Eldecalcitol ameliorates diabetic osteoporosis and glucolipid metabolic disorder by promoting Treg cell differentiation through SOCE.

Active vitamin D, known for its role in promoting osteoporosis, has immunomodulatory effects according to the latest evidence. Eldecalcitol (ED-71) is a representative of the third-generation novel active vitamin D analogs, and its specific immunological mechanisms in ameliorating diabetic osteoporosis remain unclear. We herein evaluated the therapeutic effects of ED-71 in the context of type 2 diabetes mellitus (T2DM), delving into its underlying mechanisms. In a T2DM mouse model, ED-71 attenuated bone loss and marrow adiposity. Simultaneously, it rectified imbalanced glucose homeostasis and dyslipidemia, ameliorated pancreatic ß-cell damage and hepatic glycolipid metabolism disorder. Subsequently, in mice injected with the Treg cell-depleting agent CD25, we observed that the beneficial effects of ED-71 mentioned earlier were partially contingent on the Treg subsets ratio. Mechanistically, ED-71 promoted the differentiation of CD4+ T cells into Treg subsets, facilitating Ca2+ influx and the expression of ORAI1 and STIM1, pivotal proteins in store-operated Ca2+ entry (SOCE). The SOCE inhibitor, 2-APB, partially attenuated the positive effects of ED-71 observed in the above results. Overall, ED-71 regulates SOCE-mediated Treg cell differentiation, accomplishing the dual purpose of simultaneously ameliorating diabetic osteoporosis and glucolipid metabolic disorders, showcasing its potential in osteoimmunity therapy and interventions for diseases involving SOCE.

Complications of ultrasound-guided thermal ablation of thyroid nodules and associated risk factors: an experience from 9667 cases.

OBJECTIVES: To evaluate the safety of ultrasound-guided thermal ablation (UGTA) for thyroid nodules (TNs) by analysing complications and related risks. MATERIALS AND METHODS: This retrospective, single-centre study reviewed patients who underwent UGTA (microwave or radiofrequency ablation) between January 2018 and March 2023. The incidence of complications was recorded and assessed during and immediately after ablation,1-3 h later, and at 1 month, 3 months, and 6 months. Univariate and multivariate analyses were performed to identify risk factors for hoarseness and haemorrhagic complications. RESULTS: We reviewed 9667 cases in this study. Overall, 4494 (46.49%) cases underwent microwave ablation, while 5173 (53.51%) cases underwent radiofrequency ablation. The overall complication rate was 4.43%. The incidence of major complications was 1.94% (haemorrhage, 1.32%; hoarseness, 0.54%; and symptomatic aseptic necrosis, 0.08%). The incidence of minor complications was 2.45%. A large nodule volume, radiofrequency ablation, hyper-enhancing nodules, benign nodules, higher preoperative blood pressure, hyperthyroidism, and higher ablation power were independent risk factors for haemorrhage. Dorsal nodules and a higher ablation power were independent risk factors for hoarseness. All complications were resolved. CONCLUSION: This study suggests that UGTA is a safe treatment for TNs. Several risk factors for haemorrhage and hoarseness should be considered before performing UGTA. Different ablation modalities should be considered for patients with different conditions. CLINICAL RELEVANCE STATEMENT: Thermal ablation may be a safe treatment for eligible patients with TNs. KEY POINTS: We analysed the complications and risk factors associated with UGTA in 9667 cases. The complication rate was 4.43%; 1.94% were major complications. Risk factors of haemorrhage and hoarseness should be considered. UGTA was a safe method for the treatment of TNs.

Tracking Carbon and Ammonia Emission Flows of China's Nitrogen Fertilizer System: Implications for Domestic and International Trade.

China is the world's largest producer, consumer, and exporter of synthetic nitrogen (N) fertilizer. To assess the impact of domestic demand and international exports, we quantified the life-cycle CO2eq and ammonia (NH3) emissions by tracking carbon (C) and nitrogen (N) flows from coal/gas mining through ammonia production to N fertilizer production, application, and export. In 2020, China's N fertilizer system emitted 496.04 Tg of CO2eq and 3.74 Tg of NH3, with ammonia production and N fertilizer application processes contributing 36 and 85% of the life-cycle CO2eq and NH3 emissions, respectively. As the largest importers of N fertilizer, India, Myanmar, South Korea, Malaysia, and the Philippines collectively shifted 112.41 Tg of CO2eq. For every ton of N fertilizer produced and used in China, 16 t of CO2eq and 0.18 t of NH3 were emitted, compared to 9.7 t of CO2eq and 0.13 t of NH3 in Europe. By adopting currently available technologies, improving N fertilizer utilization efficiency and employing nitrification inhibitors could synergistically reduce CO2eq emissions by 20% and NH3 emissions by 75%, while energy transformation efforts would primarily reduce CO2eq emissions by 59%. The production of ammonia using green electricity or green hydrogen could significantly enhance the decarbonization of China's N fertilizer system.

Capsaicin attenuates Porphyromonas gingivalis-suppressed osteogenesis of periodontal ligament stem cells via regulating mitochondrial function and activating PI3K/AKT/mTOR pathway.

BACKGROUND AND OBJECTIVE: Prevention of periodontal bone resorption triggered by Porphyromonas gingivalis (P. gingivalis) is crucial for dental stability. Capsaicin, known as the pungent ingredient of chili peppers, can activate key signaling molecules involved in osteogenic process. However, the effect of capsaicin on osteogenesis of periodontal ligament stem cells (PDLSCs) under inflammation remains elusive. METHODS: P. gingivalis culture suspension was added to mimic the inflammatory status after capsaicin pretreatment. The effects of capsaicin on the osteogenesis of PDLSCs, as well as mitochondrial morphology, Ca2+ level, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and osteogenesis-regulated protein expression levels were analyzed. Furthermore, a mouse experimental periodontitis model was established to evaluate the effect of capsaicin on alveolar bone resorption and the expression of osteogenesis-related proteins. RESULTS: Under P. gingivalis stimulation, capsaicin increased osteogenesis of PDLSCs. Not surprisingly, capsaicin rescued the damage to mitochondrial morphology, decreased the concentration of intracellular Ca2+ and ROS, enhanced MMP and activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. The in vivo results showed that capsaicin significantly attenuated alveolar bone loss and augmented the expression of bone associated proteins. CONCLUSION: Capsaicin increases osteogenesis of PDLSCs under inflammation and reduces alveolar bone resorption in mouse experimental periodontitis.

Reciprocal Relationship Between Learning Interest and Learning Persistence: Roles of Strategies for Self-Regulated Learning Behaviors and Academic Performance.

Learning interest (internal driving motivation) and learning persistence (explicit behaviors) are important factors affecting students' academic development, yet whether they operate reciprocally and how to bolster them are still issues requiring attention. This study aimed to examine the reciprocal relationship between learning interest and persistence as well as the potential mechanisms behind the relationship from the perspectives of internal self-regulation and external feedback (i.e., academic performance). 510 students (Mage = 13.71, SD = 1.77, 44.1% girls) were tracked for one year using questionnaires. Results showed that higher learning interest was linked to greater subsequent learning persistence and vice versa; and both predicted each other over time indirectly through academic performance and the multiple mediating paths from strategies for self-regulated learning behaviors to academic performance. Ancillary analysis verifies the robustness of these results. The findings not only provide evidence of a dynamic relationship between learning motivation and behaviors, highlighting the important role of positive performance feedback in leading to a benign cycle, but also contribute to understanding the potential avenue (i.e., teaching strategies for self-regulation) for optimizing student learning.

The histone acetyltransferase Mof regulates Runx2 and Osterix for osteoblast differentiation.

Osteoblast differentiation is regulated by various transcription factors, signaling molecules, and posttranslational modifiers. The histone acetyltransferase Mof (Kat8) is involved in distinct physiological processes. However, the exact role of Mof in osteoblast differentiation and growth remains unknown. Herein, we demonstrated that Mof expression with histone H4K16 acetylation increased during osteoblast differentiation. Inhibition of Mof by siRNA knockdown or small molecule inhibitor, MG149 which is a potent histone acetyltransferase inhibitor, reduced the expression level and transactivation potential of osteogenic key markers, Runx2 and Osterix, thus inhibiting osteoblast differentiation. Besides, Mof overexpression also enhanced the protein levels of Runx2 and Osterix. Mof could directly bind the promoter region of Runx2/Osterix to potentiate their mRNA levels, possibly through Mof-mediated H4K16ac to facilitate the activation of transcriptional programs. Importantly, Mof physically interacts with Runx2/Osterix for the stimulation of osteoblast differentiation. Yet, Mof knockdown showed indistinguishable effect on cell proliferation or apoptosis in MSCs and preosteoblast cells. Taken together, our results uncover Mof functioning as a novel regulator of osteoblast differentiation via the promotional effects on Runx2/Osterix and rationalize Mof as a potential therapeutic target, like possible application of inhibitor MG149 for the treatment of osteosarcoma or developing specific Mof activator to ameliorate osteoporosis.

Prediction of Drug-Drug Interactions with Ensartinib as a Time-Dependent CYP3A Inhibitor Using Physiologically Based Pharmacokinetic Model.

Ensartinib (X-396) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of ALK-positive patients with locally advanced or metastatic non-small cell lung cancer. Although in vitro experiments and molecular docking suggested its potential as a cytochrome P450 inhibitor, no further investigation or clinical trials have been conducted to assess its drug-drug interaction (DDI) risk. In this study, we conducted a series of in vitro experiments to elucidate the inhibition mechanism of ensartinib. Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed based on in vitro, in silico, and in vivo parameters, verified using clinical data, and applied to predict the clinical DDI mediated by ensartinib. The in vitro incubation experiments suggested that ensartinib exhibited strong time-dependent inhibition. Simulation results from the PBPK model indicated a significant increase in the exposure of CYP3A substrates in the presence of ensartinib, with the maximal plasma concentration and area under the plasma concentration-time curve increasing up to 12-fold and 29-fold for sensitive substrates. Based on these findings, it is evident that co-administration of ensartinib and CYP3A substrates requires careful regulatory consideration. SIGNIFICANCE STATEMENT: Ensartinib was found to be a strong time-dependent inhibitor of CYP3A for the first time based on in vitro experiments, but there was no research conducted to estimate the risk of drug-drug interaction (DDI) of ensartinib in clinic. Therefore, the first ensartinib physiologically based pharmacokinetic model was developed and applied to predict various untested scenarios. The simulation result indicated that the exposure of CYP3A substrate increased significantly and urged the further clinical DDI study.

Identification and evaluation of potential probiotics against skin-ulceration disease in the Chinese tongue sole (Cynoglossus semilaevis).

In this study, three highly pathogenic bacterial strains (Vibrio harveyi TB6, Vibrio alginolyticus TN1, and Vibrio parahaemolyticus TN3) were isolated from skin ulcers and intestines of diseased Chinese tongue sole (Cynoglossus semilaevis). The bacteria were investigated using hemolytic activity tests, in vitro co-culture with intestinal epithelial cells, and artificial infection of C. semilaevis. A further 126 strains were isolated from the intestines of healthy C. semilaevis. The three pathogens were used as indicator bacteria, and the antagonistic strains were identified from the 126 strains. The activities of exocrine digestive enzymes in the strains were also tested. Four strains with antibacterial and digestive enzyme activities were obtained and the best strains, Bacillus subtilis Y2 and Bacillus amyloliquefaciens Y9, were selected according to their ability to protect epithelial cells from infection. In addition, the effects of strains Y2 and Y9 at the individual level were investigated, finding that the activities of the immune-related enzymes superoxide dismutase, catalase, acid phosphatase, and peroxidase were significantly increased in the sera of the treatment group compared with the control group (p < 0.05). The specific growth rate (SGR, %) was also increased, especially in the Y2 group, and was significantly higher compared with the controls (p < 0.05). The result of the artificial infection test showed that the cumulative mortality within 72 h in the Y2 group was the lowest (50.5%), and in the Y9 group (68.5%) it was significantly lower than that in the control group (100%) (p < 0.05). Analysis of the intestinal microbial communities indicated that Y2 and Y9 could alter the composition of the intestinal flora, increasing both species richness and evenness, and inhibiting the growth of Vibrio in the intestine. These results suggested food supplemented with Y2 and Y9 could improve both immune function and disease resistance, as well as have a positive effect on the growth performance and the intestinal morphology of C. semilaevis.

Regulatory T cells showed characteristics of T helper-17(Th17) cells in mice periodontitis model.

OBJECTIVES: This study aimed to clarify the regulatory role of Th17-Treg balance in periodontitis and further reveal Treg plasticity. MATERIALS AND METHODS: An experimental periodontitis model was established by ligation and injection of Pg-LPS. Inflammatory factors were measured by ELISA and RT-PCR. Alveolar bone absorption was evaluated by micro-CT and histomorphology. Quantities of Treg and Th17 cell and their related gene expression were examined. Furthermore, after magnetic bead-sorting spleen Treg cells, Treg/Th17 characteristic genes were explored. Immunofluorescence double staining of Foxp3 and IL-17 was conducted to further reveal Treg plasticity. RESULTS: Inflammatory cytokines in serum and gingival tissue increased significantly in periodontitis, which revealed obvious crestal bone loss. Further analysis showed that the number of Th17 cells and expression of related genes increased more significantly than Treg cells, demonstrating Treg-Th17 imbalance. Flow cytometry showed that the proportions of Treg cells in the blood and spleen were lower in periodontitis group. Furthermore, Foxp3 was downregulated, and Rorc/ IL-17A were increased in Treg cells of periodontitis group. Immunofluorescence double staining showed significantly increased number of IL-17+Foxp3+ cells in periodontitis. CONCLUSIONS: These results provided evidence that Treg cells showed characteristics of Th17 cells in mice with periodontitis, although its mechanisms require further study.

Periostin regulates LPS-induced apoptosis via Nrf2/HO-1 pathway in periodontal ligament fibroblasts.

OBJECTIVE: Periostin is important for the maintenance of periodontal tissue, but its role in periodontitis is controversial. This research investigated the effect of periostin in periodontitis and the underlying mechanism. DESIGN: Mouse periodontitis models in vivo and inflammation model in vitro which were induced by Porphyromonas gingivalis lipopolysaccharide were established to evaluate periostin expression. Human periodontal ligament fibroblasts (PDLFs) were treated with lipopolysaccharide and N-acetylcysteine, fluorescence staining, flow cytometry, Western blot, and qRT-PCR were used to detect reactive oxygen species (ROS), periostin expression, and apoptosis-related makers. The periostin gene was successfully transfected into PDLFs to verify the effect of periostin on apoptosis. Then, the Nrf2 inhibitor was added to clarify the mechanism. RESULTS: Periostin expression decreased in the periodontal ligaments of mouse periodontitis models and lipopolysaccharide-induced PDLFs. Lipopolysaccharide promoted the activation of ROS and apoptosis in PDLFs, whereas N-acetylcysteine reversed this condition. Overexpression of periostin suppressed apoptosis of PDLFs and reversed the inhibitory effect of lipopolysaccharide on nuclear Nrf2 expression. Moreover, the Nrf2 inhibitor attenuated the protective effect of periostin on lipopolysaccharide-induced apoptosis. CONCLUSIONS: Lipopolysaccharide induced apoptosis in PDLFs by inhibiting periostin expression and thus Nrf2/HO-1 pathway, indicating that periostin could be a potential therapeutic target for periodontitis.

The IBA-ISMO Method for Rolling Bearing Fault Diagnosis Based on VMD-Sample Entropy.

Rolling bearings are important supporting components of large-scale electromechanical equipment. Once a fault occurs, it will cause economic losses, and serious accidents will affect personal safety. Therefore, research on rolling bearing fault diagnosis technology has important engineering practical significance. Feature extraction with high price density and fault identification are two keys to overcome in the field of fault diagnosis of rolling bearings. This study proposes a feature extraction method based on variational modal decomposition (VMD) and sample entropy and also designs an improved sequence minimization algorithm with optimal parameters to identify the fault. Firstly, a variational modal decomposition system based on vibration signals is designed, and the sample entropy of the components is extracted as the eigenvalue of the signal. Secondly, in order to improve the accuracy of fault diagnosis, the sequence minimum optimization algorithm optimized by the bat algorithm is used as the classifier. Certainly, the traditional bat algorithm (BA) and the sequence minimum optimization algorithm (SMO) are improved, respectively. Therefore, a fault diagnosis algorithm based on IBA-ISMO is obtained. Finally, the experimental verification is designed to prove that the algorithm model has a good state recognition rate for bearings.

Protective effects of interleukin-22 on oxalate-induced crystalline renal injury via alleviating mitochondrial damage and inflammatory response.

Oxalate-induced crystalline kidney injury is one of the most common types of crystalline nephropathy. Unfortunately, there is no effective treatment to reduce the deposition of calcium oxalate crystals and alleviate kidney damage. Thus, proactive therapeutic is urgently needed to alleviate the suffering it causes to patient. Here, we investigated whether IL-22 exerted nephroprotective effects to sodium oxalate-mediated kidney damage and its potential mechanism. Crystalline kidney injury models were developed in vitro and in vivo that was often observed in clinic. We provided evidence that IL-22 could effectively decrease the accumulation of ROS and mitochondrial damage in cell and animal models and reduce the death of TECs. Moreover, IL-22 decreased the expression of the NLRP3 inflammasome and mature IL-1ß in renal tissue induced by sodium oxalate. Further studies confirmed that IL-22 could play an anti-inflammatory role by reducing the levels of cytokines such as IL-1ß, IL-18, and TNF-α in serum. In conclusion, our study confirmed that IL-22 has protective effects on sodium oxalate-induced crystalline kidney injury by reducing the production of ROS, protecting mitochondrial membrane potential, and inhibiting the inflammatory response. Therefore, IL-22 may play a potential preventive role in sodium oxalate-induced acute renal injury. KEY POINTS: • IL-22 could reduce sodium oxalate-mediated cytotoxicity and ameliorate renal injury. • IL-22 could alleviate oxidative stress and mitochondrial dysfunction induced by sodium oxalate. • IL-22 could inhibit inflammatory response of renal injury caused by sodium oxalate.

Convolutional Long-Short Term Memory Network with Multi-Head Attention Mechanism for Traffic Flow Prediction.

Accurate predictive modeling of traffic flow is critically important as it allows transportation users to make wise decisions to circumvent traffic congestion regions. The advanced development of sensing technology makes big data more affordable and accessible, meaning that data-driven methods have been increasingly adopted for traffic flow prediction. Although numerous data-driven methods have been introduced for traffic flow predictions, existing data-driven methods cannot consider the correlation of the extracted high-dimensional features and cannot use the most relevant part of the traffic flow data to make predictions. To address these issues, this work proposes a decoder convolutional LSTM network, where the convolutional operation is used to consider the correlation of the high-dimensional features, and the LSTM network is used to consider the temporal correlation of traffic flow data. Moreover, the multi-head attention mechanism is introduced to use the most relevant portion of the traffic data to make predictions so that the prediction performance can be improved. A traffic flow dataset collected from the Caltrans Performance Measurement System (PeMS) database is used to demonstrate the effectiveness of the proposed method.

Novel Nitric Oxide Donor Dinitroazetidine-Coumarin Hybrids as Potent Anti-Intrahepatic Cholangiocarcinoma Agents.

Intrahepatic cholangiocarcinoma (iCC) is a serious liver cancer threatening human health. However, there are a few chemotherapeutic drugs for the treatment of iCC in the clinic. It is extremely urgent to develop new drugs for iCC. In this study, twenty dinitroazetidine and coumarin hybrids were synthesized and evaluated anti-iCC bioactivity as a new type of nitric oxide (NO) donors. Among them, compounds 2-5 and 21 showed a higher antiproliferative activity against RBE cell lines (human intrahepatic cholangiocarcinoma cell lines) and low cytotoxicity in nontumor cells (HOSEpiC and T29). The preliminary study of pharmacology mechanism indicated that compounds 2-5 and 21 could release effective concentration of NO in RBE cell lines, which leaded to inhibit the proliferation of RBE cell lines. The research results revealed that compound 3 inhibited the proliferation of RBE cell lines by inducing apoptosis and arresting cell cycle at G2/M phase. Additionally, compound 3 had acceptable metabolic stability. Therefore, compound 3 was merited to further explore for developing a desirable NO donor lead with anti-iCC activity.

Interaction mechanism of benzophenone-type UV filters on bovine serum albumin: Insights from structure-affinity relationship.

Benzophenone (BP)-type UV filters can cause structural changes of carrier protein in plasma. The binding process of five BP-type UV filters with bovine serum albumin (BSA) was investigated by multiple characterization methods, along with their structure-affinity relationship involving the structure of the five BP-type UV filters and their binding affinity for BSA. The BP-type UV filters investigated bound to BSA spontaneously, and altered conformation of BSA. The binding constants and number of binding sites between BP-type UV filters and BSA were 103-106 M-1 and 0.82-1.26, respectively. These BP-type UV filters and BSA interacted with the same binding forces and went through the similar binding process, suggesting that the benzophenone skeleton structure was primarily responsible for the BP-type UV filters and BSA binding, and changes in the structure of the BSA. The BP-type UV filters with hydroxyl substituent (BP-1 and BP-9) and non-polar molecules (BP-6) had a high affinity for binding BSA and had a greater impact on BSA conformation.

The value of transbronchial lung biopsy in the diagnosis of lymphangioleiomyomatosis.

BACKGROUND: Transbronchial lung biopsy (TBLB) in the diagnosis of lymphangioleiomyomatosis (LAM) is not a common approach, although TBLB is often performed in diffuse lung diseases. We aimed to examine the diagnostic value and safety of TBLB in LAM patients based on the data collected in our center. METHODS: We reviewed LAM patients registered in our LAM Clinic from December 8, 2006, to December 31, 2019. All patients with definite or probable diagnosis of LAM who had been examined using TBLB were included. All available pathology slides were reviewed by an experienced LAM pathologist. All complications were reviewed by the medical records and confirmed using telephone interviews. RESULTS: The pathology results of 86 patients (including 74 definite LAM and 12 probable LAM) were available. The positive rate of TBLB in LAM patients was 49/86 (57.0%). The positive rates of SMA, HMB-45, ER, and PR in LAM patients were 97.6%, 93%, 84.6%, and 78.4% respectively. The positive rate of TBLB was 40%, 60% and 60.8% in patients with CT Grade I, Grade II, and Grade III respectively, and the difference was not significant. Patients who had 3-4 or 5-6 biopsied specimens had a higher rate of diagnosis than those with 1-2 biopsied specimens. Four patients (5.6%) reported pneumothorax. No major hemoptysis was reported. CONCLUSIONS: TBLB is a feasible and safe procedure for obtaining a pathological diagnosis of LAM. Taking more than 2 samples during the biopsy procedure increased the rate of diagnosis.

AGGF1 inhibits the expression of inflammatory mediators and promotes angiogenesis in dental pulp cells.

OBJECTIVES: To determine the role of angiogenic factor with G-patch and FHA domain 1 (AGGF1) in inflammatory response of human dental pulp cells (DPCs) and the underneath mechanism and to explore its role in angiogenesis. MATERIALS AND METHODS: The expression of AGGF-1 in human healthy and inflammatory pulp tissues was detected by immunohistochemistry. RT-qPCR and Western blot were used to evaluate the expression of AGGF1 in DPCs stimulated by lipopolysaccharide (LPS). After AGGF1 was knocked down, the expression of LPS-induced inflammatory cytokines in DPCs was quantified by RT-qPCR and ELISA. Immunofluorescence and Western blot were used to assess the activation of NF-κB signaling. Inflammatory cytokines were detected by RT-qPCR and ELISA in DPCs pretreated with NF-κB pathway inhibitors before LPS stimulation, and then the effect of AGGF1 on angiogenesis was also evaluated. RESULTS: AGGF1 expression increased in inflammatory dental pulp tissues. In DPCs stimulated by LPS, AGGF1 was upregulated in a dose-dependent manner (P < 0.05). In AGGF1 knockdown cells, the expression of IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1/CCL-2) increased by LPS stimulation (P < 0.001). Nuclear translocation of p65 was promoted, and the addition of NF-κB inhibitors inhibited the expression of inflammatory factors. Meanwhile, knockdown of AGGF1 inhibited vascularization. CONCLUSIONS: AGGF1 inhibited the synthesis of inflammatory cytokines through NF-κB signaling pathway and promoted the angiogenesis of DPCs. CLINICAL RELEVANCE: This study might shed light in the treatment of pulpitis and regeneration of dental pulp tissues; however, more clinical trials are required to validate these findings.

Targeting PARP and autophagy evoked synergistic lethality in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), one of the most lethal malignancies worldwide, has limited efficient therapeutic options. Here, we first demonstrated that simultaneously targeting poly (ADP-ribose) polymerase (PARP) and autophagy could evoke striking synergistic lethality in HCC cells. Specifically, we found that the PARP inhibitor Niraparib induced cytotoxicity accompanied by significant autophagy formation and autophagic flux in HCC cells. Further experiments showed that Niraparib induced suppression of the Akt/mTOR pathway and activation of the Erk1/2 cascade, two typical signaling pathways related to autophagy. In addition, the accumulation of reactive oxygen species was triggered, which was involved in Niraparib-induced autophagy. Blocking autophagy by chloroquine (CQ) in combination with Niraparib further enhanced cytotoxicity, induced apoptosis and inhibited colony formation in HCC cells. Synergistic inhibition was also observed in Huh7 xenografts in vivo. Mechanistically, we showed that autophagy inhibition abrogated Niraparib-induced cell-cycle arrest and checkpoint activation. Cotreatment with CQ and Niraparib promoted the formation of γ-H2AX foci while inhibiting the recruitment of the homologous recombination repair protein RAD51 to double-strand break sites. Thus, the present study developed a novel promising strategy for the management of HCC in the clinic and highlighted a potential approach to expand the application of PARP inhibitors.

Interleukin-22 ameliorated acetaminophen-induced kidney injury by inhibiting mitochondrial dysfunction and inflammatory responses.

Acetaminophen (APAP) overdose can lead to acute, severe kidney injury, which has recently attracted considerable attention among researchers and clinicians. Unfortunately, there are no well-established treatments for APAP-induced renal injury, and the molecular mechanism of APAP-induced kidney injury is still unclear. Herein, we explored the protective effects of interleukin (IL)-22 on APAP-induced renal injury and the underlying molecular basis. We found that IL-22 could significantly alleviate the accumulation of reactive oxygen species (ROS) and ameliorate mitochondrial dysfunction, reducing APAP-induced renal tubular epithelial cell (TEC) death in vitro and in vivo. Furthermore, IL-22 could downregulate the APAP-induced NLRP3 inflammasome activation and mature IL-1ß release in kidney injury. Additionally, the APAP-mediated upregulation of the serum levels of IL-18, TNF-α, IL-6, and IL-1ß was obviously decreased, suggesting IL-22 has inhibitory effects on inflammatory responses. Conclusively, our study demonstrated that IL-22 exerted ameliorative effects on APAP-induced kidney injury by alleviating mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that IL-22 represents a potential therapeutic approach to treat APAP-induced kidney injury. KEY POINTS: • IL-22 could ameliorate APAP that triggered oxidative stress and mitochondrial dysfunction. • IL-22 could reduce APAP that caused inflammatory responses. Graphical abstract.

Evaluation of the Impacts of Formulation Parameters on the Pharmacokinetics and Bioequivalence of Risperidone Orodispersible Film: a Physiologically Based Pharmacokinetic Modeling Approach.

The purpose of this study was to investigate the impacts of the formulation parameters on the pharmacokinetics and bioequivalence of risperidone orodispersible film (ODF) using physiologically based pharmacokinetic model. The pharmacokinetic profiles of two risperidone ODFs, which exhibit different in vitro dissolution, were examined in Beagle dogs after supralingual administration. Subsequently, a physiologically based pharmacokinetic (PBPK) model was constructed to evaluate the in vivo performance of risperidone ODF. The parameter sensitivity analysis (PSA) was used to access the impacts of formulation parameters on the pharmacokinetics of risperidone. Moreover, the validated PBPK model was applied to predict human pharmacokinetic profiles and examine the bioequivalence of these two ODFs. These two ODFs displayed similar risperidone pharmacokinetic profiles in dogs. The parameter sensitivity analysis indicated that the changes in the solubility, particle size, particle density, and diffusion coefficient did not have obvious influence on the in vivo properties of risperidone ODF. Alternation of the in vitro complete dissolution time in water from 15 to 30 min led to a 30% decrease in Cmax and 20% of increase in Tmax. AUC0-∞ would be decreased if risperidone was not fully released within 1 h. As both ODFs completely released risperidone within 15 min, the difference in the extent of in vivo absorption, intestinal regional absorption location, and plasma concentration-time curves between these two ODFs was almost negligible. Consequently, a bioequivalence was foreseen in humans. The in vitro cumulative dissolution percentage in water at 15 min was found to be the major determinant on the in vivo properties of risperidone ODF. PBPK modeling appears to be an innovative strategy to guide the development of risperidone ODF.