Effect of photodynamic therapy mediated by hematoporphyrin derivatives on small cell lung cancer H446 cells and bronchial epithelial BEAS-2B cells.

To investigate the effects of photodynamic therapy (PDT) mediated by hematoporphyrin derivatives (HPD) on the proliferation of small cell lung cancer H446 cells and bronchial epithelial BEAS-2B cells. H446 cells and BEAS-2B cells were cultured in vitro with different concentrations of HPD(0, 5, 10, 12, 15, 20 µg/mL) for 4 h, and then irradiated with 630 nm laser with different energy densities (0, 25, 50, 75, 100 mW/cm2). Cell viability of H446 cells and BEAS-2B cells were detected by CCK8 assay. The cell apoptosis was observed with Annexin V-FTTC/PI double staining and Hoechst 33258. The RT-PCR examination was applied to detect the transcriptional changes of the mRNA of Bax、Bcl-2, and Caspase-9. The results of CCK8 showed that when the HPD was 15 µg/mL and the laser power density reached 50 mW/cm2, the cell viability was significantly decreased compared with the black control group. Hoechst 33258 staining showed that with the increase of HPD concentration, the cell density was reduced, and apoptotic cells increased. Flow cytometry assay revealed that the apoptotic rates of the HPD-PDT group of H446 cells and BEAS-2B cells were significantly different from those of the blank control group. The RT-PCR examination showed that the expression levels of Bax and Caspase-9 mRNA in the HPD-PDT group were up-regulated, while the expression levels of Bcl-2 mRNA were down-regulated significantly. HPD-PDT can inhibit H446 cells and BEAS-2B cells growth. The mechanism may be related to up-regulating the expression levels of Bax and Caspase-9 mRNA and down-regulating the expression levels of Bcl-2 mRNA.

Effects of 630 nm laser on apoptosis, metastasis, invasion and epithelial-to-mesenchymal transition of human lung squamous cell carcinoma H520 cells mediated by hematoporphyrin derivatives.

Photodynamic therapy (PDT) has significant advantages in the treatment of malignant lung tumors. The research on the mechanism of PDT mediated by hematoporphyrin derivatives (HPD) and its cytotoxic effects on lung cancer cells has primarily focused on lung adenocarcinoma cells. However, the impact of HPD-PDT on lung squamous cell carcinoma has not been thoroughly studied. This study aimed to investigate the effects of 630 nm laser on apoptosis, metastasis, invasion, and epithelial-mesenchymal transition (EMT) in human lung squamous cell carcinoma H520 cells mediated by HPD. H520 cells were divided into four groups: control group, photosensitizer group, irradiation group, and HPD-PDT group. Cell proliferation was assessed using CCK8 assay; cell apoptosis was detected by Hoechst 33258 staining and flow cytometry; cell migration and invasion abilities were evaluated using wound-healing and invasion assays; and protein and mRNA expressions were analyzed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) respectively. Results showed that HPD-PDT significantly inhibited cell proliferation, promoted apoptosis (P < 0.05), suppressed cell migration and invasion (P < 0.05), decreased Bcl-2 mRNA expression, and increased Bax and Caspase-9 mRNA expression(P < 0.05). Western blotting analysis indicated increased expression of Bax, Caspase-9, and E-cadherin, and decreased expression of Bcl-2, N-cadherin, and Vimentin (P < 0.05). In conclusion, 630 nm laser mediated by HPD promoted cell apoptosis via upregulation of Bax and caspase-9, and downregulation of Bcl-2, and inhibited cell migration and invasion by regulating EMT in H520 cells.

Dephosphorylation of AMP-activated protein kinase exacerbates ischemia/reperfusion-induced acute kidney injury via mitochondrial dysfunction.

Kidney tubular epithelial cells are high energy-consuming epithelial cells that depend mainly on fatty acid oxidation for an energy supply. AMP-activated protein kinase (AMPK) is a key regulator of energy production in most cells, but the function of AMPK in tubular epithelial cells in acute kidney disease is unclear. Here, we found a rapid decrease in Thr172-AMPKα phosphorylation after ischemia/reperfusion in both in vivo and in vitro models. Mice with kidney tubular epithelial cell-specific AMPKα deletion exhibited exacerbated kidney impairment and apoptosis of tubular epithelial cells after ischemia/reperfusion. AMPKα deficiency was accompanied by the accumulation of lipid droplets in the kidney tubules and the elevation of ceramides and free fatty acid levels following ischemia/reperfusion injury. Mechanistically, ischemia/reperfusion triggered ceramide production and activated protein phosphatase PP2A, which dephosphorylated Thr172-AMPKα. Decreased AMPK activity repressed serine/threonine kinase ULK1-mediated autophagy and impeded clearance of the dysfunctional mitochondria. Targeting the PP2A-AMPK axis by the allosteric AMPK activator C24 restored fatty acid oxidation and reduced tubular cell apoptosis during ischemia/reperfusion-induced injury, by antagonizing PP2A dephosphorylation and promoting the mitophagy process. Thus, our study reveals that AMPKα plays an important role in protecting against tubular epithelial cell injury in ischemia/reperfusion-induced acute kidney injury. Hence, activation of AMPK could be a potential therapeutic strategy for acute kidney injury treatment.

Rhodomeroterpene alleviates macrophage infiltration and the inflammatory response in renal tissue to improve acute kidney injury.

Inflammation is broadly recognized as an important factor in the pathogenesis of acute kidney injury (AKI), but pharmacological approaches to alleviate inflammation in AKI have not been proved successful in clinical trials. Macrophage infiltration into renal tissue promotes inflammatory responses that contribute to the pathogenesis of AKI. Suppression of renal tissue inflammatory responses is postulated to improve renal injury of patients and animals. Rhodomeroterpene (RMT) is a novel meroterpenoid isolated from the Rhododendron genus that was shown to exert anti-inflammatory action in vivo or in vitro in this study. We investigated the treatment effects of RMT on LPS-induced sepsis and two different AKI models. The results showed that pretreatment with RMT (30 mg kg-1  d-1 , ip, for 3 days) significantly inhibited acute inflammatory responses in LPS-induced septic mice. In both renal ischemia-reperfusion injury (I/R) and sepsis-induced AKI models, RMT (30 mg kg-1  d-1 , ip, for 3 days) ameliorated renal function and injury and alleviated inflammation by reducing the infiltration of immune cells, including macrophages and neutrophils. Furthermore, our study demonstrated that RMT inhibits inflammatory responses in macrophages. The anti-inflammatory effects of RMT may be due to the inactivation of the IKK/NF-κB and PI3K/PDK1/Akt inflammatory signaling pathways in macrophages. Collectively, our findings indicate that RMT ameliorates renal injury and alleviates the renal inflammatory state in different AKI models, suggesting that RMT may be a potential agent for the treatment of AKI.

Sarsasapogenin improves adipose tissue inflammation and ameliorates insulin resistance in high-fat diet-fed C57BL/6J mice.

Insulin resistance is a major cause of type 2 diabetes and metabolic syndrome. Macrophage infiltration into obese adipose tissue promotes inflammatory responses that contribute to the pathogenesis of insulin resistance. Suppression of adipose tissue inflammatory responses is postulated to increase insulin sensitivity in obese patients and animals. Sarsasapogenin (ZGY) is one of the metabolites of timosaponin AIII in the gut, which has been shown to exert anti-inflammatory action. In this study, we investigated the effects of ZGY treatment on obesity-induced insulin resistance in mice. We showed that pretreatment with ZGY (80 mg·kg-1·d-1, ig, for 18 days) significantly inhibited acute adipose tissue inflammatory responses in LPS-treated mice. In high-fat diet (HFD)-fed obese mice, oral administration of ZGY (80 mg·kg-1·d-1, for 6 weeks) ameliorated insulin resistance and alleviated inflammation in adipose tissues by reducing the infiltration of macrophages. Furthermore, we demonstrated that ZGY not only directly inhibited inflammatory responses in macrophages and adipocytes, but also interrupts the crosstalk between macrophages and adipocytes in vitro, improving adipocyte insulin resistance. The insulin-sensitizing and anti-inflammatory effects of ZGY may result from inactivation of the IKK /NF-κB and JNK inflammatory signaling pathways in adipocytes. Collectively, our findings suggest that ZGY ameliorates insulin resistance and alleviates the adipose inflammatory state in HFD mice, suggesting that ZGY may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.

AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models.

Dyslipidemia is a chronic metabolic disease characterized by elevated levels of lipids in plasma. Recently, various studies demonstrate that the increased activity of adenosine 5'-monophosphate-activated protein kinase (AMPK) causes health benefits in energy regulation. Thus, great efforts have been made to develop AMPK activators as a metabolic syndrome treatment. In the present study, we investigated the effects of the AMPK activator C24 on dyslipidemia and the potential mechanisms. We showed that C24 (5-40 µM) dose-dependently increased the phosphorylation of AMPKα and acetyl-CoA carboxylase (ACC), and inhibited lipogenesis in HepG2 cells. Using compound C, an AMPK inhibitor, or hepatocytes isolated from liver tissue-specific AMPK knockout AMPKα1α2fl/fl;Alb-cre mice (AMPK LKO), we demonstrated that the lipogenesis inhibition of C24 was dependent on hepatic AMPK activation. In rabbits with high-fat and high-cholesterol diet-induced dyslipidemia, administration of C24 (20, 40, and 60 mg · kg-1· d-1, ig, for 4 weeks) dose-dependently decreased the content of TG, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in plasma and played a role in protecting against hepatic dysfunction by decreasing lipid accumulation. A lipid-lowering effect was also observed in high-fat and high-cholesterol diet-fed hamsters. In conclusion, our results demonstrate that the small molecular AMPK activator C24 alleviates hyperlipidemia and represents a promising compound for the development of a lipid-lowering drug.

Analysis of the short-term effect of photodynamic therapy on primary bronchial lung cancer.

To analyze the short-term clinical effect of photodynamic therapy on bronchial lung cancer and provide relevant practical experience for its better application in clinical practice. Twenty patients with bronchial lung cancer diagnosed by pathology were treated with photodynamic therapy or interventional tumor reduction combined with photodynamic therapy. Follow-up at 3 months after treatment, the chest CT and bronchoscopy were reexamined. The lesions were observed under a microscope, and the pathological specimens of living tissues were stained with HE and TUNEL to evaluate the short-term clinical effect. The volume of the tumor in the trachea or bronchus was smaller than before and the obstruction improved after the PDT from the chest CT. We could conclude that after PDT, the tumor volume was reduced and the pathological tissue appeared necrotic, the surface was pale, and the blood vessels were fewer while compared with before, and less likely to bleed when touched from the results of the bronchoscopy. HE staining showed that before treatment, there were a large number of tumor cells, closely arranged and disordered, or agglomerated and distributed unevenly. The cell morphology was not clear and the sizes were various with large and deeply stained nucleus, and the intercellular substance was less. After treatment, the number of tumor cells decreased significantly compared with before and the arrangement was relatively loose and orderly. The cells were roughly the same size; the intercellular substance increased obviously and showed uniform staining. The nuclei morphology was incomplete and fragmented, and tumor cells were evenly distributed among the intercellular substance. TUNEL staining showed that the number of cells was large and the nucleus morphology was regular before treatment; the nuclear membrane was clear and only a small number of apoptotic cells could be seen. However, the number of cells decreased and arranged loosely after treatment, with evenly stained cytoplasm. The nuclear morphology was irregular and the nuclear membrane cannot be seen clearly. Apoptotic cells with typical characteristics such as karyopyknosis, karyorrhexis, and karyolysis were common. Photodynamic therapy for bronchial lung cancer can achieve a satisfactory short-term clinical treatment effect and improve the life quality of patients, but the long-term clinical effect remains to be further studied.

The study of killing effect and inducing apoptosis of 630-nm laser on lung adenocarcinoma A549 cells mediated by hematoporphyrin derivatives in vitro.

To investigate the killing effect and inducing apoptosis of 630-nm laser mediated by hematoporphyrin derivatives (HPD) on human lung adenocarcinoma A549 cells. The human lung adenocarcinoma A549 cells were incubated at random with different concentrations of HPD (5, 10, 12, 15, 20 µg/ml) for 4 h and then illuminated by 630-nm laser with different energy densities (25, 50, 75, 100 mW/cm2). And, meanwhile, the simple photosensitizer group, laser irradiation group, and blank control group were established. Then, CCK8, Hoechst 33258 staining, RT-PCR, and Western blot were employed. HPD-PDT proved no killing effect on the lung adenocarcinoma A549 cells with photosensitizer or laser irradiation alone. With the combination, the killing effect was obvious. CCK8 showed that the A549 cell viability in 15 µg/ml and 20 µg/ml HPD group as well as 50 mW/cm2, 75 mW/cm2, and 100 mW/cm2 power density group decreased significantly compared with the control group. Hoechst 33258 staining showed that with the increase of HPD concentration, the cells presented chromatin fixation and hyperchromatic nuclei. The Annexin V-FITC/PI double staining was used to detect the apoptosis rate, and the difference was statistically significant. RT-PCR and Western blot showed that the expression of Caspase-3 and Bax were significantly up-regulated. However, the Bcl-2 and Survivin were significantly down-regulated in the HPD-PDT group, while those of the other three groups showed no significant changes. HPD-PDT has a significant effect on A549 cells. The mechanism of action may be related to the upregulation of the expression of Caspase-3, Bax, and downregulation of the expression of Bcl-2 and Survivin.

Exploring the Potential of HySpex Hyperspectral Imagery for Extraction of Copper Content.

Detritus geochemical information has been proven through research to be an effective prospecting method in mineral exploration. However, the traditional detritus metal content monitoring methods based on field sampling and laboratory chemical analysis are time-consuming and may not meet the requirements of large-scale metal content monitoring. In this study, we obtained 95 detritus samples and seven HySpex hyperspectral imagery scenes with a spatial resolution of 1 m from Karatag Gobi area, Xinjiang, China, and used partial least squares and wavebands selection methods to explore the usefulness of super-low-altitude HySpex hyperspectral images in estimating detritus feasibility and effectiveness of Cu element content. The results show that: (1) among all the inversion models of transformed spectra, power-logarithm transformation spectrum was the optimal prediction model (coefficient of determination(R2) = 0.586, mean absolute error(MAE) = 21.405); (2) compared to the genetic algorithm (GA) and continuous projection algorithm (SPA), the competitive weighted resampling algorithm (CARS) was the optimal feature band-screening method. The R2 of the inversion model was constructed based on the characteristic bands selected by CARS reaching 0.734, which was higher than that of GA (0.519) and SPA (0.691), and the MAE (19.926) was the lowest. Only 20 bands were used in the model construction, which is lower than that of GA (105) and SPA (42); (3) The power-logarithm transforms, and CARS combined with the model of HySpex hyperspectral images and the Cu content distribution in the study area were obtained, consistent with the actual survey results on the ground. Our results prove that the method incorporating the HySpex hyperspectral data to invert copper content in detritus is feasible and effective, and provides data and a reference method for obtaining geochemical element distribution in a large area and for reducing key areas of geological exploration in the future.

Alogliptin alleviates liver fibrosis via suppression of activated hepatic stellate cell.

Liver fibrosis occurs in most types of chronic liver diseases. The understanding of the pathogenesis of liver fibrosis has grown considerably, but the effective treatments are still lacking. Alogliptin, a classical Dipeptidyl peptidase-4 (DPP4) inhibitor with great effects on type 2 diabetes, has shown the potential to protect liver, but its effects on the progression of liver fibrosis have not been clarified. Herein, we explored the anti-fibrosis effects of alogliptin. In vitro, we demonstrated that alogliptin suppressed the activation of LX-2 upon transforming growth factor-ß (TGF-ß) challenge. In vivo, chronic treatment with alogliptin alleviated hepatic steatosis and protected from the liver injury in ob/ob mice, which delayed the progression of liver fibrosis. Furthermore, alogliptin significantly relieved the hepatic fibrosis in CCl4-induced liver fibrosis mouse model. In conclusion, our results demonstrate that negatively modulation of alogliptin on hepatic stellate cell (HSC) activation might contribute to liver fibrosis alleviation. Our research provides the potential possibility of alogliptin on the application for liver fibrosis therapy and suggests that DPP4 may be a novel target for liver fibrosis therapy.

LncRNA ATB promotes proliferation and metastasis in A549 cells by down-regulation of microRNA-494.

Lung cancer is a commonly diagnosed disease with poor prognosis. Novel therapeutic targets and deep understanding of the regulatory mechanisms in lung cancer are of great importance. We aimed to figure out the functional roles of lncRNA-activated by transforming growth factor-ß (ATB) in A549 cells as well as the underlying molecular mechanisms. ATB was non-physiologically expressed in A549 cells after cell transfection. Then, cell proliferation, expressions of proteins related to proliferation and epithelial-mesenchymal transition (EMT), migration, and invasion were measured by BrdU incorporation assay, Western blot analysis, and Transwell assay, respectively. Afterwards, miR-494 expression in transfected A549 cells was determined by quantitative reverse transcription PCR. Meanwhile, effects of miR-494 overexpression on ATB-overexpressed cells were assessed. Finally, the phosphorylation levels of AKT and key kinases in the Janus-activated kinase (JAK)/signal transducer and activator of transcription-3 (STAT3) pathway were detected by Western blot analysis. ATB overexpression promoted proliferation, migration, and invasion of A549 cells. Meanwhile, EMT of A549 cells was also enhanced. ATB silence showed the opposite influence. Expression of miR-494 was negatively regulated by ATB. Following experiments showed ATB-induced alterations of proliferation, migration, invasion, and EMT were all reversed by miR-494 overexpression. Finally, we proved that ATB increased phosphorylated levels of AKT, JAK1, and STAT3, and those increases were all reversed by miR-494 overexpression. We interestingly figured out that ATB promoted proliferation, migration, invasion, and EMT through down-regulating miR-494 in A549 cells. Moreover, ATB might activate AKT and the JAK/STAT3 pathway via down-regulating miR-494.

18ß-Glycyrrhetinic acid protects against alpha-naphthylisothiocyanate-induced cholestasis through activation of the Sirt1/FXR signaling pathway.

Cholestasis is a common feature of liver injury, which manifests as bile acid excretion and/or enterohepatic circulation disorders. However, very few effective therapies exist for cholestasis. Recently, 18ß-Glycyrrhetinic acid (18b-GA), a major metabolic component of glycyrrhizin, which is the main ingredient of licorice, was reported to protect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. However, its protective mechanism remains unclear. We hypothesized that 18b-GA may stimulate the signaling pathway of bile acid (BA) transportation in hepatocytes, resulting its hepatoprotective effect. According to the results, 18b-GA markedly attenuated ANIT-induced liver injury as indicated the hepatic plasma chemistry index and histopathology examination. In addition, the expression levels of nuclear factors, including Sirt1, FXR and Nrf2, and their target efflux transporters in the liver, which mainly mediate bile acid homeostasis in hepatocytes, significantly increased. Furthermore, we first revealed that 18b-GA treatment significantly activated FXR, and which can be significantly reduced by EX-527 (a potent and selective Sirt1 inhibitor), indicating that 18b-GA activates FXR through Sirt1. Taken together, 18b-GA confers hepatoprotection against ANIT-induced cholestasis by activating FXR through Sirt1, which promotes gene expression of the efflux transporter, and consequently attenuates dysregulation of bile acid homeostasis in hepatocyte compartments.

Novel substituted pyrazolone derivatives as AMP-activated protein kinase activators to inhibit lipid synthesis and reduce lipid accumulation in ob/ob mice.

Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized by hepatic steatosis. NAFLD is closely linked to obesity, insulin resistance and dyslipidemia. AMP-activated protein kinase (AMPK) functions as an energy sensor and plays a central role in regulating lipid metabolism. In this study, we identified a series of novel pyrazolone AMPK activators using a homogeneous time-resolved fluorescence assay (HTRF) based on the AMPKα2ß1γ1 complex. Compound 29 (C29) is a candidate compound that directly activated the kinase domain of AMPK with an EC50 value of 2.1-0.2 µmol/L and acted as a non-selective activator of AMPK complexes. Treatment of HepG2 cells with C29 (20, 40 µmol/L) dose-dependently inhibited triglyceride accumulation. Chronic administration of C29 (10, 30 mg/kg every day, po, for 5 weeks) significantly improved lipid metabolism in both the liver and the plasma of ob/ob mice. These results demonstrate that the AMPK activators could be part of a novel treatment approach for NAFLD and associated metabolic disorders.

Tailoring broadband acoustic energy suppression characteristics of double porosity metamaterials with compression constraints and mass inclusions.

A metamaterial that capitalizes on a double porosity architecture is introduced for controlling broadband acoustic energy suppression properties. When the metamaterial is subjected to static compressive stress, a global rotation of the internal metamaterial architecture is induced that softens the effective stiffness and results in a considerable means to tailor wave transmission and absorption properties. The influences of mass inclusions and compression constraints are examined by computational and experimental efforts. The results indicate that the mass inclusions and applied constraints can significantly impact the absorption and transmission properties of double porosity metamaterials, while the appropriate utilization of the underlying poroelastic media can further magnify these parametric influences. Based on the widespread implementation of compressed poroelastic media in applications, the results of this research uncover how internal metamaterial architecture and constraints may be exploited to enhance engineering noise control properties while using less poroelastic material mass.

Splicing factor NSSR1 reduces neuronal injury after mouse transient global cerebral ischemia.

This study focuses on the function of NSSR1, a splicing factor, in neuronal injury in the ischemic mouse brain using the transient global cerebral ischemic mouse model and the cultured cells treated with oxygen-glucose deprivation (OGD). The results showed that the cerebral ischemia triggers the expression of NSSR1 in hippocampal astrocytes, predominantly the dephosphorylated NSSR1 proteins, and the Exon3 inclusive NCAM-L1 variant and the Exon4 inclusive CREB variant. While in the hippocampus of astrocyte-specific NSSR1 conditional knockdown (cKD) mice, where cerebral ischemia no longer triggers NSSR1 expression in astrocytes, the expression of Exon3 inclusive NCAM-L1 variant and Exon4 inclusive CREB variant were no longer triggered as well. In addition, the injury of hippocampal neurons was more severe in astrocyte-specific NSSR1 cKD mice compared with in wild-type mice after brain ischemia. Of note, the culture media harvested from the astrocytes with overexpression of NSSR1 or the Exon3 inclusive NCAM-L1 variant, or Exon4 inclusive CREB variant were all able to reduce the neuronal injury induced by OGD. The results provide the evidence demonstrating that: (1) Splicing factor NSSR1 is a new factor involved in reducing ischemic injury. (2) Ischemia induces NSSR1 expression in astrocytes, not in neurons. (3) NSSR1-mediated pathway in astrocytes is required for reducing ischemic neuronal injury. (4) NCAM-L1 and CREB are probably mediators in NSSR1-mediated pathway. In conclusion, our results suggest for the first time that NSSR1 may provide a novel mechanism for reducing neuronal injury after ischemia, probably through regulation on alternative splicing of NCAM-L1 and CREB in astrocytes.

A real-world disproportionality analysis of Everolimus: data mining of the public version of FDA adverse event reporting system.

Background: Everolimus is an inhibitor of the mammalian target of rapamycin and is used to treat various tumors. The presented study aimed to evaluate the Everolimus-associated adverse events (AEs) through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: The AE records were selected by searching the FDA Adverse Event Reporting System database from the first quarter of 2009 to the first quarter of 2022. Potential adverse event signals were mined using the disproportionality analysis, including reporting odds ratio the proportional reporting ratio the Bayesian confidence propagation neural network and the empirical Bayes geometric mean and MedDRA was used to systematically classify the results. Results: A total of 24,575 AE reports of Everolimus were obtained using data from the FAERS database, and Everolimus-induced AEs occurrence targeted 24 system organ classes after conforming to the four algorithms simultaneously. The common significant SOCs were identified, included benign, malignant and unspecified neoplasms, reproductive system and breast disorders, etc. The significant AEs were then mapped to preferred terms such as stomatitis, pneumonitis and impaired insulin secretion, which have emerged in the study usually reported in patients with Everolimus. Of note, unexpected significant AEs, including biliary ischaemia, angiofibroma, and tuberous sclerosis complex were uncovered in the label. Conclusion: This study provided novel insights into the monitoring, surveillance, and management of adverse drug reaction associated with Everolimus. The outcome of serious adverse events and the corresponding detection signals, as well as the unexpected significant adverse events signals are worthy of attention in order to improving clinical medication safety during treatment of Everolimus.

A real-world disproportionality analysis of cyclosporine from the FDA Adverse Event Reporting System (FAERS) database.

Cyclosporine is an immunosuppressant used to prevent organ rejection in kidney, liver, and heart allogeneic transplants. This study aimed to assess the safety of cyclosporine through the analysis of adverse events (AEs) related to cyclosporine in the US Food and Drug Administration Adverse Event Reporting System (FAERS). To detect AEs associated with cyclosporine, a pharmacovigilance analysis was conducted using four algorithms on the FAERS database: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM). A statistical analysis was performed on data extracted from the FAERS database, covering 19,582 case reports spanning from 2013 to 2022. Among these cases, 3,911 AEs were identified, with 476 linked to cyclosporine as the primary suspected drug. Cyclosporin-induced AEs targeted 27 System Organ Classes (SOCs). Notably, the highest case at the SOC level included eye disorders, injury, poisoning, and procedural complications, as well as immune system disorders, all of which are listed on the cyclosporine label. Furthermore, we discovered novel potential AEs associated with hepatobiliary disorders, among others. Moreover, unexpected adverse drug reactions (ADRs), such as biliary anastomosis complication and spermatozoa progressive motility decrease, were identified. Importantly, these newly identified ADRs were not mentioned on the cyclosporine label, which were involved in injury, poisoning, and procedural complications, and investigations at the SOC level. The study used pharmacovigilance analysis of FAERS database to identify new and unexpected potential ADRs relating to cyclosporine, which can provide safety tips for the safe use of cyclosporine.

Research on the Performance and Modification Mechanism of Gutta-Percha-Modified Asphalt.

Presently, there is a significant focus on the investigation and advancement of polymer-modified asphalt that is both high-performing and environmentally sustainable. This study thoroughly examined the performance and modification mechanism of gutta-percha (GP) as a novel asphalt modifier. The investigation was conducted using a combination of macro- and microscopic testing, as well as molecular dynamics simulations. This work primarily examined the compatibility of GP with asphalt molecular modeling. This paper used molecular dynamics to identify the most suitable mixing temperature. Next, the gray correlation theory was used to discuss the most effective method for preparing gutta-percha-modified asphalt (GPMA). The macro-rheological tests and microscopic performance analysis provided a full understanding of the impact of GP on asphalt properties and the process of alteration. The findings indicate that eucommia ulmoides gum (EUG) exhibits good compatibility with asphalt, while sulfur-vulcanized eucommia ulmoides gum (SEUG) does not demonstrate compatibility with asphalt. Both EUG and SEUG enhance the thermal stability and resistance to deformation of asphalt at high temperatures, with SEUG having a particularly notable effect. However, both additives do not improve the resistance of asphalt to cracking at low temperatures. The manufacturing method for EUG-modified asphalt (EUGMA) involves physical mixing, whereas sulfur-vulcanized eucommia ulmoides gum-modified asphalt (SEUGMA) involves physical mixing together with certain chemical processes. This research establishes a theoretical foundation for the advancement of GP as a novel environmentally friendly and highly effective asphalt modification.

Sequence-dependent effects of hematoporphyrin derivatives (HPD) photodynamic therapy and cisplatin on lung adenocarcinoma cells.

BACKGROUND: Hematoporphyrin derivatives (HPD)-Photodynamic therapy (PDT) in combination with cisplatin (DDP) is an effective anticancer strategy. However, whether the order of combination affects efficacy has not been studied. METHODS: The human lung adenocarcinoma (LUAD) A549 cells were used as the study subjects. After A549 cells were treated with a single medication (PDT/DDP) or a sequential combination (PDT + DDP / DDP + PDT), the cell viability was assayed using the cell counting kit-8 method. Hoechst staining, Annexin-V/propidium iodide (PI) double staining, western blotting, and a real-time quantitative polymerase chain reaction (RT-qPCR) were performed to examine the mechanisms behind the combined effects. RESULTS: A synergistic impact between HPD-PDT and DDP was found. The cell viability in the PDT+DDP group was significantly lower than in the DDP+PDT group. A significant apoptotic profile and a high apoptotic rate were seen in the PDT + DDP group. The western blot showed that the expression levels of Bcl2-associated x(Bax) and cleaved-poly ADP-ribose polymerase (PARP) increased, and those of B-cell lymphoma-2 (Bcl-2) and Caspase-9 decreased in the PDT + DDP group. At the same time, the RT-qPCR revealed the upregulation of Bax and PARP mRNA and the downregulation of Bcl-2 and Caspase-9 mRNA. CONCLUSION: The order of the combination therapy (PDT + DDP / DDP + PDT) was important. The HPD-PDT followed by DDP significantly inhibited LUAD cell viability, which may be related to the mitochondrial apoptotic pathway.

Oral nifedipine may be a preferential option for treating acute severe hypertension during pregnancy: a meta-analysis.

AIM: To compare oral nifedipine and intravenous labetalol in the treatment of acute severe hypertension in pregnancy (SHP). METHODS: The primary outcomes were the required time to achieve target blood pressure (RTATBP), systolic blood pressure (SBP) and diastolic BP (DBP) after treatment, secondary outcomes were the number of doses (NoD) and adverse events (AEs). RESULTS: There was no difference between oral nifedipine and intravenous labetalol in SBP, DBP, and AE. However, oral nifedipine provided less RTATBP and NoD. CONCLUSION: Oral nifedipine was associated with less RTATBP and NoD and otherwise did not differ from intravenous labetalol.