Association Between Individualized Versus Conventional Blood Glucose Thresholds and Acute Kidney Injury After Cardiac Surgery: A Retrospective Observational Study.

OBJECTIVES: This study was designed to compare individualized and conventional hyperglycemic thresholds for the risk of acute kidney injury (AKI) after cardiac surgery. DESIGN: This was an observational study. SETTING: The study took place in a single-center tertiary teaching hospital. PARTICIPANTS: Adult patients who underwent cardiac surgery between January 2012 and November 2021 were enrolled. MEASUREMENTS AND MAIN RESULTS: Two blood glucose thresholds were used to define intraoperative hyperglycemia. While the conventional hyperglycemic threshold (CHT) was 180 mg/dL in all patients, the individualized hyperglycemic threshold (IHT) was calculated based on the preoperative hemoglobin A1c level. Various metrics of intraoperative hyperglycemia were calculated using both thresholds: any hyperglycemic episode, duration of hyperglycemia, and area above the thresholds. Postoperative AKI associations were compared using receiver operating characteristic curves and logistic regression analysis. Among the 2,427 patients analyzed, 823 (33.9%) developed AKI. The C-statistics of IHT-defined metrics (0.58-0.59) were significantly higher than those of the CHT-defined metrics (all C-statistics, 0.54; all p < 0.001). The duration of hyperglycemia (adjusted odds ratio, 1.09; 95% confidence interval, 1.02-1.16) and area above the IHT (1.003; 1.001-1.004) were significantly associated with the risk of AKI, except for the presence of any hyperglycemic episode. None of the CHT-defined metrics were significantly associated with the risk of AKI. CONCLUSIONS: Individually defined intraoperative hyperglycemia better predicted postcardiac surgery AKI than universally defined hyperglycemia. Intraoperative hyperglycemia was significantly associated with the risk of AKI only for the IHT. Target blood glucose levels in cardiac surgical patients may need to be individualized based on preoperative glycemic status.

A Prospective Comparative Study of 18 F-FDOPA PET/CT Versus 123 I-MIBG Scintigraphy With SPECT/CT for the Diagnosis of Pheochromocytoma and Paraganglioma.

PURPOSE: This study aimed to compare the diagnostic performances of 18 F-FDOPA PET/CT and 123 I-MIBG scintigraphy with SPECT/CT for detection of pheochromocytoma and paraganglioma (PPGL). PATIENTS AND METHODS: We conducted a prospective, single-institution comparative study. Patients suspected of having PPGL or those showing recurrence and/or distant metastasis of PPGL were enrolled. The primary objective was to affirm the noninferiority of 18 F-FDOPA PET/CT for diagnostic sensitivity. Both 123 I-MIBG scintigraphy with SPECT/CT (at 4 and 24 hours) and 18 F-FDOPA PET/CT (at 5 and 60 minutes after radiotracer administration) were performed. The final diagnosis was established either pathologically or via clinical follow-up. Nuclear physicians, unaware of the clinical data, undertook image analysis. RESULTS: Thirty-two patients were evaluated: 14 of 21 with an initial diagnosis and 9 of 11 with recurrence/metastasis had PPGLs in their final diagnoses. In patient-based analyses, 18 F-FDOPA PET/CT (95.7%) exhibited noninferior sensitivity compared with 123 I-MIBG SPECT/CT (91.3%), within the predetermined noninferiority margin of -12% by a 95% confidence interval lower limit of -10%. Both modalities showed no significant difference in specificity (88.9% vs 88.9%). In the region-based analysis for the recurrence/metastasis group, 18 F-FDOPA PET/CT demonstrated significantly higher sensitivity compared with 123 I-MIBG SPECT/CT (86.2% vs 65.5%, P = 0.031) and superior interobserver agreement (κ = 0.94 vs 0.85). The inclusion of an early phase in dual-phase 18 F-FDOPA PET/CT slightly improved diagnostic performance, albeit not to a statistically significant degree. CONCLUSIONS: 18 F-FDOPA PET/CT demonstrated noninferior sensitivity and comparable specificity to 123 I-MIBG SPECT/CT in the diagnosing PPGL. Notably, in the assessment of PPGL recurrence and metastasis, 18 F-FDOPA PET/CT outperformed 123 I-MIBG SPECT/CT in terms of both sensitivity and interobserver agreement.

A clinical retrospective study of implant as a risk factor for medication-related osteonecrosis of the jaw: surgery vs loading?

BACKGROUND: Risk factors for developing medication-related osteonecrosis of the jaw (MRONJ) include the general condition of the patient, smoking habit, poor oral hygiene, and the type, duration, and administration route of the drug, dentoalveolar surgery, such as implant placement. This study aimed to discuss whether implants may induce osteonecrosis in older patients receiving long-term medication and to analyze the radiological pattern of the bone necrosis. METHODS: This study included 33 patients diagnosed with dental implant-associated medication-related osteonecrosis of the jaw. Data regarding the medical history, type of medication used, durations of administration, laboratory test results, onset of bone necrosis since implant placement, type of opposing teeth, and radiological pattern of the bone necrosis on cone-beam computed tomography were recorded in patients with and without implants. RESULTS: The most commonly used drug was bisphosphonate, with an average duration of use of 61.37 (± 53.72) months. The laboratory results showed average serum C-terminal cross-linking telopeptide (CTX) level of 0.23 ng/mL, vitamin D, 23.42 ng/mL, and osteocalcin, 4.92 ng/mL. Osteonecrosis occurred after an average of 51.03 (± 39.75) months following implant placement. Radiological evaluation revealed obvious sequestration in the implant-absent group, and the formation of a unit sequestration with an implant fixture (en bloc) was observed in the implant-present group. The patients underwent surgical treatment of sequestrectomy and explantation. CONCLUSION: Implant placement, especially loading, may be considered a potential risk factor for the development of osteonecrosis in patients undergoing antiresorptive treatment.

Clinical outcome of narrow diameter dental implants: a 3-year retrospective study.

BACKGROUND: This study aimed to analyze the clinical outcome and complications of narrow-diameter dental implants (NDIs) (diameter ≤3.5 mm). METHODS: The 274 NDIs that met the selection criteria from 2013 to 2018 were included in the retrospective study, and the survival rates (SVR) were compared. Mechanical complications included screw loosening and fractures of the implant components, such as the implant fixture, abutment, and prosthesis. In addition, marginal bone loss (MBL) was measured immediately after surgery and 1 year after loading. RESULTS: The 3-year cumulative SVR was 92.4%. Nineteen fixtures failed during the follow-up. The failure rate was significantly higher (OR=4.573, p<0.05) in smokers and was significantly higher in osteoporosis patients (OR=3.420, p<0.05). The vertical and horizontal values of MBL were 0.33±0.32 mm and 0.18±0.17 mm, respectively. Mechanical complications included screw loosening (5.5%) and porcelain fracture (2.2%), but no fractures of the fixture or components were observed. The choice of titanium and zirconium (TiZr) alloy implant was significantly more frequent in the posterior region. Bone graft was significantly more frequently done in the anterior region. CONCLUSIONS: According to the high SVR and stability of NDIs, the findings of the study suggest that NDIs may be a replacement for regular diameter dental implants (RDIs) and the use of TiZr alloy could extend the indication of NDIs. In the esthetic area, contour augmentation may be a reason for increasing the frequency of bone grafts.

Selection of iPSCs without mtDNA deletion for autologous cell therapy in a patient with Pearson syndrome.

Screening for genetic defects in the cells should be examined for clinical application. The Pearson syndrome (PS) patient harbored nuclear mutations in the POLG and SSBP1 genes, which could induce systemic large-scale mitochondrial genome (mtDNA) deletion. We investigated iPSCs with mtDNA deletions in PS patient and whether deletion levels could be maintained during differentiation. The iPSC clones derived from skin fibroblasts (9% deletion) and blood mononuclear cells (24% deletion) were measured for mtDNA deletion levels. Of the 13 skin-derived iPSC clones, only 3 were found to be free of mtDNA deletions, whereas all blood-derived iPSC clones were found to be free of deletions. The iPSC clones with (27%) and without mtDNA deletion (0%) were selected and performed in vitro and in vivo differentiation, such as embryonic body (EB) and teratoma formation. After differentiation, the level of deletion was retained or increased in EBs (24%) or teratoma (45%) from deletion iPSC clone, while, the absence of deletions showed in all EBs and teratomas from deletion-free iPSC clones. These results demonstrated that non-deletion in iPSCs was maintained during in vitro and in vivo differentiation, even in the presence of nuclear mutations, suggesting that deletion-free iPSC clones could be candidates for autologous cell therapy in patients. [BMB Reports 2023; 56(8): 463-468].

SMO-CRISPR-mediated apoptosis in CD133-targeted cancer stem cells and tumor growth inhibition.

Cancer stem cells (CSCs) possess the ability to indefinitely proliferate and resist therapy, leading to cancer relapse and metastasis. To address this, we aimed to develop a CSC-inclusive therapy that targets both CSCs and non-CSC glioblastoma (GBM) cells. We accomplished this by using a smoothened (SMO) CRISPR/Cas9 plasmid to suppress the hedgehog pathway in CSCs, in combination with inhibiting the serine hydroxymethyl transferase 1 (SHMT1)-driven thymidylate biosynthesis pathway in non-CSC GBM cells using SHMT1 siRNA (siSHMT1). We targeted CSCs using a CD133 peptide attached to an osmotically active vitamin B6-coupled polydixylitol vector (VPX-CD133) by a photoactivatable heterobifunctional linker. VPX-CD133 nanocomplexes in comparison to VPX complexes remarkably targeted and transfected CSCs both in vitro and in subcutaneous tumor. The VPX-CD133-mediated targeted delivery of SMO CRISPR in CSCs led to SMO suppression that negatively affected its growth. Next, we performed comprehensive therapy in xenograft mice using VPX-CD133, which delivered SMO-CRISPR to CSCs, and VPX, which delivered siSHMT1 to non-CSC GBM cells. The combined treatment induced apoptosis in a large number of cells, reduced tumor volume by up to 81%, and improved the health of treated mice significantly. By eliminating CSCs together with the non-CSC GBM cells, the combined study paves the way for developing CSC-inclusive therapies for GBM.

Safety and Efficacy of Allogeneic Natural Killer Cells in Combination with Pembrolizumab in Patients with Chemotherapy-Refractory Biliary Tract Cancer: A Multicenter Open-Label Phase 1/2a Trial.

BACKGROUND AND AIM: This study investigated the administration of combination therapy, allogeneic natural killer (NK) cells and pembrolizumab in the treatment of advanced biliary tract cancer to determine the safety and tolerability (phase 1) and the efficacy and safety (phase 2a). METHODS: Forty patients (phase 1, n = 6; phase 2a, n = 34) were enrolled between December 2019 and June 2021. The patients received highly activated allogeneic NK cells ("SMT-NK") on weeks 1 and 2 and pembrolizumab on week 1. This 3-week schedule (one cycle) was repeated until confirmed disease progression, intolerable adverse events (AEs), patient withdrawal, or finishing the maximum treatment schedule. The tumor response was evaluated after every three cycles. RESULTS: In phase 1, four patients (66.7%) experienced seven AEs, but no severe AE was observed. In phase 2a, 126 AEs occurred in 29 patients (85.3%). Severe AEs (≥grade 3) were reported in 16 patients (47.1%). The overall response rate (ORR) was 17.4% in the full analysis set and 50.0% in the per-protocol set. CONCLUSIONS: SMT-NKs plus pembrolizumab resulted in no severe AEs directly related to the drug combination. The combination therapy also exerted antitumor activity with improved efficacy compared to the recent monotherapy with pembrolizumab in patients with advanced biliary tract cancer.

SHMT1 siRNA-Loaded hyperosmotic nanochains for blood-brain/tumor barrier post-transmigration therapy.

The near-perivascular accumulation in solid tumors and short-lived span in circulation, derails even the most competent nanoparticles (NPs) from achieving their maximum therapeutic potential. Moreover, delivering them across the blood brain/tumor barrier (BBB/BTB) is further challenging to sought anticancer effect. To address these key challenges, we designed a linearly aligned nucleic acid-complexed polydixylitol-based polymeric nanochains (X-NCs), with inherent hyperosmotic properties enabling transmigration of the BBB/BTB and navigation through deeper regions of the brain tumor. The high aspect ratio adds shape-dependent functional aspects to parent particles by providing effective payload increment and nuclear factor of activated T cells-5 (NFAT5)-mediated cellular uptake. Therefore, serine hydroxymethyltransferase 1 (SHMT1) siRNA-loaded nanochains not only demonstrated to transmigrate the BTB, but also resulted in remarkably reducing the tumor size to 97% in the glioblastoma xenograft brain tumor mouse models. Our study illustrates how the hyperosmotic nanochains with high aspect ratio and aligned structure can accelerate a therapeutic effect in aggressive brain tumors post-transmigration of the BBB/BTB by utilizing an NFAT5 mode of uptake mechanism.

A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. The nonreceptor tyrosine kinase c-Abl has shown a potential role in the progression of PD. As such, c-Abl inhibition is a promising candidate for neuroprotection in PD and α-synucleinopathies. Compound 5 is a newly synthesized blood-brain barrier penetrant c-Abl inhibitor with higher efficacy than existing inhibitors. The objective of the current study was to demonstrate the neuroprotective effects of compound 5 on the α-synuclein preformed fibril (α-syn PFF) mouse model of PD. Compound 5 significantly reduced neurotoxicity, activation of c-Abl, and Lewy body pathology caused by α-syn PFF in cortical neurons. Additionally, compound 5 markedly ameliorated the loss of dopaminergic neurons, c-Abl activation, Lewy body pathology, neuroinflammatory responses, and behavioral deficits induced by α-syn PFF injection in vivo. Taken together, these results suggest that compound 5 could be a pharmaceutical agent to prevent the progression of PD and α-synucleinopathies.

Photobiomodulation as an antioxidant substitute in post-thawing trauma of human stem cells from the apical papilla.

Cryopreservation, the most common method of preserving stem cells, requires post-processing because it produces trauma to the cells. Post-thawing trauma typically induces cell death, elevates reactive oxygen species (ROS) concentration, and lowers mitochondrial membrane potential (MMP). Although this trauma has been solved using antioxidants, we attempted to use photobiomodulation (PBM) instead of chemical treatment. We used a 950-nm near-infrared LED to create a PBM device and chose a pulsed-wave mode of 30 Hz and a 30% duty cycle. Near-infrared radiation (NIR) at 950 nm was effective in reducing cell death caused by hydrogen peroxide induced-oxidative stress. Cryodamage also leads to apoptosis of cells, which can be avoided by irradiation at 950 nm NIR. Irradiation as post-processing for cryopreservation had an antioxidant effect that reduced both cellular and mitochondrial ROS. It also increased mitochondrial mass and activated mitochondrial activity, resulting in increased MMP, ATP generation, and increased cytochrome c oxidase activity. In addition, NIR increased alkaline phosphatase (ALP) activity, a biomarker of differentiation. As a result, we identified that 950 nm NIR PBM solves cryodamage in human stem cells from the apical papilla, indicating its potential as an alternative to antioxidants for treatment of post-thawing trauma, and further estimated its mechanism.

Enhanced Osteogenesis of Dental Pulp Stem Cells In Vitro Induced by Chitosan-PEG-Incorporated Calcium Phosphate Cement.

The use of bone graft materials is required for the treatment of bone defects damaged beyond the critical defect; therefore, injectable calcium phosphate cement (CPC) is actively used after surgery. The application of various polymers to improve injectability, mechanical strength, and biological function of injection-type CPC is encouraged. We previously developed a chitosan-PEG conjugate (CS/PEG) by a sulfur (VI) fluoride exchange reaction, and the resulting chitosan derivative showed high solubility at a neutral pH. We have demonstrated the CPC incorporated with a poly (ethylene glycol) (PEG)-grafted chitosan (CS/PEG) and developed CS/PEG CPC. The characterization of CS/PEG CPC was conducted using Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). The initial properties of CS/PEG CPCs, such as the pH, porosity, mechanical strength, zeta potential, and in vitro biocompatibility using the WST-1 assay, were also investigated. Moreover, osteocompatibility of CS/PEG CPCs was carried out via Alizarin Red S staining, immunocytochemistry, and Western blot analysis. CS/PEG CPC has enhanced mechanical strength compared to CPC, and the cohesion test also demonstrated in vivo stability. Furthermore, we determined whether CS/PEG CPC is a suitable candidate for promoting the osteogenic ability of Dental Pulp Stem Cells (DPSC). The elution of CS/PEG CPC entraps more calcium ion than CPC, as confirmed through the zeta potential test. Accordingly, the ion trapping effect of CS/PEG is considered to have played a role in promoting osteogenic differentiation of DPSCs. The results strongly suggested that CS/PEG could be used as suitable additives for improving osteogenic induction of bone substitute materials.

Effect and timing of parathyroid hormone analog administration for preventing medication-related osteonecrosis of the jaws in a murine model.

The aim of this study was to investigate the effect and timing of recombinant human parathyroid hormone analog (PTH) administration for preventing medication-related osteonecrosis of the jaws (MRONJ) using a murine model. After standardized MRONJ induction using zoledronic acid and dexamethasone injections, 48 female Sprague-Dawley rats were divided into four groups according to the timing of PTH administration before or after dental extraction. Rats were euthanized 3 weeks after dental extraction, followed by clinical and histologic analyses. No clinical improvements were observed in the preoperative and postoperative PTH groups, compared to controls (p = 0.638 and 0.496, respectively). However, on histological analysis, the number of empty lacunae reduced significantly, and the number of blood vessels increased in the preoperative PTH group (p = 0.004 and 0.002, respectively). The postoperative PTH group did not show significant differences for empty lacunae and blood vessels compared to controls (p = 0.075 and 0.194, respectively). The reduction in the empty lacunae and the increase in the blood vessels in the preoperative PTH group were significant compared to other groups, suggesting more viable bone tissue in this group. In perspective, preoperative PTH use may represent a better prophylactic regimen for preventing the occurrence of MRONJ after traumatic dental or surgical procedures, especially in patients with a history of long-term bisphosphonate administration or at high risk of developing MRONJ. However, the findings should be proven in further studies on other animals followed by clinical trials.

Aligned Nanofiber-Guided Bone Regeneration Barrier Incorporated with Equine Bone-Derived Hydroxyapatite for Alveolar Bone Regeneration.

Post-surgery failure of dental implants due to alveolar bone loss is currently critical, disturbing the quality of life of senior dental patients. To overcome this problem, bioceramic or bone graft material is loaded into the defect. However, connective tissue invasion instead of osteogenic tissue limits bone tissue regeneration. The guided bone regeneration concept was adapted to solve this problem and still has room for improvements, such as biochemical similarity or oriented structure. In this article, an aligned electrospun-guided bone regeneration barrier with xenograft equine bone-derived nano hydroxyapatite (EBNH-RB) was fabricated by electrospinning EBNH/PCL solution on high-speed rotating drum collector and fiber characterization, viability and differentiation enhancing properties of mesenchymal dental pulp stem cell on the barrier was determined. EBNH-RB showed biochemical and structural similarity to natural bone tissue electron microscopy image analysis and x-ray diffractometer analysis, and had a significantly better effect in promoting osteogenesis based on the increased bioceramic content by promoting cell viability, calcium deposition and osteogenic marker expression, suggesting that they can be successfully applied to regenerate alveolar bone as a guided bone regeneration barrier.

Hesperetin inhibit EMT in TGF-ß treated podocyte by regulation of mTOR pathway.

Renal fibrosis is one of the characteristic features of chronic kidney disease (CKD). Fibrotic change not only impairs the filtration function of the kidney but is also recognized as a marker of end-stage renal disease (ESRD). The epithelial to mesenchymal transition (EMT) is known to play a role in embryonic development and organ formation, but it is getting much attention for its pathological role in the invasion and metastasis of carcinoma. Recently, it has also been reported that EMT plays a role in the formation of fibrosis during chronic inflammation. EMT contribute to the development of the fibrosis in CKD. Moreover, glomerular podocytes and tubular epithelial cells can also undergo mesenchymal transition in CKD. Hesperetin is a flavonoid present in citrus and is well known for its antioxidant and anti-inflammatory properties. In this study, we investigated the effects of hesperetin on the EMT-elicited podocytes. First, we generated an EMT model by treating transforming growth factor (TGF)-ß1, a potent inducer of EMT to the podocytes. TGF-ß1 decreased the expression of epithelial markers such as nephrin, zonula occludens-1 (ZO-1), while it increased the mesenchymal markers, including fibronectin (FN), vimentin, and α-smooth muscle actin (α-SMA) in the podocytes. Hesperetin suppressed EMT-like changes elicited by TGF-ß1. Interestingly, hesperetin did not interfere with the Smad signaling-the classical TGF-ß signaling-pathway, which was confirmed by the experiment with smad 2/3 -/- podocytes. Instead, hesperetin suppressed EMT-like changes by inhibiting the mTOR pathway-one of the alternative TGF-ß signaling pathways. In conclusion, hesperetin has a protective effect on the TGF-ß1 elicited EMT-like changes of podocytes through regulation of mTOR pathway. It could be a good candidate for the suppression of kidney fibrosis in various CKD.

Development of a docetaxel micellar formulation using poly(ethylene glycol)-polylactide-poly(ethylene glycol) (PEG-PLA-PEG) with successful reconstitution for tumor targeted drug delivery.

Docetaxel (DTX)-loaded polymeric micelles (DTBM) were formulated using the triblock copolymer, poly(ethylene glycol)-polylactide-poly(ethylene glycol) (PEG-PLA-PEG), to comprehensively study their pharmaceutical application as anticancer nanomedicine. DTBM showed a stable formulation of anticancer nanomedicine that could be reconstituted after lyophilization (DTBM-R) in the presence of PEG 2000 and D-mannitol (Man) as surfactant and protectant, respectively. DTBM-R showed a particle size less than 150 nm and greater than 90% of DTX recovery after reconstitution. The robustly formed micelles might minimize systemic toxicity due to their sustained drug release and also maximize antitumor efficacy through increased accumulation and release of DTX from the micelles. From the pharmaceutical development point of view, DTBM-R showing successful reconstitution could be considered as a potent nanomedicine for tumor treatment.

Correction: Synergistic photodynamic therapeutic effect of indole-3-acetic acid using a pH sensitive nano-carrier based on poly(aspartic acid-graft-imidazole)-poly(ethylene glycol).

Correction for 'Synergistic photodynamic therapeutic effect of indole-3-acetic acid using a pH sensitive nano-carrier based on poly(aspartic acid-graft-imidazole)-poly(ethylene glycol)' by Taehoon Sim et al., J. Mater. Chem. B, 2017, 5, 8498-8505.

Inhibitory effect of 1­tetradecanol on Helicobacter pylori­induced production of interleukin­8 and vascular endothelial growth factor in gastric epithelial cells.

Helicobacter pylori (H. pylori) infection activates pro­inflammatory mediators, including interleukin (IL)­8 and vascular endothelial growth factor (VEGF) in gastric epithelial cells. 1­Tetradecanol (1­TD) has been purified from Dendropanax morbifera Leveille; its physiological activities are poorly understood. The present study assessed whether 1­TD has an effect on H. pylori­mediated inflammation in AGS gastric epithelial cells. 1­TD reduced IL­8 production by AGS cells in response to H. pylori in a significant and dose­dependent manner, as measured by ELISA. Western blot analysis demonstrated that 1­TD also suppressed the activation of nuclear factor­κB, and two mitogen activated protein kinase species (p38 and extracellular signal­regulated kinase 1/2), but not c­Jun N­terminal kinase in H. pylori­infected AGS cells. As predicted, VEGF expression and hypoxia inducible factor­1α stabilization induced by H. pylori in AGS cells were inhibited by 1­TD. In addition, 1­TD directly inhibited the growth of H. pylori in a dose­dependent manner, as investigated by measuring the optical density. These findings indicated that 1­TD may be a potential preventive or therapeutic agent for H. pylori­induced gastric inflammation.

Synergistic photodynamic therapeutic effect of indole-3-acetic acid using a pH sensitive nano-carrier based on poly(aspartic acid-graft-imidazole)-poly(ethylene glycol).

Poly(aspartic acid-graft-imidazole)-poly(ethylene glycol) (P(Asp-g-Im)-PEG) was utilized as a pH-sensitive nanocarrier of the photosensitizer indole-3-acetic acid (IAA) for the treatment of skin cancer. IAA loaded micelles (ILMs) exhibited the formation of ca. 140 nm spherical particles at pH 7.4. The micelles disintegrated at acidic pHs, resulting in pH-dependent IAA release and cytotoxicity. Treatment of ILMs with visible light at a wavelength of 480 nm caused pH dependent synergistic cell damage in both in vitro and in vivo models using the B16F10 melanoma cell line. Interestingly, ILMs synergistically produced reactive oxygen species (ROS) at an acidic pH of 6.5 with visible light irradiation by proton coupled electron transfer (PCET). The pH sensitive ILMs could be considered a potent nanomedicine used to exert synergistic photodynamic therapeutic effects to treat cancers.

Withaferin A Inhibits Helicobacter pylori-induced Production of IL-1ß in Dendritic Cells by Regulating NF-κB and NLRP3 Inflammasome Activation.

Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, and gastric cancer. There is evidence that IL-1ß is associated with the development of gastric cancer. Therefore, downregulation of H. pylori-mediated IL-1ß production may be a way to prevent gastric cancer. Withaferin A (WA), a withanolide purified from Withania somnifera, is known to exert anti-inflammatory and anti-tumor effects. In the present study, we explored the inhibitory activity of WA on H. pylori-induced production of IL-1ß in murine bone marrow-derived dendritic cells (BMDCs) and the underlying cellular mechanism. Co-treatment with WA decreased IL-1ß production by H. pylori in BMDCs in a dose-dependent manner. H. pylori-induced gene expression of IL-1ß and NLRP3 (NOD-like receptor family, pyrin domain containing 3) were also suppressed by WA treatment. Moreover, IκB-α phosphorylation by H. pylori infection was suppressed by WA in BMDCs. Western blot analysis revealed that H. pylori induced cleavage of caspase-1 and IL-1ß, as well as increased procaspase-1 and pro IL-1ß protein levels, and that both were suppressed by co-treatment with WA. Finally, we determined whether WA can directly inhibit ac tivation of the NLRP3 inflammasome. NLRP3 activators induced IL-1ß secretion in LPS-primed macrophages, which was inhibited by WA in a dose-dependent manner, whereas IL-6 production was not affected by WA. Moreover, cleavage of IL-1ß and caspase-1 by NLRP3 activators was also dose-dependently inhibited by WA. These findings suggest that WA can inhibit IL-1ß production by H. pylori in dendritic cells and can be used as a new preventive and therapeutic agent for gastric cancer.