HepG2 cells. Peripheral NKB cells and IL-18 secretion were reduced in HCC patients, while liver-infiltrating NKB cells and IL-18 secretion were also decreased in HCC tumor sites. Increased IL-35 level was negatively correlated with NKB cell percentage and IL-18 production in HCC. NKB cells induced the elevation of CD8+ T cell cytotoxicty, and this enhancement could be inhibited by IL-18 binding protein. IL-35 stimulation dampened NKB cell percentage and IL-18 production, leading to the suppression of NKB cell-mediated CD8+ T cell cytotoxicity in HCC patients. Our current data revealed that IL-35 might suppress NKB cell activity in HCC patients. [ABSTRACT FROM AUTHOR]

A preterm infant with birth weight 1,550 g had an intravenous foreign body between the external iliac vein and the common iliac vein, which accidentally happened during peripheral intravascular central catheter insertion by the Seldinger technique. The infant initially received conservative management and close monitoring. Antibiotics were administered 4 weeks to treat culture positive sepsis and meningitis. The infant was clinically stable till the cannula fragment migrated to the heart 34 days later. At that time, his weight was 2,200 g, and he was full fed. The cannula fragment was retrieved by emergency interventional radiology via the right femoral access, with no complications. The infant was discharged at 45 days of age and closely followed up post-discharge. He is currently 6 months old, with normal development. This is the first case of successful percutaneous retrieval of an intracardiac intravenous cannula fragment via femoral access in a premature infant in China. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) has a poor prognosis due to the lack of effective molecular biomarkers for early diagnosis. Recent studies have investigated the use of exosomal microRNAs (exmiRs) as diagnostic biomarkers in cancer. The present study examined exmiR-21, exmiR-10b and exmiR-212-3p expression in patients with PC and healthy individuals. The expression levels of exmiR-21, exmiR-10b and exmiR-212-3p were examined in the peripheral blood plasma of 36 patients with PC and 65 healthy controls, using tethered cationic lipoplex nanoparticle biochip. The levels of exmiR-21 in the plasma of 34 mice were also evaluated. The expression levels of exmiR-21 and exmiR-10b were significantly greater in patients with PC compared with the control group. The receiver operating characteristic (ROC) analysis indicated that exmiR-21 had better diagnostic performance (P=0.0003; AUC, 0.7171) compared with the other two exmiRs. The diagnostic value of exmiR-21 improved when combined with exmiR-10b (P<0.0001; AUC, 0.791). Furthermore, exmiR-21 was capable of distinguishing patients with early-stage PC from controls and advanced-stage PC (P<0.05, early stage vs. healthy; P<0.001, early stage vs. advanced stage). The results of the present study revealed that the plasma levels of exmiR-21 and exmiR-10b were upregulated in patients with PC. The ROC analyses indicated that exmiR-21 had the best diagnostic performance among the three exmiRs. Furthermore, exmiR-21 was capable of discriminating patients with early-stage PC from healthy controls. These findings indicate the potential of determining the expression of exmiR-21 from serum using a tethered cationic lipoplex nanoparticle biochip as a novel non-invasive strategy for the early diagnosis of PC. [ABSTRACT FROM AUTHOR]

Interferon gamma (IFN-γ) is a dimeric soluble cytokine and the only type II interferon. Accumulated evidence suggests that IFN-γ inhibits tumor progression. This study investigated the effects of IFN-γ on the proliferation and migration of pancreatic cancer (PC) cells and the underlying mechanism. IFN-γ treatment decreased the expression and secretion of CXCL8 in BxPC-3 PC cells, suppressed the proliferation and migration of these cells, and enhanced their apoptosis, as determined by increased levels of cleaved Caspase-8 and Bax together with reduced expression of Bcl-2. These effects were abolished by overexpression of CXCL8. Moreover, IFN-γ treatment downregulated RhoGDI2 expression. Depletion of RhoGDI2 and Rac1 by using small interfering RNAs and inhibition of NF-κB by BMS-345541 (an IκB kinase [IKK] inhibitor) suppressed expression of CXCL8. Our results indicate that IFN-γ inhibits the proliferation and migration of PC cells by suppressing CXCL8 expression via a RhoGDI2/Rac1/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are membrane vesicles encapsulated by lipid membranes present in most body fluids. These EVs contain abundant biomolecular composition, including proteins, nucleic acids, lipids, metabolites, etc., and thus play an important role in intercellular communication. However, EVs are highly heterogeneous in terms of physical properties and biomolecular composition. Therefore, it is crucially important to study EV on single cell and single particle level for precise analysis and functional evaluation. Microfluidic platforms provide the possibility for single-cell EV analysis by integrating cell manipulation, EV enrichment, sensitive nucleic acid and protein detection together. In this review, we have summarized current status in single-cell EV and single EV particle study by microfluidic platform with advanced detection tools. The importance of single-cell EV on heterogeneity and future development are also discussed and prospected. • Microfluidic platform is explored for single cell isolation and EV capture. • Advances on analytical tools are summarized for single cell and single particle EV characterization and analysis. • The heterogeneity study on single-cell EV level is discussed and prospected. [ABSTRACT FROM AUTHOR]

Aims Puerarin is a phytoestrogen that shows osteogenic effects. Meanwhile, zinc stimulates bone formation and inhibits bone resorption. The study aims to investigate the effects of coadministration of puerarin (low dose) and zinc on bone formation in ovariectomized rats. Materials and methods Co-administration or use alone of puerarin (low dose) and/or zinc were gavaged in OVX rats. The estrogen-like effects were detected by the uterus weight, the histologic observation and the IGF-1 protein expression. The osteogenic effects were determined by bone histomorphometric and mechanical parameters, osteogenic and adipogenic blood markers, and so on. Key findings The results showed that oral administration of puerarin (low dose) plus zinc didn't significantly increase uterus weight. The glandular epithelial of endometrium had no proliferation and no protein expression of IGF-1. Moreover, co-administration attenuated bone loss and biomechanical decrease more than single use of puerarin or zinc ( p < 0.05). Next, combined administration of puerarin and zinc promoted the serological level of osteocalcin, bone marrow stromal cell (BMSC) proliferation, and the expression of alkaline phosphatase (ALP), and suppressed the serological level of adiponectin and adiposity in bone marrow (BM). Significance In conclusion, co-administrated puerarin (low dose) and zinc can partially reverse OVX-induced bone loss and suppress the adiposity of BM in rats, which shed light on the potential use of puerarin and zinc in the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

• Plasma and ascitic IL-35 was elevated in SBP. • Ascitic CD8+ T cells exhibited exhausted phenotype in SBP. • IL-35 suppressed cytotoxicity of ascitic CD8+ T cells. • IL-35 suppressed cytotoxic molecules expression in ascitic CD8+ T cells. • IL-35 promoted immune-checkpoint molecules expression in ascitic CD8+ T cells. Interleukin (IL) -35 induces immunotolerance by suppression of CD8+ T cells during chronic infections and cancers. In the present study, we amined to investigate the role of IL-35-mediated regulation of CD8+ T cells in patients with liver cirrhosis. Seventy-one patients with liver cirrhosis (46 patients with untainted ascites and 25 patients with spontaneous bacterial peritonitis [SBP]) and 22 controls were enrolled. Plasma and ascitic IL-35 levels were measured using ELISA. Peripheral and ascitic CD4+ and CD8+ T cells were purified to investigate their functional phenotypes. IL-35-stimulated CD8+ T cells were cultured with HepG2 cells in direct and indirect contact systems. Lactate dehydrogenase expression and cytokine secretion were measured to determine the cytotoxicity of CD8+ T cells. Plasma IL-35 was elevated in patients with liver cirrhosis, and ascitic IL-35 levels were higher in the SBP group than in the untainted ascites group. No significant differences in transcription factor expression or cytokine production in peripheral and ascitic CD4+ T cells were observed among groups. In the SBP group, ascitic CD8+ T cells expressed decreased cytotoxic molecules, along with the reduced secretion of interferon-γ and tumor necrosis factor-α when compared with the untainted ascites group. IL-35 stimulation suppressed ascitic CD8+ T cell cytotoxicity and cytokine production in both direct and indirect contact culture systems. This process was accompanied by decreased cytotoxic molecule expression and increased immune-checkpoint molecules in ascitic CD8+ T cells. The present findings revealed that overexpression of ascitic IL-35 dampened the cytotoxicity of CD8+ T cells in liver cirrhotic patients with SBP. [ABSTRACT FROM AUTHOR]