Melatonin prevents EAAC1 deletion-induced retinal ganglion cell degeneration by inhibiting apoptosis and senescence.

Normal tension glaucoma (NTG) is referred to as a progressive degenerative disorder of the retinal ganglion cells (RGCs), resulting in nonreversible visual defects, despite intraocular pressure levels within the statistically normal range. Current therapeutic strategies for NTG yield limited benefits. Excitatory amino acid carrier 1 (EAAC1) knockout (EAAC1-/- ) in mice has been shown to induce RGC degeneration without elevating intraocular pressure, mimicking pathological characteristics of NTG. In this study, we explored whether daily oral administration of melatonin could block RGCs loss and prevent retinal morphology and function defects associated with EAAC1 deletion. We also explored the molecular mechanisms underlying EAAC1 deletion-induced RGC degeneration and the neuroprotective effects of melatonin. Our RNA sequencing and in vivo data indicated EAAC1 deletion caused elevated oxidative stress, activation of apoptosis and cellular senescence pathways, and neuroinflammation in RGCs. However, melatonin administration efficiently prevented these detrimental effects. Furthermore, we investigated the potential role of apoptosis- and senescence-related redox-sensitive factors in EAAC1 deletion-induced RGCs degeneration and the neuroprotective effects of melatonin administration. We observed remarkable upregulation of p53, whereas NRF2 and Sirt1 expression were significantly decreased in EAAC1-/- mice, which were prevented by melatonin treatment, suggesting that melatonin exerted its neuroprotective effects possibly through modulating NRF2/p53/Sirt1 redox-sensitive signaling pathways. Overall, our study provided a solid foundation for the application of melatonin in the management of NTG.

Values of OAS gene family in the expression signature, immune cell infiltration and prognosis of human bladder cancer.

BACKGROUND: Bladder cancer (BLCA) is one of the most common genitourinary malignancies in the world, but its pathogenic genes have not been fully identified and the treatment outcomes are still unsatisfactory. Although the members of 2', 5'-oligoadenylate synthetase (OAS) gene family are known involved in some tumorous biological processes, the roles of the OAS gene family in BLCA are still undetermined. METHODS: By combining vast bioinformatic datasets analyses of BLCA and the experimental verification on clinical BLCA specimen, we identified the expressions and biological functions of OAS gene family members in BLCA with comparison to normal bladder tissues. RESULTS: The expression levels of OAS gene family members were higher in BLCA than in normal bladder tissues. The expression levels of most OAS genes had correlations with genomic mutation and methylation, and with the infiltration levels of CD4 + T cells, CD8 + T cells, neutrophils, and dendritic cells in the microenvironment of BLCA. In addition, high expressions of OAS1, OAS2, OAS3, and OASL predicted better overall survival in BLCA patients. CONCLUSIONS: The highly expressed OAS genes in BLCA can reflect immune cells infiltration in the tumor microenvironment and predict the better overall survival of BLCA, and thus may be considered as a signature of BLCA. The study provides new insights into the diagnosis, treatment, and prognosis of BLCA.

Anti-PANoptosis is involved in neuroprotective effects of melatonin in acute ocular hypertension model.

Acute ocular hypertension (AOH) is the most important characteristic of acute glaucoma, which can lead to retinal ganglion cell (RGC) death and permanent vision loss. So far, approved effective therapy is still lacking in acute glaucoma. PANoptosis (pyroptosis, apoptosis, and necroptosis), which consists of three key modes of programmed cell death-apoptosis, necroptosis, and pyroptosis-may contribute to AOH-induced RGC death. Previous studies have demonstrated that melatonin (N-acetyl-5-methoxytryptamine) exerts a neuroprotective effect in many retinal degenerative diseases. However, whether melatonin is anti-PANoptotic and neuroprotective in the progression of acute glaucoma remains unclear. Thus, this study aimed to explore the role of melatonin in AOH retinas and its underlying mechanisms. The results showed that melatonin treatment attenuated the loss of ganglion cell complex thickness, retinal nerve fiber layer thickness, and RGC after AOH injury, and improved the amplitudes of a-wave, b-wave, and oscillatory potentials in the electroretinogram. Additionally, the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells was decreased, and the upregulation of cleaved caspase-8, cleaved caspase-3, Bax, and Bad and downregulation of Bcl-2 and p-Bad were inhibited after melatonin administration. Meanwhile, both the expression and activation of MLKL, RIP1, and RIP3, along with the number of PI-positive cells, were reduced in melatonin-treated mice, and p-RIP3 was in both RGC and microglia/macrophage after AOH injury. Furthermore, melatonin reduced the expression of NLRP3, ASC, cleaved caspase-1, gasdermin D (GSDMD), and cleaved GSDMD, and decreased the number of Iba1/interleukin-1ß-positive cells. In conclusion, melatonin ameliorated retinal structure, prevented retinal dysfunction after AOH, and exerted a neuroprotective effect via inhibition of PANoptosis in AOH retinas.

Compositions and Biological Activities of Pomegranate Peel Polyphenols Extracted by Different Solvents.

Pomegranate peel extract (PPE), which is abundant in polyphenols, holds immerse prospects for the treatment of airway infection. In this study, water and ethanol of 30%, 50%, and 80% were used to prepare PPE. A total of 18 phenols belonging to 8 categories of polyphenols were identified in PPE by HPLC-MS/MS. The PPE from the four extraction solvents possessed different antioxidant, antibacterial, and anti-inflammatory activities. Principal component analysis revealed that though total flavonoids (TFs), total polyphenols (TPs), and total tannins (TTs) were responsible for the reducing power of PPE, only TFs contributed to the effect of PPE in inhibiting lipid membrane peroxidation. TPs, TTs, and punicalagin were positively correlated with the antibacterial strength against S. aureus while TTs alone contributed to the inhibition of methicillin-resistant S. aureus, implying the crucial role of TT in suppressing bacteria. Meanwhile, TTs was associated with the prevention of IL-6 release. The PPE with higher contents of TPs, TTs, and punicalagin had a weaker capacity to decrease nitric oxide secretion. PPE of 30% ethanol gained the highest integrated score due to its stronger antioxidant, antibacterial, and anti-inflammatory activities. It is a suitable candidate for the therapy of respiratory tract infection.

Precision hyperthermia-induced miRNA-409-3p upregulation inhibits migration, invasion, and EMT of gastric cancer cells by targeting KLF17.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is widely used for clinical treatment of advanced cancers. However, the regulatory mechanism underlying precise hyperthermia treatment in advanced gastric cancer (AGC) remains unclear. MiR-409-3p is reportedly downregulated in a variety of cancers, although its role in regulating treatment of AGC by precise hyperthermia remains unclear. The underlying mechanisms of miRNA-medicated regulation have been investigated using predicted and validated miRNA-gene targets, confirming the role of miRNA in HIPEC; METHODS: We used quantitative real time PCR (qRT-PCR) to detect miR-409-3p expression in gastric cancer (GC), as well as adjacent normal tissues, following exposure to varying temperatures. We detected miR-409-3p targets using dual-luciferase assay, then performed cell apoptosis, western blotting, invasion, and migration assays to detect GC functions; RESULTS: MiR-409-3p was upregulated and downregulated in precise hyperthermia and AGC, respectively. Moreover, miR-409-3p upregulated the Krüppel-like-factor 17 (KLF17), which subsequently inhibited migration, invasiveness, and epithelial-mesenchymal transition (EMT) but promoted apoptosis in GC cells; CONCLUSIONS: Precise hyperthermia upregulated miR-409-3p and KLF17 indirectly, thereby inhibiting invasion, migration, and EMT, and promoting apoptosis of gastric cancer cells.

Upregulation of α enolase (ENO1) crotonylation in colorectal cancer and its promoting effect on cancer cell metastasis.

Lysine crotonylation (Kcr) is a newly identified protein translational modification and is involved in major biological processes including glycolysis, but its role in colorectal cancer (CRC) is unknown. Here, we found that the Kcr of α enolase (ENO1) was significantly elevated in human CRC tissues compared with the paratumoral tissues. CREB-binding protein (CBP) functioned as a crotonyltranferase of ENO1, and SIRT2 was involved in the decrotonylation of ENO1. Using quantitative mass spectrometry for crotonylomics analysis, we further found that K420 was the main Kcr site of ENO1 and ENO1 K420 Kcr promoted the growth, migration, and invasion of CRC cells in vitro by enhancing the activity of ENO1 and regulating the expression of tumor-associated genes. Our study reveals an important mechanism by which ENO1 regulates CRC through crotonylation.

Impact of time of flight and point spread function on quantitative parameters of lung lesions in 18F-FDG PET/CT.

BACKGROUND: Image reconstruction algorithm is one of the important factors affecting the quantitative parameters of PET/CT. The purpose of this study was to investigate the effects of time of flight (TOF) and point spread function (PSF) on quantitative parameters of lung lesions in 18F-FDG PET/CT. METHODS: This retrospective study evaluated 60 lung lesions in 39 patients who had undergone 18F-fluoro-deoxy-glucose (FDG) PET/CT. All lesions larger than 10 mm in diameter were included in the study. The PET data were reconstructed with a baseline ordered-subsets expectation-maximization (OSEM) algorithm, OSEM + PSF, OSEM + TOF and OSEM + TOF + PSF respectively. The differences of maximum standard uptake value (SUVmax), mean standard uptake value (SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG)and signal to noise ratio (SNR)were compared among different reconstruction algorithms. RESULTS: Compared with OSEM reconstruction, using OSEM + TOF + PSF increased SUVmean and SUVmax by 23.73% and 22.71% respectively, and SNR increased by 70.18%, MTV decreased by 23.84% (p < 0.01). The percentage difference was significantly higher in smaller lesions (diameter 10-22 mm) than in larger lesions (diameter 23-44 mm), and significantly higher in low contrast lesions (SNR ≤ 15.31) than in high contrast lesions (SNR > 15.31). The difference of TLG among various reconstruction algorithms is relatively small, the highest value is - 6.48% of OSEM + TOF + PSF, and the lowest value is 0.81% of OSEM + TOF. CONCLUSION: TOF and PSF significantly affected the quantitative parameters of lung lesions in 18F-FDG PET/CT. OSEM + TOF + PSF can significantly increased SUVmax, SUVmean and SNR, and significantly reduce MTV, especially in small lesions and low contrast lesions. TLG can be relatively stable in different reconstruction algorithms.

Systems pharmacology reveals the mechanism of activity of Physalis alkekengi L. var. franchetii against lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI) is an important cause of mortality of patients with sepsis, shock, trauma, pneumonia, multiple transfusions and pancreatitis. Physalis alkekengi L. var. franchetii (Mast.) Makino (PAF) has been extensively used in Chinese folk medicine because of a good therapeutic effect in respiratory diseases. Here, an integrated approach combining network pharmacology, proton nuclear magnetic resonance-based metabolomics, histopathological analysis and biochemical assays was used to elucidate the mechanism of PAF against ALI induced by lipopolysaccharide (LPS) in a mouse model. We found that the compounds present in PAF interact with 32 targets to effectively improve the damage in the lung undergoing ALI. We predicted the putative signalling pathway involved by using the network pharmacology and then used the orthogonal signal correction partial least-squares discriminant analysis to analyse the disturbances in the serum metabolome in mouse. We also used ELISA, RT-qPCR, Western blotting, immunohistochemistry and TUNEL assay to confirm the potential signalling pathways involved. We found that PAF reduced the release of cytokines, such as TNF-α, and the accumulation of oxidation products; decreased the levels of NF-κB, p-p38, ERK, JNK, p53, caspase-3 and COX-2; and enhanced the translocation of Nrf2 from the cytoplasm to the nucleus. Collectively, PAF significantly reduced oxidative stress injury and inflammation, at the same time correcting the energy metabolism imbalance caused by ALI, increasing the amount of antioxidant-related metabolites and reducing the apoptosis of lung cells. These observations suggest that PAF may be an effective candidate preparation alleviating ALI.

Safety-by-Design of Metal Oxide Nanoparticles Based on the Regulation of their Energy Edges.

The safety of metal oxide (MOx) nanoparticles (NPs) has been highly concerned because of their wide application and potential toxicological injury. The safe-by-design strategy is usually developed to make safer MOx NPs based on regulation of their physicochemical properties. In the present study, manganese oxide (Mn3 O4 ) NPs, as a representative of insoluble toxic MOx NPs, are doped with a series of transition metal to regulate their conduction band energy (Ec ) out of biological redox potential range (BRPR) or Fermi energy (Ef ) far away from valence band energy (Ev ), aiming at completely eliminating the toxicity or significantly reducing the toxicity. It is found that all these M-doping cannot move Ec of Mn3 O4 NPs out of the BRPR but zinc (Zn)-, copper (Cu)-, and chromium (Cr)-doping do move Ef far away from Ev , where Zn-doping results in the largest |Ef - Ev | value. Various abiotic, in vitro and in vivo assessments reveal that Zn-, Cu-, and Cr-doped Mn3 O4 NPs can generate lower amount of •OH and trigger weaker injury than Mn3 O4 NPs, where Zn-doped Mn3 O4 NPs show the lowest toxicity. Regulating Ef far away from Ev becomes a feasible safe-by-design approach to achieve safe MOx NPs.

Serum anion gap at admission predicts all-cause mortality in critically ill patients with cerebral infarction: evidence from the MIMIC-III database.

BACKGROUND: Recent studies reported that serum anion gap could be regarded as a prognostic biomarker for patients admitted to intensive care units. However, the association between AG and mortality in cerebral infarction patients remained largely unknown. METHODS: Relevant clinical data were collected from Medical Information Mart for Intensive Care III. Patients were divided into three groups according to tertiles of AG. Kaplan-Meier curve and Cox proportional hazards models were used to evaluate the association between AG levels and all-cause mortality. Subgroup analyses were performed to verify the predictive role of AG on mortality. RESULTS: Kaplan-Meier analysis showed that patients with higher AG had shorter survival time. Cox regression model indicated high AG as an independent risk factor of 30-day, 60-day and 180-day all-cause mortality (30-day: HR = 2.45, 95% CI = 1.21-4.97, 60-day: HR = 2.04, 95% CI = 1.07-3.89, and 180-day: HR = 1.85, 95% CI = 1.02-3.36). However, no significance was observed between AG and 365-day all-cause mortality (HR = 1.56, 95% CI = 0.87-2.78). CONCLUSIONS: High AG was associated with increased risk of all-cause mortality, and AG could be an independent short-term prognostic factor for cerebral infarction.

Electron Compensation Effect Suppressed Silver Ion Release and Contributed Safety of Au@Ag Core-Shell Nanoparticles.

Silver nanoparticles (Ag NPs) have promising plasmonic properties, however, they are rarely used in biomedical applications because of their potent toxicity. Herein, an electron compensation effect from Au to Ag was applied to design safe Au@Ag core-shell NPs. The Ag shell thickness was precisely regulated to enable the most efficient electron enrichment in Ag shell of Au@Ag2.4 NPs, preventing Ag oxidation and subsequent Ag+ ion release. X-ray photoelectron spectroscopy and X-ray absorption near-edge structure analysis revealed the electron transfer process from Au core to Ag shell, and inductively coupled plasma optical emission spectroscopy analysis confirmed the low Ag+ ion release from Au@Ag2.4 NPs. Bare Au@Ag2.4 NPs showed much lower toxicological responses than Ag NPs in BEAS-2B and Raw 264.7 cells and acute lung inflammation mouse models, and PEGylation of Au@Ag2.4 NPs could further improve their safety to L02 and HEK293T cells as well as mice through intravenous injection. Further, diethylthiatri carbocyanine iodide attached pAu@Ag2.4 NPs exhibited intense surface-enhanced Raman scattering signals and were used for Raman imaging of MCF7 cells and Raman biosensing in MCF7 tumor-bearing mice. This electron compensation effect opens up new opportunity for broadening biomedical application of Ag-based NPs.

Nitric Oxide Stimulated Programmable Drug Release of Nanosystem for Multidrug Resistance Cancer Therapy.

Nitric oxide (NO) molecular messenger can reverse the multidrug resistance (MDR) effect of cancer cells through reducing P-glycoprotein (P-gp) expression, beneficial for creating a favorable microenvironment for the treatment of doxorubicin (Dox)-resistant cancer cells. Development of sophisticated nanosystems to programmably release NO and Dox becomes an efficient strategy to overcome the MDR obstacles and achieve promising therapeutic effects in Dox-resistant cancer. Herein, a NO stimulated nanosystem was designed to engineer a significant time gap between NO and Dox release, promoting MDR cancer therapy. A o-phenylenediamine-containing lipid that can hydrolyze in response to NO was embedded in the phospholipid bilayer structure of liposome to form NO-responsive liposome, which could further encapsulate l-arginine (l-Arg)/Dox-loaded gold@copper sulfide yolk-shell nanoparticls (ADAu@CuS YSNPs) to form ADLAu@CuS YSNPs. Under 808 nm laser irradiation, the unique resonant energy transfer (RET) process and reactive oxygen species (ROS) generation in the confined space of ADLAu@CuS YSNPs could effectively convert l-Arg into NO, regionally destabilizing the phospholipid bilayer structure, as a result of NO release. However, at this early stage Dox could not be released from YSNPs due to the molecular scaffold limit. As the NO release progressed, the NO-responsive liposome layer was deteriorated more severely, allowing Dox to escape. This NO and Dox sequential release of ADLAu@CuS YSNPs could significantly inhibit P-gp expression and enhance Dox accumulation in Dox-resistant MCF-7/ADR cells, leading to promising in vitro and in vivo therapeutic effects and presenting their great potential for MDR cancer therapy.

Resonance Energy Transfer-Promoted Photothermal and Photodynamic Performance of Gold-Copper Sulfide Yolk-Shell Nanoparticles for Chemophototherapy of Cancer.

Gold (Au) core@void@copper sulfide (CuS) shell (Au-CuS) yolk-shell nanoparticles (YSNPs) were prepared in the present study for potential chemo-, photothermal, and photodynamic combination therapy, so-called "chemophototherapy". The resonance energy transfer (RET) process was utilized in Au-CuS YSNPs to achieve both enhanced photothermal and photodynamic performance compared with those of CuS hollow nanoparticles (HNPs). A series of Au nanomaterials as cores that had different localized surface plasmon resonance (LSPR) absorption peaks at 520, 700, 808, 860, and 980 nm were embedded in CuS HNPs to screen the most effective Au-CuS YSNPs according to the RET process. Thermoresponsive polymer was fabricated on these YSNPs' surface to allow for controlled drug release. Au808-CuS and Au980-CuS YSNPs were found capable of inducing the largest temperature elevation and producing the most significant hydroxyl radicals under 808 and 980 nm laser irradiation, respectively, which could accordingly cause the most severe 4T1 cell injury through oxidative stress mechanism. Moreover, doxorubicin-loaded (Dox-loaded) P(NIPAM-co-AM)-coated Au980-CuS (p-Au980-CuS@Dox) YSNPs could more efficiently kill cells than unloaded particles upon 980 nm laser irradiation. After intravenous administration to 4T1 tumor-bearing mice, p-Au980-CuS YSNPs could significantly accumulate in the tumor and effectively inhibit the tumor growth after 980 nm laser irradiation, and p-Au980-CuS@Dox YSNPs could further potentiate the inhibition efficiency and exhibit excellent in vivo biocompatibility. Taken together, this study sheds light on the rational design of Au-CuS YSNPs to offer a promising candidate for chemophototherapy.

NLRP3 inflammasome activation and lung fibrosis caused by airborne fine particulate matter.

Airborne fine particulate matter (PM2.5) has been known capable of causing lung inflammation and fibrosis, as a result of a series of chronic respiration diseases. Although NLRP3 inflammasome activation is essential for development of many chronic diseases, the relationship between PM2.5-induced toxicological effect and NLRP3 inflammasome activation is rarely investigated. Since PM2.5 contains a large population of nanosized materials and many types of nanomaterials can activate NLRP3 inflammasome, the NLRP3 inflammasome activation and lung fibrosis induced by PM2.5 were investigated in the present study. PM2.5 was found capable of causing weak cell death but potent IL-1ß secretion in THP-1 cells, which was involved in NLRP3 inflammasome activation as evidenced by Z-YVAD-FMK inhibited IL-1ß secretion and overexpressed ASC and NLRP3 protein in PM2.5 treated cells. PM2.5 could be internalized into cells through multiple endocytosis processes, such as phagocytosis and pinocytosis (macropinocytosis, clathrin- and caveolin-mediated endocytosis), and activate NLRP3 inflammasome through cathepsin B release, ROS production, and potassium efflux. After 21 days of exposure to PM2.5 through oropharyngeal aspiration, Balb/c mice showed increased IL-1ß and TGF-ß1 levels in the bronchoalveolar lavage fluid (BALF) of lung and significant collagen deposition around small airways of mice, suggesting potential lung inflammation and pulmonary fibrosis.

Different acquisition arcs for better imaging left ventricular wall in myocardial perfusion single photon emission tomography.

OBJECTIVE: Conventional Single-photon emission tomography (SPET) myocardial perfusion imaging (MPI) is performed in the supine position range RAO 45o-LPO 45o, but the effect of other acquisition arcs on imaging quality have not been well described. In this study, we compared the radioactivity over left ventricle walls as measured by different acquisition arcs to identify the best specific applications. SUBJECTS AND METHODS: A total of 125 low-risk coronary heart disease patients underwent technetium-99m methoxy isobutyl isonitrile (99mTc-MIBI) stress MPI, of which 52 received 360o acquisition with reconstruction using different 180o projections and the remaining 73 received conventional 180o (LPO 45o-RAO 45o) and left-side 180o (POST 180o-ANT 0o) acquisition consecutively. We statistically compared the radioactivity and defect score of each left ventricular wall from different acquisition arcs. RESULTS: Myocardial slices reconstructed from POST 180o-ANT 0o yielded highest radioactivity uptake for lateral, inferior and septal walls, LPO 45 -RAO 45 for the anterior wall and LPO 35o-RAO 55o for the apical region. Compared to conventional 180o acquisition, the segments with decreased defect scores were observed in 27.67% using left-side 180o acquisition. The proportion was significantly higher for males (P=0.035) and patients with high body mass index (BMI) (P=0.036). Segments with decreased defect scores were mainly in the inferior, septal and lateral walls and more in males than in females in the inferior wall (P=0.004). CONCLUSION: The different arc of data acquisition could significantly affect the appearance of each wall of the left ventricle, POST 180o-ANT 0o acquisition arc represented a significantly enhanced imaging quality of inferior walls as compared to the conventional acquisition arc LPO 45 -RAO 45 in 180 protocol, especially in males.

Deep-Level Defect Enhanced Photothermal Performance of Bismuth Sulfide-Gold Heterojunction Nanorods for Photothermal Therapy of Cancer Guided by Computed Tomography Imaging.

Bismuth sulfide (Bi2 S3 ) nanomaterials are emerging as a promising theranostic platform for computed tomography imaging and photothermal therapy of cancer. Herein, the photothermal properties of Bi2 S3 nanorods (NRs) were unveiled to intensely correlate to their intrinsic deep-level defects (DLDs) that potentially could work as electron-hole nonradiative recombination centers to promote phonon production, ultimately leading to photothermal performance. Bi2 S3 -Au heterojunction NRs were designed to hold more significant DLD properties, exhibiting more potent photothermal performance than Bi2 S3 NRs. Under 808 nm laser irradiation, Bi2 S3 -Au NRs could trigger higher cellular heat shock protein 70 expression and more apoptotic cells than Bi2 S3 NRs, and caused severe cell death and tumor growth inhibition, showing great potential for photothermal therapy of cancer guided by computed tomography imaging.

Simulated Sunlight-Mediated Photodynamic Therapy for Melanoma Skin Cancer by Titanium-Dioxide-Nanoparticle-Gold-Nanocluster-Graphene Heterogeneous Nanocomposites.

Simulated sunlight has promise as a light source able to alleviate the severe pain associated with patients during photodynamic therapy (PDT); however, low sunlight utilization efficiency of traditional photosensitizers dramatically limits its application. Titanium-dioxide-nanoparticle-gold-nanocluster-graphene (TAG) heterogeneous nanocomposites are designed to efficiently utilize simulated sunlight for melanoma skin cancer PDT. The narrow band gap in gold nanoclusters (Au NCs), and staggered energy bands between Au NCs, titanium dioxide nanoparticles (TiO2 NPs), and graphene can result in efficient utilization of simulated sunlight and separation of electron-hole pairs, facilitating the production of abundant hydroxyl and superoxide radicals. Under irradiation of simulated sunlight, TAG nanocomposites can trigger a series of toxicological responses in mouse B16F1 melanoma cells, such as intracellular reactive oxygen species production, glutathione depletion, heme oxygenase-1 expression, and mitochondrial dysfunctions, resulting in severe cell death. Furthermore, intravenous or intratumoral administration of biocompatible TAG nanocomposites in B16F1-tumor-xenograft-bearing mice can significantly inhibit tumor growth and cause severe pathological tumor tissue changes. All of these results demonstrate prominent simulated sunlight-mediated PDT effects.

Assessment of 25 CYP2D6 alleles found in the Chinese population on propafenone metabolism in vitro.

Cytochrome P450 enzyme 2D6 (CYP2D6) is an important member of the cytochrome P450 enzyme superfamily, with more than 100 CYP2D6 allelic variants being previously reported. The aim of this study was to assess the catalytic characteristics of 25 alleles (CYP2D6.1 and 24 CYP2D6 variants) and their effects on the metabolism of propafenone in vitro. Twenty-five CYP2D6 alleles were expressing in 21 Spodoptera frugiperda (Sf) insect cells, and each variant was evaluated using propafenone as the substrate. Reactions were performed at 37 °C with 1-100 µmol/L propafenone for 30 min. After termination, the product 5-OH-propafenone was extracted and used for signal collection by ultra-performance liquid chromatography (UPLC). Compared with wild type CYP2D6.1, the intrinsic clearance (Vmax and Km) values of all variants were significantly altered. Three variants (CYP2D6.87, CYP2D6.90, CYP2D6.F219S) exhibited markedly increased intrinsic clearance values (129% to 165%), whereas 21 variants exhibited significantly decreased values (16% to 85%) due to increased Km and (or) decreased Vmax values. These results indicated that the majority of tested alleles had significantly altered catalytic activity towards propafenone hydroxylation in this expression system. Attention should be paid to subjects carrying these rare alleles when treated with propafenone.

Metformin Inhibits NLRP3 Inflammasome Expression and Regulates Inflammatory Microenvironment to Delay the Progression of Colorectal Cancer.

BACKGROUND: Colorectal cancer is a common malignant tumor, with about one million people diagnosed with it worldwide each year. Recent studies have found that metformin can inhibit the production of inflammatory factors and regulate the polarization of immune cells. However, whether metformin can regulate the inflammatory microenvironment and delay the progression of colorectal cancer by inhibiting the inflammatory response has not been deeply studied yet. OBJECTIVE: This study aimed to explore the molecular mechanism by which metformin inhibits the expression of NLRP3 inflammasome, regulates the inflammatory microenvironment, and delays the progression of colorectal cancer through in vitro cell experiments. METHODS: In this research, NLRP3 was knocked down in human colorectal cancer cells, and metformin was added to them. Cell proliferation ability was detected by CCK8, and cell migration and invasion abilities were assessed by Transwell assay. The apoptosis rate was determined by flow cytometry. In addition, the expression of NLRP3 inflammatory vesicles and inflammatory factors in each group of cells was studied by qRT-PCR and Western blotting. Finally, clinical colorectal cancer samples were analyzed by immunohistochemistry. RESULTS: The results of the study showed that NLRP3 expression was significantly increased in colorectal cancer cell lines and human colorectal cancer tissues. Knockdown of NLRP3 significantly inhibited tumor cell proliferation, migration, and invasion. In addition, the proliferation, migration and invasion of tumor cells were also significantly reduced by the addition of metformin intervention. Furthermore, qRT-PCR and WB results demonstrated that the expression of IL-1ß, IL-6, TNF- α, TGF-ß, and IL-10 was down-regulated in LS1034 tumor cells after NLRP3 knockdown. In addition, metformin intervention also resulted in different degrees of downregulation of NLRP3 and inflammatory factor expression (p <0.05). Notably, the reduction in inflammatory factors was more pronounced after the combination of NLRP3 knockdown and metformin intervention. CONCLUSION: Metformin can inhibit the expression of NLRP3 inflammasome, thereby suppressing the expression of inflammation-related factors, reducing the damage of the inflammatory microenvironment to normal cells, and delaying the progression of colorectal cancer.

Manipulating calcium homeostasis with nanoplatforms for enhanced cancer therapy.

Calcium ions (Ca2+) are indispensable and versatile metal ions that play a pivotal role in regulating cell metabolism, encompassing cell survival, proliferation, migration, and gene expression. Aberrant Ca2+ levels are frequently linked to cell dysfunction and a variety of pathological conditions. Therefore, it is essential to maintain Ca2+ homeostasis to coordinate body function. Disrupting the balance of Ca2+ levels has emerged as a potential therapeutic strategy for various diseases, and there has been extensive research on integrating this approach into nanoplatforms. In this review, the current nanoplatforms that regulate Ca2+ homeostasis for cancer therapy are first discussed, including both direct and indirect approaches to manage Ca2+ overload or inhibit Ca2+ signalling. Then, the applications of these nanoplatforms in targeting different cells to regulate their Ca2+ homeostasis for achieving therapeutic effects in cancer treatment are systematically introduced, including tumour cells and immune cells. Finally, perspectives on the further development of nanoplatforms for regulating Ca2+ homeostasis, identifying scientific limitations and future directions for exploitation are offered.