miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells.

JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Promotive effect of skin precursor-derived Schwann cells on brachial plexus neurotomy and motor neuron damage repair through milieu-regulating secretome.

Brachial plexus injury (BPI) with motor neurons (MNs) damage still remain poor recovery in preclinical research and clinical therapy, while cell-based therapy approaches emerged as novel strategies. Previous work of rat skin precursor-derived Schwann cells (SKP-SCs) provided substantial foundation for repairing peripheral nerve injury (PNI). Given that, our present work focused on exploring the repair efficacy and possible mechanisms of SKP-SCs implantation on rat BPI combined with neurorrhaphy post-neurotomy. Results indicated the significant locomotive and sensory function recovery, with improved morphological remodeling of regenerated nerves and angiogenesis, as well as amelioration of target muscles atrophy and motor endplate degeneration. Besides, MNs could restore from oxygen-glucose-deprivation (OGD) injury upon SKP-SCs-sourced secretome treatment, implying the underlying paracrine mechanisms. Moreover, rat cytokine array assay detected 67 cytokines from SKP-SC-secretome, and bioinformatic analyses of screened 32 cytokines presented multiple functional clusters covering diverse cell types, including inflammatory cells, Schwann cells, vascular endothelial cells (VECs), neurons, and SKP-SCs themselves, relating distinct biological processes to nerve regeneration. Especially, a panel of hypoxia-responsive cytokines (HRCK), can participate into multicellular biological process regulation for permissive regeneration milieu, which underscored the benefits of SKP-SCs and sourced secretome, facilitating the chorus of nerve regenerative microenvironment. Furthermore, platelet-derived growth factor-AA (PDGF-AA) and vascular endothelial growth factor-A (VEGF-A) were outstanding cytokines involved with nerve regenerative microenvironment regulating, with significantly elevated mRNA expression level in hypoxia-responsive SKP-SCs. Altogether, through recapitulating the implanted SKP-SCs and derived secretome as niche sensor and paracrine transmitters respectively, HRCK would be further excavated as molecular underpinning of the neural recuperative mechanizations for efficient cell therapy; meanwhile, the analysis paradigm in this study validated and anticipated the actions and mechanisms of SKP-SCs on traumatic BPI repair, and was beneficial to identify promising bioactive molecule cocktail and signaling targets for cell-free therapy strategy on neural repair and regeneration.

Anti-osteosarcoma trimodal synergistic therapy using NiFe-LDH and MXene nanocomposite for enhanced biocompatibility and efficacy.

Osteosarcoma is usually resistant to immunotherapy and, thus primarily relies on surgical resection and high-dosage chemotherapy. Unfortunately, less invasive or toxic therapies such as photothermal therapy (PTT) and chemodynamic therapy (CDT) generally failed to show satisfactory outcomes. Adequate multimodal therapies with proper safety profiles may provide better solutions for osteosarcoma. Herein, a simple nanocomposite that synergistically combines CDT, PTT, and chemotherapy for osteosarcoma treatment was fabricated. In this composite, small 2D NiFe-LDH flakes were processed into 3D hollow nanospheres via template methods to encapsulate 5-Fluorouracil (5-FU) with high loading capacity. The nanospheres were then adsorbed onto larger 2D Ti3C2 MXene monolayers and finally shielded by bovine serum albumin (BSA) to form 5-FU@NiFe-LDH/Ti3C2/BSA nanoplatforms (5NiTiB). Both in vitro and in vivo data demonstrated that the 5-FU induced chemotherapy, NiFe-LDH driven chemodynamic effects, and MXene-based photothermal killing collectively exhibited a synergistic "all-in-one" anti-tumor effect. 5NiTiB improved tumor suppression rate from <5% by 5-FU alone to ∼80.1%. This nanotherapeutic platform achieved higher therapeutic efficacy with a lower agent dose, thereby minimizing side effects. Moreover, the composite is simple to produce, enabling the fine-tuning of dosages to suit different requirements. Thus, the platform is versatile and efficient, with potential for further development.

Circulating immunotherapy strategy based on pyroptosis and STING pathway: Mn-loaded paclitaxel prodrug nanoplatform against tumor progression and metastasis.

Immunotherapy has emerged as a promising strategy against tumors. However, its efficacy is limited by low immunogenicity, poor antigen presentation, and inadequate lymphocyte infiltration. Herein, we develop a nanoplatform (Mn-HSP) loaded with manganese ions (Mn2+) and paclitaxel (PTX) prodrug based on hyaluronic acid. PTX in Mn-HSP induces DNA damage and pyroptosis to release tumor-associated antigens (TAAs), enhancing tumor-specific adaptive immunity. Meanwhile, Mn2+ in Mn-HSP, together with PTX-induced DNA damage, activates the stimulator of interferon gene (STING) pathway to amplify innate immunity. Mn-HSP combines with adaptive and innate immunity, effectively enhancing the presentation of antigen-presenting cells (APCs) and promoting tumor infiltration of cytotoxic T lymphocytes (CTLs). In turn, the granzyme B (GZMB) secreted by CTLs triggers pyroptosis again, thereby establishing a "circulating immunotherapy" against tumors. Our results demonstrate that Mn-HSP efficiently inhibits primary breast tumors, as well as rechallenge tumors and lung metastasis in vivo. Therefore, the circulating immunotherapy that combines pyroptosis mediated adaptive immunity and STING pathway amplified innate immunity provides a novel strategy for enhancing tumor immunotherapy.

Co-delivery of oxaliplatin prodrug liposomes with Bacillus Calmette-Guérin for chemo-immunotherapy of orthotopic bladder cancer.

To reduce recurrence rate after transurethral resection of bladder tumor, long-term intravesical instillations of Bacillus Calmette-Guérin (BCG) and/or chemotherapeutic drugs is the standard treatment for non-muscle invasive bladder carcinoma. However, the main challenges of intravesical therapy, such as short retention time and poor permeability of drugs in the bladder, often require frequent and high-dose administrations, leading to significant adverse effects and financial burden for patients. Aiming at addressing these challenges, we developed a novel approach, in which the cell-penetrating peptide modified oxaliplatin prodrug liposomes and a low-dose BCG were co-delivered via a viscous chitosan solution (LRO-BCG/CS). LRO-BCG/CS addressed these challenges by significantly improving the retention capability and permeability of chemotherapy agents across the bladder wall. Then, oxaliplatin triggered the immunogenic cell death, and the combination of BCG simultaneously further activated the systemic anti-tumor immune response in the MB49 orthotopic bladder tumor model. As a result, LRO-BCG/CS demonstrated superior anti-tumor efficacy and prolonged the survival time of tumor-bearing mice significantly, even at relatively low doses of oxaliplatin and BCG. Importantly, this combinational chemo-immunotherapy showed negligible side effects, offering a promising and well-tolerated therapeutic strategy for bladder cancer patients.

Bioequivalence study of dacomitinib and Vizimpro® in healthy Chinese volunteers under fasting and fed conditions: A randomized, open-label, single-dose, crossover trial.

This study aimed to evaluate the bioequivalence between test tablet dacomitinib and reference product Vizimpro® under fasting and fed conditions and assess their pharmacokinetic (PK) and safety profiles for gaining marketing approval of the new generic drug. A single-center, randomized, open-label, single-dose, two-treatment, two-period, crossover bioequivalence study was conducted in healthy Chinese subjects. Eligible healthy subjects randomly received a single 45 mg dose of test or reference formulations with an administration sequence of test tablet (T), reference tablet (R), or (RT), under both fasting and fed conditions, and each single administration was followed by a 21-day washout period. Plasma concentrations and corresponding non-compartmental PK parameters of dacomitinib were determined. The 90% confidence intervals of the geometric mean ratio (GMR) (test/reference) for Cmax , AUC0-t , and AUC0-∞ , respectively, were 97.75%-119.99%, 101.00%-115.09%, and 100.27%-113.90% under fasting conditions and 95.20%-104.94%, 97.24%-102.23%, and 97.27%-101.88% under fed conditions, which were within the limits of 80%-125%. Under fasting and fed conditions, the PK characteristics of the test dacomitinib tablet and reference Vizimpro® were comparable; the two formulations of dacomitinib were demonstrated to be bioequivalent and well-tolerated in healthy Chinese volunteers.

Hair and cord blood element levels and their relationship with air pollution, dietary intake, gestational diabetes mellitus, and infant neurodevelopment.

BACKGROUND & AIMS: Exposure to a range of elements, air pollution, and specific dietary components in pregnancy has variously been associated with gestational diabetes mellitus (GDM) risk or infant neurodevelopmental problems. We measured a range of pregnancy exposures in maternal hair and/or infant cord serum and tested their relationship to GDM and infant neurodevelopment. METHODS: A total of 843 pregnant women (GDM = 224, Non-GDM = 619) were selected from the Complex Lipids in Mothers and Babies cohort study. Forty-eight elements in hair and cord serum were quantified using inductively coupled plasma-mass spectrometry analysis. Binary logistic regression was used to estimate the associations between hair element concentrations and GDM risk, while multiple linear regression was performed to analyze the relationship between hair/cord serum elements and air pollutants, diet exposures, and Bayley Scales of infant neurodevelopment at 12 months of age. RESULTS: After adjusting for maternal age, BMI, and primiparity, we observed that fourteen elements in maternal hair were associated with a significantly increased risk of GDM, particularly Ta (OR = 9.49, 95% CI: 6.71, 13.42), Re (OR = 5.21, 95% CI: 3.84, 7.07), and Se (OR = 5.37, 95% CI: 3.48, 8.28). In the adjusted linear regression model, three elements (Rb, Er, and Tm) in maternal hair and infant cord serum were negatively associated with Mental Development Index scores. For dietary exposures, elements were positively associated with noodles (Nb), sweetened beverages (Rb), poultry (Cs), oils and condiments (Ca), and other seafood (Gd). In addition, air pollutants PM2.5 (LUR) and PM10 were negatively associated with Ta and Re in maternal hair. CONCLUSIONS: Our findings highlight the potential influence of maternal element exposure on GDM risk and infant neurodevelopment. We identified links between levels of these elements in both maternal hair and infant cord serum related to air pollutants and dietary factors.

High-accuracy positivity-preserving numerical method for Keller-Segel model.

The Keller-Segel model is a time-dependent nonlinear partial differential system, which couples a reaction-diffusion-chemotaxis equation with a reaction-diffusion equation; the former describes cell density, and the latter depicts the concentration of chemoattractants. This model plays a vital role in the simulation of the biological processes. In view of the fact that most of the proposed numerical methods for solving the model are low-accuracy in the temporal direction, we aim to derive a high-precision and stable compact difference scheme by using a finite difference method to solve this model. First, a fourth-order backward difference formula and compact difference operators are respectively employed to discretize the temporal and spatial derivative terms in this model, and a compact difference scheme with the space-time fourth-order accuracy is proposed. To keep the accuracy of its boundary with the same order as the main scheme, a Taylor series expansion formula with the Peano remainder is used to discretize the boundary conditions. Then, based on the new scheme, a multigrid algorithm and a positivity-preserving algorithm which can guarantee the fourth-order accuracy are established. Finally, the accuracy and reliability of the proposed method are verified by diverse numerical experiments. Particularly, the finite-time blow-up, non-negativity, mass conservation and energy dissipation are numerically simulated and analyzed.

A Review of Trends in Corrosion-Resistant Structural Steels Research-From Theoretical Simulation to Data-Driven Directions.

This paper provides a review of models commonly used over the years in the study of microscopic models of material corrosion mechanisms, data mining methods and the corrosion-resistant performance control of structural steels. The virtual process of material corrosion is combined with experimental data to reflect the microscopic mechanism of material corrosion from a nano-scale to macro-scale, respectively. Data mining methods focus on predicting and modeling the corrosion rate and corrosion life of materials. Data-driven control of the corrosion resistance of structural steels is achieved through micro-alloying and organization structure control technology. Corrosion modeling has been used to assess the effects of alloying elements, grain size and organization purity on corrosion resistance, and to determine the contents of alloying elements.

Loganin alleviated cognitive impairment in 3×Tg-AD mice through promoting mitophagy mediated by optineurin.

ETHNOPHARMACOLOGICAL RELEVANCE: Corni Fructus is a traditional Chinese herb and widely applied for treatment of age-related disorders in China. Iridoid glycoside was considered as the active ingredient of Corni Fructus. Loganin is one of the major iridoid glycosides and quality control components of Corni Fructus. Emerging evidence emphasized the beneficial effect of loganin on neurodegenerative disorders, such as Alzheimer's disease (AD). However, the detailed mechanism underlying the neuroprotective action of loganin remains to be unraveled. AIM OF THE STUDY: To explore the improvement of loganin on cognitive impairment in 3 × Tg-AD mice and reveal the potential mechanism. MATERIALS AND METHODS: Eight-month 3 × Tg-AD male mice were intraperitoneally injected with loganin (20 and 40 mg/kg) for consecutive 21 days. Behavioral tests were used to evaluated the cognition-enhancing effects of loganin, and Nissl staining and thioflavine S staining were performed to analyze neuronal survival and Aß pathology. Western blot analysis, transmission electron microscopy and immunofluorescence were utilized to explore the molecular mechanism of loganin in AD mice involved mitochondrial dynamics and mitophagy. Aß25-35-induced SH-SY5Y cells were applied to verify the potential mechanism in vitro. RESULTS: Loganin significantly mitigated the learning and memory deficit and amyloid ß-protein (Aß) deposition, and recovered synaptic ultrastructure in 3 × Tg-AD mice. Perturbed mitochondrial dynamics characterized by excessive fission and insufficient fusion were restored after loganin treatment. Meanwhile, loganin reversed the increase of mitophagy markers (LC3II, p62, PINK1 and Parkin) and mitochondrial markers (TOM20 and COXIV) in hippocampus of AD mice, and enhanced the location of optineurin (OPTN, a well-known mitophagy receptor) to mitochondria. Accumulated PINK1, Parkin, p62 and LC3II were also revealed in Aß25-35-induced SH-SY5Y cells, which were ameliorated by loganin. Increased OPTN in Aß25-35-treated SH-SY5Y cells was further upregulated by loganin incubation, along with the reduction of mitochondrial ROSand elevation ofmitochondrial membrane potential (MMP). Conversely, OPTN silence neutralized the effect of loganin on mitophagy and mitochondrial function, which is consistent with the finding that loganin presented strong affinity with OPTN measured by molecular docking in silico. CONCLUSIONS: Our observations confirmed that loganin enhanced cognitive function and alleviated AD pathology probably by promoting OPTN-mediated mitophagy,. Loganin might be a potential drug candidate for AD therapy via targeting mitophagy.

Myricetin improves pathological changes in 3×Tg-AD mice by regulating the mitochondria-NLRP3 inflammasome-microglia channel by targeting P38 MAPK signaling pathway.

BACKGROUND: Alzheimer's disease (AD) represents the common neurodegenerative disease featured by the manifestations of cognitive impairment and memory loss. AD could be alleviated with medication and improving quality of life. Clinical treatment of AD is mainly aimed at improving the cognitive function of patients. Donepezil, memantine and galantamine are commonly used drug. But they could only relieve AD, not cure it. Therefore, new treatment strategies focusing on AD pathogenesis are of great significance and value. Myricetin (Myr) is a natural flavonoid extracted from Myrica rubra. And it shows different bioactivities, such as anti-inflammation, antioxidation as well as central nervous system (CNS) activities. Nonetheless, its associated mechanism in treating AD remains unknown. PURPOSE: Here we focused on investigating Myr's effect on treating AD and exploring if its protection on the nervous system activity was associated with specifically inhibiting P38 MAPK signaling pathway while regulating mitochondria-NLRP3 inflammasome-microglia. STUDY DESIGN AND METHODS: This work utilized triple transgenic mice (3 × Tg-AD) as AD models and Aß25-35 was used to induce BV2 cells to build an in vitro AD model. Behavioristics, pathology and related inflammatory factors were examined. Molecular mechanisms are investigated by western-blot, immunofluorescence staining, CETSA, molecular docking, network pharmacology. RESULTS: According to our findings, Myr could remarkably improve memory loss, spatial learning ability, Aß plaque deposition, neuronal and synaptic damage in 3 × Tg-AD mice through specifically inhibiting P38 MAPK pathway activation while restraining microglial hyperactivation. Furthermore, Myr promoted the transformation of microglial phenotype, restored the mitochondrial fission-fusion balance, facilitated mitochondrial biogenesis, and restrained NLRP3 inflammasome activation and neuroinflammation. For the in-vitro experiments, P38 agonist dehydrocorydaline (DHC) was utilized to confirm the key regulatory role of P38 MAPK signaling pathway on the mitochondria-NLRP3 inflammasome-microglia channel. CONCLUSIONS: Our results revealed the therapeutic efficacy of Myr in experimental AD, and implied that the associated mechanism is possibly associated with inhibiting tmitochondrial dysfunction, activating NLRP3 inflammasome, and neuroinflammation which was mediated by P38 MAPK pathway. Myr is the drug candidate in AD therapy via targeting P38 MAPK pathway.

Research Progress of Traditional Chinese Medicine Monomers in Reversing Multidrug Resistance of Breast Cancer.

Breast cancer is a malignant disease with an increasing incidence. Chemotherapy is still an important means for breast cancer treatment, but multidrug resistance (MDR) greatly limits its clinical application. Therefore, the high-efficiency MDR reversal agents are urgently needed. Traditional Chinese medicine (TCM) monomers have unique advantages in reversing chemotherapeutic MDR because of its low toxicity, high efficiency, and ability to impact multiple targets. This review firstly summarizes the major mechanisms of MDR in breast cancer, including the reduced accumulation of intracellular chemotherapeutic drugs, the promoted inactivation of intracellular chemotherapeutic drugs, and the enhanced damage repair ability of DNA, etc., and secondly highlights the research progress of 15 kinds of TCM monomers, including curcumin, resveratrol, emodin, apigenin, tetrandrine, gambogic acid, matrine, paeonol, schisandrin B, [Formula: see text]-elemene, astragaloside IV, berberine, puerarin, tanshinone IIA, and quercetin, in reversing MDR of breast cancer. This review also provides the suggestion for the future research of MDR reversal agents in breast cancer.

Neuroprotective Effect of Phthalide Derivative CD21 against Ischemic Brain Injury:Involvement of MSR1 Mediated DAMP peroxiredoxin1 Clearance and TLR4 Signaling Inhibition.

The macrophage scavenger receptor 1 (MSR1)-induced resolution of neuroinflammation may be a novel therapeutic strategy for ischemic stroke. Our previous study showed that the neuroprotective and anti-inflammatory effects of phthalide are associated with the inhibition of the post-ischemic damage-associated molecular pattern (DAMP)/Toll-like receptor 4 (TLR4) pathway. This study investigated the effects of the phthalide derivative CD21 on ischemic brain injury and the mechanism underlying MSR1-induced resolution of neuroinflammation. Using a rat model of 2 h transient middle cerebral artery occlusion (MCAO), MSR1-induced peroxiredoxin1 (PRX1) clearance in RAW264.7 macrophages were investigated. We show here that CD21 significantly ameliorated infarct volumes and neurological deficits in a dose-dependent manner with a ≥ 12 h therapeutic time window. Moreover, administration of 5 mg/kg/day CD21 over 24 h significantly reduced pathological damages, with associated inhibition of PRX1 expression, reduced TLR4/nuclear factor-κB activation and the suppression of the inflammatory response in MCAO rats. Furthermore, the expression of MAFB/MSR1 in the ischemic brain was elevated and the phagocytosis of PRX1 in CD68-positive macrophages isolated from the ischemic brain was enhanced. Further in vitro studies show that CD21 (20 µM) strongly enhanced the Msr1 mRNA and MSR1 protein levers in RAW264.7 cells and PRX1 internalization in cellular lysosomes, which were significantly reversed by N-acetylcysteine treatment. These results suggest that CD21 may exert neuroprotective and anti-inflammatory effects with a wide time window for the treatment of ischemic stroke. The anti-stroke effects of CD21 appear to be mediated partially via the induction of MSR1-promoted DAMP (PRX1) clearance, TLR4/nuclear factor-κB pathway inhibition, and the resolution of inflammation. Graphical Abstract The neuroprotective action of CD21 was associated with the resolution of neuroinflammation through enhancement of the MAFB-MSR1 pathway that leads to DAMP (PRX1) phagocytosis and TLR4 pathway inhibition. Red solid arrows represent promotion, red dotted arrow represents the positive correlation, green arrows represent inhibition.

Microbiologically influenced corrosion of X80 pipeline steel by nitrate reducing bacteria in artificial Beijing soil.

In this work, we investigated microbiologically influenced corrosion (MIC) of X80 pipeline steel caused by nitrate-reducing bacteria Brevibacterium frigoritolerans (B. frigoritolerans) in an artificial Beijing soil using electrochemical measurements and surface analyses under aerobic conditions. The B. frigoritolerans was isolated from the surrounding soil of the X80 pipeline steel specimen in Beijing using culturing and molecular biology techniques. Confocal laser scanning microscopy images showed that the largest pit depth after 14 days due to B. frigoritolerans was approximately 7.16 µm. Electrochemical tests showed that the B. frigoritolerans could change the stability of the corrosion products on the 7th day. Inhomogeneous biofilm and the conductivity of Fe2O3 accelerated the corrosion process. The presence of NH4+ on the surface of the X80 pipeline steel revealed that the B. frigoritolerans acted as a biological cathode to promote the cathodic reaction.

Apocynin Attenuates Acute Kidney Injury and Inflammation in Rats with Acute Hypertriglyceridemic Pancreatitis.

BACKGROUND: Acute hypertriglyceridemic pancreatitis (HTGP) is more likely to be severe and complicated with extrapancreatic organ injury. NOX may be involved in the occurrence and development of high fat acute pancreatitis, but the specific mechanism is not clear. AIMS: To investigate the protective effects of apocynin, an inhibitor of NOX, on kidney injury associated with the HTGP and its potential mechanisms in a rat model. METHODS: In this study, HTGP rat model was induced by intraperitoneal injection of P-407 and L-Arg in combination. Apocynin was given by subcutaneously injection 30 min before the model was induced. The pancreatic and renal histopathology changes were analyzed. Serum AMY, BUN, Cr levels were measured by the Automatic Biochemistry Analyzer. The expression levels of protein associated with NOX/Akt pathway in the kidney were detected. ROS level in kidney and serum was measured by DHE staining and MDA, SOD kits, respectively. Serum TNF-α and IL-6 were detected by ELISA kits. RESULTS: In HTGP group, the levels of serum AMY, BUN, Cr, TNF- α, and IL-6 were significantly increased, and the injury of pancreas and kidney was aggravated. The levels of NOX4, NOX2, ROS, p-Akt, GSK-3ß, NF-κB, and TNF-α in the kidney were detected, suggesting that NOX may regulate the activity of downstream p-Akt and GSK-3ß by regulating ROS levels, thereby affecting the release of inflammatory mediators and regulating HTGP-related kidney injury. After application of apocynin, the expression of NOX4 and NOX2 and the level of ROS in the kidney were reduced, the release of inflammatory mediators decreased, and the histopathology injury of pancreas and kidney was improved obviously. CONCLUSION: NOX may play an important role in HTGP-associated kidney injury through Akt/GSK-3ß pathway. Apocynin can significantly downregulate the level of NOX and play a protective role in HTGP-related kidney injury through Akt/GSK-3ß pathway.

Double-edge Role of B Cells in Tumor Immunity: Potential Molecular Mechanism.

B cells are a heterogeneous population, which have distinct functions of antigen presentation, activating T cells, and secreting antibodies, cytokines as well as protease. It is supposed that the balance among these B cells subpopulation (resting B cells, activated B cells, Bregs, and other differentiated B cells) will determine the ultimate role of B cells in tumor immunity. There has been increasing evidence supporting opposite roles of B cells in tumor immunity, though there are no general acceptable phenotypes for them. Recent years, a new designated subset of B cells identified as Bregs has emerged from immunosuppressive and/or regulatory functions in tumor immune responses. Therefore, transferring activated B cells would be possible to become a promising strategy against tumor via conquering the immunosuppressive status of B cells in future. Understanding the potential mechanism of double-edge role of B cells will help researchers utilize activated B cells to improve their anti-tumor response. Moreover, the molecular pathways related to B cell differentiation are involved in its tumor-promoting effect, such as NF-κB, STAT3, BTK. So, we review the molecular and signaling pathway mechanisms of B cells involved in both tumor-promoting and tumor-suppressive immunity, in order to help researchers optimize B cells to fight cancer better.

Glycogen synthase kinase-3 beta inhibitors protectagainst the acute lung injuries resulting from acute necrotizing pancreatitis.

PURPOSE: The research is intended for clarification of the efficacy as well as the underlying mechanism of GSK-3ß inhibitors on the advancement of acute lung injuries in acute necrotizing pancreatitis (ANP) in rats. METHODS: Seventy-two rats were randomly divided into 6 groups: (1)ANP-vehicle; (2)ANP-TDZD-8;(3)ANP-SB216763;(4)Sham-vehicle;(5)Sham-TDZD-8;(6)Sham-SB216763; Blood biochemical test, histopathological examination and immunohistochemical analysis of rats pancreas and lung tissues were performed. The protein expression of GSK-3ß, phospho-GSK-3ß (Ser9), iNOS, ICAM-1, TNF-α, and IL-10 were detected in lung tissues by Western-blot. RESULTS: The outcomes revealed that the intervention of GSK-3ß inhibitors alleviated the pathological damage of pancreas and lung (P<0.01), reduced serum amylase, lipase, hydrothorax and lung Wet-to-Dry Ratio, attenuated serum concentrations of IL-1ß and IL-6 (P<0.01), inhibited the activation of NF-κB, and abated expression of iNOS, ICAM-1 and TNF-α protein, but up-regulated IL-10 expression in lung of ANP rats (P<0.01). The inflammatory response and various indicators in ANP-TDZD-8 groups were lower than those in ANP-SB216763 groups. CONCLUSIONS: Inhibition of GSK-3ß weakens acute lung injury related to ANP via the inhibitory function of NF-κB signaling pathway. Different kinds of GSK-3ß inhibitors have different effects to ANP acute lung injury.

Apocynin alleviates lung injury by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis.

Mounting evidence has demonstrated that acute pancreatitis (AP) is one of the causes of multiple organ damage. NADPH (nicotinamide adenine dinucleotide phosphate) act as a substrate of NADPH oxidase (NOX) to generate reactive oxygen species (ROS), but the role NADPH oxidase signaling pathway plays in AP-induced acute lung injury remains unclear. Apocynin, an inhibitor of NOX, is highly effective in suppressing the production of ROS. Here, we used rat model of severe acute pancreatitis (SAP) to explore whether the NOX inhibitor apocynin produced protective effects in against SAP-induced lung injury via inhibition of inflammation and oxidation. We observed that apocynin significantly attenuated severe acute pancreatitis-induced increase of NOX2, NOX4 and ROS expressions in lung tissues. In addition, the phosphorylation and degradation of IκBα, and the nuclear localization of NF-κB p65 in SAP-induced lung injury were also inhibited after using apocynin. Simultaneously, down-regulation of NOX suppressed the levels of inflammasome proteins including NLRP3, ASC, pro-Caspase-1 and cleaved-Caspase-1 in the lung. Serum levels of TNF-α, interleukin (IL)-1ß and IL-6 were also reduced. Our findings suggest that beyond anti-oxidative effects, apocynin may also have anti-inflammatory effects by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis. Therefore, apocynin may have therapeutic potential in the treatment of SAP and SAP-induced lung injury.

[Experimental study on the mechanism of glycogen synthase kinase-3ß inhibitor on acute kidney injury of acute necrotizing pancreatitis in rats].

OBJECTIVE: To explore the protective mechanism of glycogen synthase kinase-3ß (GSK-3ß) inhibitor TDZD-8 on acute necrotizing pancreatitis (ANP) associated kidney injury in rats. METHODS: SPF male Wistar rats were randomly divided into four groups (n = 20): sham operation group (Sham group), ANP model group, TDZD-8 intervention group and TDZD-8 control group. The rat ANP model was prepared by retrograde injection of 5% sodium taurocholate into the bile duct; the same volume of normal saline was injected into the pancreatic duct of the Sham group. The TDZD-8 intervention group and the TDZD-8 control group were injected with GSK-3ß inhibitor TDZD-8 (1 mL/kg) via the femoral vein 30 minutes before the model or sham operation; the ANP model group and the Sham group were injected equal volume of 10% dimethyl sulfoxide (DMSO). Rats in each group were sacrificed at 12 hours after operation to measure the serum amylase (AMY), blood lipase (LIPA), serum creatinine (SCr) and blood urea nitrogen (BUN) levels and to observe the pathological changes of pancreatic tissues and kidney tissues. Ultrastructural change of renal cells was analyzed by transmission electron microscopy. Serum interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) levels were evaluated by enzyme linked immunosorbent assay (ELISA). The activation of nuclear factor-ΚBp65 (NF-ΚBp65) was evaluated by immunohistochemistry assay. The protein expressions of GSK-3ß, phospho-GSK-3ß (Ser 9), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1) and interleukin-10 (IL-10) in the kidney were determined by Western Blot. RESULTS: Compared with the Sham group, the serum and inflammatory factors levels of the ANP model group were significantly increased, the pathological damage of the pancreas and kidney tissues were severe, the histopathological score was significantly increased, the expression of NF-ΚBp65 was enhanced in the nucleus of the kidney tissue, and the expressions of GSK-3ß, TNF-α, ICAM-1 and iNOS were significantly enhanced, and the expressions of p-GSK-3ß(Ser 9) and IL-10 were significantly attenuated. Compared with the ANP model group, TDZD-8 pretreatment significantly reduced serum and inflammatory factor levels in the ANP model group [AMY (kU/L): 5.60±0.30 vs. 10.07±0.34, LIPA (U/L): 1 111.0±110.8 vs. 2 375.0±51.1, SCr (µmol/L): 47.38±1.48 vs. 72.50±2.43, BUN (mmol/L): 17.6±1.0 vs. 26.0±1.0, IL-1ß (ng/L): 195.90±5.50 vs. 332.40±38.29, IL-6 (ng/L): 246.10±26.74 vs. 385.30±32.19, all P < 0.01]; pathological damage of pancreas and kidney tissue (histopathological score: 7.1±0.4 vs. 12.1±0.3, 301.2±7.5 vs. 433.5±13.8, both P < 0.01) and ultrastructural damage of renal cells were alleviated; the expression of NF-ΚBp65 in the nucleus was significantly decreased; the expression of p-GSK-3ß (Ser 9) was significantly increased, and blocking GSK-3ß activity could inhibit the expressions of TNF-α, ICAM-1, iNOS and increase the expression of IL-10, while the expression of GSK-3ß in renal tissues was not statistically significant. There were no significant differences between the TDZD-8 control group and the Sham group. CONCLUSIONS: Blockade of GSK-3ß activity by TDZD-8 exerts the protective effect against kidney injury by inhibiting the inflammation signaling pathway in ANP. It can alleviate histopathological and ultrastructural changes in kidney injury, which protection mechanism is mediated by NF-ΚB and its related inflammatory mediators.

LINC00052 functions as a tumor suppressor through negatively modulating miR-330-3p in pancreatic cancer.

Pancreatic cancer is a serious solid malignant tumor worldwide. Increasing evidence has pointed out that abnormal expressions of long noncoding RNAs are involved in various tumors. Meanwhile, LINC00052 is reported as a famous tumor regulator in several cancers. Nevertheless, the biological role of LINC00052 in pancreatic cancer progression is still unknown. Our study was to explore the specific mechanism of LINC00052 in pancreatic cancer. First, we observed that the LINC00052 was obviously downregulated in several pancreatic cancer cell lines. Overexpression of LINC00052 greatly repressed AsPC-1 and SW1990 cell proliferation, triggered the apoptosis and prevented cell cycle in the G1 phase. For another, AsPC-1 and SW1990 cell migration and invasion capacity were also obviously repressed by LINC00052 upregulation. Moreover, miR-330-3p was elevated in pancreatic cancer cells and can function as a target of LINC00052 confirmed by luciferase reporter and RNA Immunoprecipitation (RIP) experiments. Inhibition of miR-330-3p could depress pancreatic cancer progression while overexpressed miR-330-3p exhibited an opposite process. Finally, our data indicated that the LINC00052 also remarkably suppressed pancreatic tumor growth via modulating miR-330-3p in vivo. To conclude, our study revealed that the LINC00052 might provide a new perspective for pancreatic cancer therapy.