First observations of core-transiting seismic phases on Mars.

We present the first observations of seismic waves propagating through the core of Mars. These observations, made using seismic data collected by the InSight geophysical mission, have allowed us to construct the first seismically constrained models for the elastic properties of Mars' core. We observe core-transiting seismic phase SKS from two farside seismic events detected on Mars and measure the travel times of SKS relative to mantle traversing body waves. SKS travels through the core as a compressional wave, providing information about bulk modulus and density. We perform probabilistic inversions using the core-sensitive relative travel times together with gross geophysical data and travel times from other, more proximal, seismic events to seek the equation of state parameters that best describe the liquid iron-alloy core. Our inversions provide constraints on the velocities in Mars' core and are used to develop the first seismically based estimates of its composition. We show that models informed by our SKS data favor a somewhat smaller (median core radius = 1,780 to 1,810 km) and denser (core density = 6.2 to 6.3 g/cm3) core compared to previous estimates, with a P-wave velocity of 4.9 to 5.0 km/s at the core-mantle boundary, with the composition and structure of the mantle as a dominant source of uncertainty. We infer from our models that Mars' core contains a median of 20 to 22 wt% light alloying elements when we consider sulfur, oxygen, carbon, and hydrogen. These data can be used to inform models of planetary accretion, composition, and evolution.

An interaction between eIF4A3 and eIF3g drives the internal initiation of translation.

An RNA structure or modified RNA sequences can provide a platform for ribosome loading and internal translation initiation. The functional significance of internal translation has recently been highlighted by the discovery that a subset of circular RNAs (circRNAs) is internally translated. However, the molecular mechanisms underlying the internal initiation of translation in circRNAs remain unclear. Here, we identify eIF3g (a subunit of eIF3 complex) as a binding partner of eIF4A3, a core component of the exon-junction complex (EJC) that is deposited onto spliced mRNAs and plays multiple roles in the regulation of gene expression. The direct interaction between eIF4A3-eIF3g serves as a molecular linker between the eIF4A3 and eIF3 complex, thereby facilitating internal ribosomal entry. Protein synthesis from in vitro-synthesized circRNA demonstrates eIF4A3-driven internal translation, which relies on the eIF4A3-eIF3g interaction. Furthermore, our transcriptome-wide analysis shows that efficient polysomal association of endogenous circRNAs requires eIF4A3. Notably, a subset of endogenous circRNAs can express a full-length intact protein, such as ß-catenin, in an eIF4A3-dependent manner. Collectively, our results expand the understanding of the protein-coding potential of the human transcriptome, including circRNAs.

Seismic detection of a deep mantle discontinuity within Mars by InSight.

Constraining the thermal and compositional state of the mantle is crucial for deciphering the formation and evolution of Mars. Mineral physics predicts that Mars' deep mantle is demarcated by a seismic discontinuity arising from the pressure-induced phase transformation of the mineral olivine to its higher-pressure polymorphs, making the depth of this boundary sensitive to both mantle temperature and composition. Here, we report on the seismic detection of a midmantle discontinuity using the data collected by NASA's InSight Mission to Mars that matches the expected depth and sharpness of the postolivine transition. In five teleseismic events, we observed triplicated P and S waves and constrained the depth of this discontinuity to be 1,006 [Formula: see text] 40 km by modeling the triplicated waveforms. From this depth range, we infer a mantle potential temperature of 1,605 [Formula: see text] 100 K, a result consistent with a crust that is 10 to 15 times more enriched in heat-producing elements than the underlying mantle. Our waveform fits to the data indicate a broad gradient across the boundary, implying that the Martian mantle is more enriched in iron compared to Earth. Through modeling of thermochemical evolution of Mars, we observe that only two out of the five proposed composition models are compatible with the observed boundary depth. Our geodynamic simulations suggest that the Martian mantle was relatively cold 4.5 Gyr ago (1,720 to 1,860 K) and are consistent with a present-day surface heat flow of 21 to 24 mW/m2.

Metabolic determinants of leukemia onset variability in genetically homogeneous AKR mice.

Leukemia is a complex disease shaped by the intricate interplay of genetic and environmental factors. Given our preliminary data showing different leukemia incidence in genetically homogenous AKR mice harboring the spontaneous leukemia-inducing mutation Rmcfs, we sought to unravel the role of metabolites and gut microbiota in the leukemia penetrance. Our metabolomic analysis revealed distinct serum metabolite profiles between mice that developed leukemia and those that did not. We discovered that linoleic acid (LA), an essential ω-6 polyunsaturated fatty acid, was significantly decreased in the leukemia group, with the lower levels observed starting from 25 weeks before the onset. A predictive model based on LA levels demonstrated high accuracy in predicting leukemia development (area under curve 0.82). In vitro experiment confirmed LA's cytotoxic effects against leukemia cells, and in vivo study showed that a diet enriched with LA prolonged survival in AKR mice. Furthermore, gut microbiome analysis identified specific Lachnospiraceae species, that affect host lipid metabolism, are exclusively present in the leukemia group, suggesting their potential influence on LA metabolism and leukemia development. These findings shed light on the complex relationship between metabolites, gut microbiota, and leukemia development, providing valuable insights into the role of non-genetic factors in leukemia penetrance and potential strategies for leukemia prevention.

Atomically Dispersed Ru-doped Ti4O7 Electrocatalysts for Chlorine Evolution Reaction with a Universal Activity.

Chlorine has been supplied by the chlor-alkali process that deploys dimensionally stable anodes (DSAs) for the electrochemical chlorine evolution reaction (ClER). The paramount bottlenecks have been ascribed to an intensive usage of precious elements and inevitable competition with the oxygen evolution reaction. Herein, a unique case of Ru2+-O4 active motifs anchored on Magnéli Ti4O7 (Ru-Ti4O7) via a straightforward wet impregnation and mild annealing is reported. The Ru-Ti4O7 performs radically active ClER with minimal deployment of Ru (0.13 wt%), both in 5 m NaCl (pH 2.3) and 0.1 m NaCl (pH 6.5) electrolytes. Scanning electrochemical microscopy demonstrates superior ClER selectivity on Ru-Ti4O7 compared to the DSA. Operando X-ray absorption spectroscopy and density functional theory calculations reveal a universally active ClER (over a wide range of pH and [Cl-]), through a direct adsorption of Cl- on Ru2+-O4 sites as the most plausible pathway, together with stabilized ClO* at low [Cl-] and high pH.

Aicardi-Goutières syndrome-associated gene SAMHD1 preserves genome integrity by preventing R-loop formation at transcription-replication conflict regions.

The comorbid association of autoimmune diseases with cancers has been a major obstacle to successful anti-cancer treatment. Cancer survival rate decreases significantly in patients with preexisting autoimmunity. However, to date, the molecular and cellular profiles of such comorbidities are poorly understood. We used Aicardi-Goutières syndrome (AGS) as a model autoimmune disease and explored the underlying mechanisms of genome instability in AGS-associated-gene-deficient patient cells. We found that R-loops are highly enriched at transcription-replication conflict regions of the genome in fibroblast of patients bearing SAMHD1 mutation, which is the AGS-associated-gene mutation most frequently reported with tumor and malignancies. In SAMHD1-depleted cells, R-loops accumulated with the concomitant activation of DNA damage responses. Removal of R-loops in SAMHD1 deficiency reduced cellular responses to genome instability. Furthermore, downregulation of SAMHD1 expression is associated with various types of cancer and poor survival rate. Our findings suggest that SAMHD1 functions as a tumor suppressor by resolving R-loops, and thus, SAMHD1 and R-loop may be novel diagnostic markers and targets for patient stratification in anti-cancer therapy.

Fewer Feedback Opportunities and Health Perception of Gastric Cancer Survivors: Opportunities for Patient Education.

This study aimed to estimate the impact of having fewer opportunities for patient education on health perception of gastric cancer survivors by examining quality-of-life (QoL) responses from patients who had been away for chemotherapy for a year. The full-surveillance (FullSV) group was comprised of gastric cancer survivors with stage I cancer who completed preoperative and postoperative 3-, 6-, 9-, and 12-month surveillances. The returning (RTN) group was comprised of 1-year survivors of stage II cancer who had been away for chemotherapy for a year. Surveillance periods were utilized to provide patient education about expected postoperative weight changes. The European Organisation for Research and Treatment of Cancer QoL questionnaires were used to assess QoL. The study included a total of 278 patients (243 in the FullSV group and 35 in the RTN group). The baseline QoL was not significantly different between the groups. Significant differences in postoperative QoL were revealed by some scales (global health status/QoL, physical functioning, fatigue, financial difficulties, anxiety, dry mouth, and body image), all in favor of the FullSV group. Despite no significant difference in their actual weight changes, stronger weight dissatisfaction was revealed among the RTN group. Patients with fewer educational inputs for postoperative adjustment of weight perception were the ones with stronger dissatisfaction about current weight. The health perception of cancer survivors is under the constant influence of clinician feedback during patient education. For the best cancer survivorship care, sufficient opportunities for adjustment of health perception through patient education need to be ensured.

The role of O-GlcNAcylation mediated by OGT during tooth development.

To understand the mechanisms underlying tooth morphogenesis, we examined the developmental roles of important posttranslational modification, O-GlcNAcylation, which regulates protein stability and activity by the addition and removal of a single sugar (O-GlcNAc) to the serine or threonine residue of the intracellular proteins. Tissue and developmental stage-specific immunostaining results against O-GlcNAc and O-GlcNAc transferase (OGT) in developing tooth germs would suggest that O-GlcNAcylation is involved in tooth morphogenesis, particularly in the cap and secretory stage. To evaluate the developmental function of OGT-mediated O-GlcNAcylation, we employed an in vitro tooth germ culture method at E14.5, cap stage before secretory stage, for 1 and 2 days, with or without OSMI-1, a small molecule OGT inhibitor. To examine the mineralization levels and morphological changes, we performed renal capsule transplantation for one and three weeks after 2 days of in vitro culture at E14.5 with OSMI-1 treatment. After OGT inhibition, morphological and molecular alterations were examined using histology, immunohistochemistry, real-time quantitative polymerase chain reaction, in situ hybridization, scanning electron microscopy, and ground sectioning. Overall, inhibition of OGT resulted in altered cellular physiology, including proliferation, apoptosis, and epithelial rearrangements, with significant changes in the expression patterns of ß-catenin, fibroblast growth factor 4 (fgf4), and sonic hedgehog (Shh). Moreover, renal capsule transplantation and immunolocalizations of Amelogenin and Nestin results revealed that OGT-inhibited tooth germs at cap stage exhibited with structural changes in cuspal morphogenesis, amelogenesis, and dentinogenesis of the mineralized tooth. Overall, we suggest that OGT-mediated O-GlcNAcylation regulates cell signaling and physiology in primary enamel knot during tooth development, thus playing an important role in mouse molar morphogenesis.

Krüppel-like factor 4 (KLF4) facilitates lipid production in immortalized human sebocytes via regulating the expression of SREBP1.

BACKGROUND: Acne is associated with the excessive production of sebum, a complex mixture of lipids, in the sebaceous glands. The transcription factor Krüppel-like factor 4 (KLF4) plays an important role in skin morphogenesis, but its role in sebum production by sebocytes is not well known. PURPOSE: In this study, we investigated the possible action mechanism of KLF4 during calcium-induced lipogenesis in immortalized human sebocytes. METHODS: Sebocytes were treated with calcium, and lipid production was confirmed by thin-layer chromatography (TLC) and Oil Red O staining. To investigate the effect of KLF4, sebocytes were transduced with the KLF4-overexpressing adenovirus, and then lipid production was evaluated. RESULTS: Calcium treatment resulted in increased sebum production in terms of squalene synthesis in sebocytes. In addition, calcium increased the expression of lipogenic regulators such as sterol-regulatory element binding protein 1 (SREBP1), sterol-regulatory element binding protein 2 (SREBP2), and stearoyl-CoA desaturase (SCD). Similarly, the expression of KLF4 was increased by calcium in sebocytes. To investigate the effect of KLF4, we overexpressed KLF4 in sebocytes using recombinant adenovirus. As a result, KLF4 overexpression increased the expression of SREBP1, SREBP2, and SCD. Parallel to this result, lipid production was also increased by KLF4 overexpression. Chromatin immunoprecipitation revealed the binding of KLF4 to the SREBP1 promoter, indicating that KLF4 may directly regulate the expression of lipogenic regulators. CONCLUSION: These results suggest that KLF4 is a novel regulator of lipid production in sebocytes.

Genetic diversity assessment and genome-wide association study reveal candidate genes associated with component traits in sweet potato (Ipomoea batatas (L.) Lam).

The Korean sweet potatoes were bred by various cultivars introduced from Japanese, American, Porto Rico, China, and Burundi. This issue enriched their genetic diversity but also resulted in a mixture of cultivars. For genotyping, we collected and sequenced 66 sweet potato germplasms from different localities around Korea, including 36 modern cultivars, 5 local cultivars, and 25 foreign cultivars. This identified 447.6 million trimmed reads and 324.8 million mapping reads and provided 39,424 single nucleotide polymorphisms (SNPs) markers. Phylogenetic clustering and population structure analysis distinctly classified these germplasms into 5 genetic groups, group 1, group 2, group 3, group 4, and group 5, containing 20, 15, 10, 7, and 14 accessions, respectively. Sixty-three significant SNPs were selected by genome-wide association for sugar composition-related traits (fructose, glucose, and total sugars), total starch, amylose content, and total carotenoid of the storage root. A total of 37 candidate genes encompassing these significant SNPs were identified, among which, 7 genes were annotated to involve in sugar and starch metabolism, including galactose metabolism (itf04g30630), starch and sucrose metabolism (itf03g13270, itf15g09320), carbohydrate metabolism (itf14g10250), carbohydrate and amino acid metabolism (itf12g19270), and amino sugar and nucleotide sugar metabolism (itf03g21950, itf15g04880). This results indicated that sugar and starch are important characteristics to determine the genetic diversity of sweet potatoes. These findings not only illustrate the importance of component traits to genotyping sweet potatoes but also explain an important reason resulting in genetic diversity of sweet potato.

Effects of 20% albumin infusion therapy during liver transplantation on plasma neutrophil gelatinase-associated lipocalin level: A randomized controlled trial.

The risk of acute kidney injury (AKI) after liver transplantation was lower in patients with serum albumin levels ≥3.0 mg/dL during surgery. We tested whether intraoperative infusion of 20% albumin affects neutrophil gelatinase-associated lipocalin (NGAL) level, a reliable indicator of AKI. We randomly assigned 134 patients undergoing liver transplantation into albumin group (n=70, 20% albumin 200 mL) and the control group (n=66, crystalloid solution 200 mL). The 2 study fluids were infused at 100 mL/h from the start of the anhepatic phase. The primary outcome was plasma NGAL level at 1 hour after graft reperfusion. Albumin level at the start of graft reperfusion was significantly greater in albumin group than in the control group [2.9 (2.4-3.3) g/dL vs. 2.3 (2.0-2.7) g/dL, p <0.001]. The NGAL level at 1 hour after graft reperfusion was not significantly different between the 2 groups [100.2 (66.7-138.8) ng/mL vs. 92.9 (70.8-120.6) ng/mL, p =0.46], and the AKI risk was not either (63.9% vs. 67.8%, adjusted p =0.73). There were no significant differences between the 2 groups regarding hospital readmission within 30 days/90 days after transplantation (32.6% vs. 41.5%, adjusted p =0.19 and 55.0% vs. 55.7%, adjusted p =0.87). Graft survival probability at 30 days/90 days/1 year after transplantation was 90.0%/84.3%/78.6% in albumin group and 97.0%/90.9%/89.4% in the control group [HR=1.6 (0.6-4.0), adjusted p =0.31]. In conclusion, intraoperative infusion of 20% albumin 200 mL increased the albumin level but failed to maintain serum albumin ≥3.0 mg/dL during surgery. The hypertonic albumin therapy did not significantly affect plasma NGAL level and clinical outcomes including AKI.

Canopy Homolog 2 contributes to liver oncogenesis by promoting unfolded protein response-dependent destabilization of tumor protein P53.

BACKGROUD AND AIMS: Abnormalities in the tumor protein P53 (p53) gene and overexpression of mouse double minute 2 homolog (MDM2), a negative regulator of p53, are commonly observed in cancers. p53 destabilization is regulated by endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in cancer. However, the mechanisms remain enigmatic. Canopy homolog 2 (CNPY2) is a key UPR initiator that primarily involved in ER stress and is highly expressed in the liver, but its functional role in regulating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of CNPY2 in hepartocarcinogenesis through URP-dependent p53 destabilization. APPROACH AND RESULTS: Here, we showed that CNPY2 expression is up-regulated in HCC and negatively correlated with survival rate in liver cancer patients. Deletion of Cnpy2 obliterates diethylnitrosamine (DEN)-induced HCC in mice. Mechanistic studies demonstrated that CNPY2 binds and prevents ribosome proteins from inhibiting MDM2 and enhances the UPR activity of protein kinase RNA-like endoplasmic reticulum kinase and inositol-requiring transmembrane kinase endoribonuclease-1α, leading to p53 destabilization and cell-cycle progression. In addition, transcriptome analyses uncovered that CNPY2 is also required for DEN-induced expression of oncogenes, including c-Jun and fibroblast growth factor 21. Intratumoral injection of nanoparticle-based CRISPR single-guide RNA/CRISPR-associated protein 9 mRNA against Cnpy2 has antitumor effects in HCC. CONCLUSIONS: These findings demonstrate that CNPY2 is crucial for liver oncogenesis through UPR-dependent repression of p53 and activation of oncogenes, providing insights into the design of a therapeutic target for HCC.

TLR7 activation by miR-21 promotes renal fibrosis by activating the pro-inflammatory signaling pathway in tubule epithelial cells.

BACKGROUND: Toll-like receptor 7 (TLR7) is an endosomal TLR activated by single-stranded RNA, including endogenous microRNAs. Although TLR7 is known to promote inflammatory responses in pathophysiological conditions, its role in renal fibrosis has not been investigated. Here, we aim to investigate the inflammatory roles of TLR7 in kidney inflammation and fibrosis. METHODS: TLR7 knockout mice (Tlr7 -/-) subjected to AD-induced kidney injury were utilized to examine the role of TLR7 in kidney fibrosis. To elucidate the role of TLR7 in renal epithelial cells, NRK52E rat renal tubule epithelial cells were employed. RESULTS: Under fibrotic conditions induced by an adenine diet (AD), TLR7 was significantly increased in damaged tubule epithelial cells, where macrophages were highly infiltrated. TLR7 deficiency protected against AD-induced tubular damage, inflammation, and renal fibrosis. Under in vitro conditions, TLR7 activation increased NF-κB activity and induced chemokine expression, whereas TLR7 inhibition effectively blocked NF-κB activation. Furthermore, among the known TLR7 endogenous ligands, miR-21 was significantly upregulated in the tubular epithelial regions. In NRK52E cells, miR-21 treatment induced pro-inflammatory responses, which could be blocked by a TLR7 inhibitor. When the TLR7 inhibitor, M5049, was administered to the AD-induced renal fibrosis model, TLR7 inhibition significantly attenuated AD-induced renal inflammation and fibrosis. CONCLUSIONS: Overall, activation of TLR7 by endogenous miR-21 in renal epithelial cells contributes to inflammatory responses in a renal fibrosis model, suggesting a possible therapeutic target for the treatment of renal fibrosis. Video Abstract.

Contribution of Salvaged Blood Red Blood Cell Transfusion During Living Donor Liver Transplantation.

BACKGROUND: Transfusion of allogeneic blood products can have adverse effects and profoundly influence postoperative liver transplantation outcomes, including graft survival. To minimize allogeneic red blood cell (RBC) transfusion, salvaged blood can be used during liver transplantation. The aim of this study was to determine the contribution of salvaged blood to allogeneic RBC transfusion in living donor liver transplantation (LDLT) recipients. METHODS: Data of 311 adult-to-adult LDLT recipients between January 2015 and April 2019 were analyzed. The primary outcome was a change in requirement for allogeneic RBCs due to the use of salvaged blood. Additionally, predictors of intraoperative allogeneic RBC transfusion were investigated. RESULTS: One hundred fifty-three (49.2%) recipients required allogeneic RBC transfusion. If recipients did not receive salvaged blood, 253 (81.4%) recipients would have needed allogeneic RBC transfusion. The total volume of salvaged blood transfused into recipients during surgery was 269,165 mL, which corresponded to 993 units of allogeneic RBCs and accounted for 76.1% of total RBC transfusion volume. Multivariate analysis showed that male recipients, model for end-stage liver disease score, preoperative hemoglobin level, and volume of salvaged blood used during surgery were independent predictors of the need for intraoperative allogenic RBC transfusion. CONCLUSIONS: Intraoperative use of salvaged blood significantly reduced allogeneic RBC transfusion in LDLT recipients. It can help transplant teams manage transfusion of allogeneic RBCs during liver transplantation.

Comparison of the perfusion index as an index of noxious stimulation in monitored anesthesia care of propofol/remifentanil and propofol/dexmedetomidine: a prospective, randomized, case-control, observational study.

BACKGROUND: Dexmedetomidine, one of the sedatives, has an analgesic effect. We aimed to investigate postoperative analgesia with dexmedetomidine as adjuvants for procedural sedation using perfusion index (PI). METHODS: In this prospective, randomized, case-control, observational study, 72 adult patients, 19-70 years, who were scheduled for chemoport insertion under monitored anesthesia care were performed. According to the group assignment, remifentanil or dexmedetomidine was simultaneously infused with propofol. The primary outcome was PI 30 min after admission to the post anesthesia care unit (PACU). And, pain severity using numerical rating scale (NRS) score and the relationship between NRS score and PI were investigated. RESULTS: During PACU staying, PI values were significantly different between the two groups PI values at 30 min after admission to the PACU were 1.3 (0.9-2.0) in the remifentanil group and 4.5 (2.9-6.8) in the dexmedetomidine group (median difference, 3; 95% CI, 2.1 to 4.2; P < 0.001). The NRS scores at 30 min after admission to the PACU were significantly lower in the dexmedetomidine group (P = 0.002). However, there was a weak positive correlation between NRS score and PI in the PACU (correlation coefficient, 0.188; P = 0.01). CONCLUSION: We could not find a significant correlation between PI and NRS score for postoperative pain control. Using PI as a single indicator of pain is insufficient. TRIAL REGISTRATION: Clinical Trial Registry of Korea, https://cris.nih.go.kr : KCT0003501, the date of registration: 13/02/2019.

The utility of the perfusion index as an indicator of anesthetic depth for repeated propofol sedation in children: An observational study.

BACKGROUND: Children receiving proton therapy require repeated sedation. In this study, we aimed to investigate the utility of the perfusion index (PI) for evaluating consciousness level during repeated propofol sedation. METHODS: In this prospective observational study, children aged from birth to 19 years old scheduled for proton therapy under repeated propofol sedation were enrolled. The primary outcome was the equivalence of PI values 5 min after anesthesia induction on consecutive sedation. Total consumption of propofol during sedation, time to reach the University of Michigan sedation scale (UMSS) score 1 after end of proton therapy, and duration of post-anesthesia care unit (PACU) stay were recorded. RESULTS: The PI values measured 5 min after induction of anesthesia were not equivalent to each other in consecutive sedation except for the second versus third (1st vs. 2nd: 97.5% CI: -1.34, 0.91; p = 0.206, 0.034; 2nd vs. 3rd: 97.5% CI: -0.87, 0.94; p = 0.023, 0.036 3rd vs. 4th: 97.5% CI: -2.08, -0.26; p < 0.99, <0.001; 4th vs. 5th: 97.5% CI: 0.21, 2.28; p < 0.001, >0.99; respectively). In consecutive sedation, there was not a significantly different difference in the time to reach UMSS score 1 (p > 0.99, all) for total consumption of propofol, time to reach UMSS score 1 after the end of proton therapy, and duration of PACU stay. CONCLUSIONS: During repeated propofol sedation in children, PI was insufficient to be used as an indicator of consciousness level assessment. However, we suggest that the information related to repeated sedation provided by this study may be helpful in clinical practice.

Development of a Polymersome-Based Nanomedicine for Chemotherapeutic and Sonodynamic Combination Therapy.

In anticancer therapy, combination therapy has been suggested as an alternative to the insufficient therapeutic efficacy of single therapy. Among combination therapies, combination chemo- and photodynamic therapy are actively investigated. However, photodynamic therapy shows a limitation in the penetration depth of the laser. Therefore, sonodynamic therapy (SDT), using ultrasound instead of a laser as a trigger, is an upcoming strategy for deep tumors. Additionally, free drugs are easily degraded by enzymes, have difficulty in reaching the target site, and show side effects after systemic administration; therefore, the development of drug delivery systems is desirable for sufficient drug efficacy for combination therapy. However, nanocarriers, such as microbubbles, and albumin nanoparticles, are unstable in the body and show low drug-loading efficiency. Here, we propose polylactide (PLA)-poly (ethylene glycol) (PEG) polymersomes (PLs) with a high drug loading rate of doxorubicin (DOX) and verteporfin (VP) for effective combination therapy in both in vitro and in vivo experiments. The cellular uptake efficiency and cytotoxicity test results of VP-DOX-PLs were higher than that of single therapy. Moreover, in vivo biodistribution showed the accumulation of the VP-DOX-PLs in tumor regions. Therefore, VP-DOX-PLs showed more effective anticancer efficacy than either single therapy in vivo. These results suggest that the combination therapy of SDT and chemotherapy could show novel anticancer effects using VP-DOX-PLs.

PPAR Pan Agonist MHY2013 Alleviates Renal Fibrosis in a Mouse Model by Reducing Fibroblast Activation and Epithelial Inflammation.

The peroxisome proliferator-activated receptor (PPAR) nuclear receptor has been an interesting target for the treatment of chronic diseases. Although the efficacy of PPAR pan agonists in several metabolic diseases has been well studied, the effect of PPAR pan agonists on kidney fibrosis development has not been demonstrated. To evaluate the effect of the PPAR pan agonist MHY2013, a folic acid (FA)-induced in vivo kidney fibrosis model was used. MHY2013 treatment significantly controlled decline in kidney function, tubule dilation, and FA-induced kidney damage. The extent of fibrosis determined using biochemical and histological methods showed that MHY2013 effectively blocked the development of fibrosis. Pro-inflammatory responses, including cytokine and chemokine expression, inflammatory cell infiltration, and NF-κB activation, were all reduced with MHY2013 treatment. To demonstrate the anti-fibrotic and anti-inflammatory mechanisms of MHY2013, in vitro studies were conducted using NRK49F kidney fibroblasts and NRK52E kidney epithelial cells. In the NRK49F kidney fibroblasts, MHY2013 treatment significantly reduced TGF-ß-induced fibroblast activation. The gene and protein expressions of collagen I and α-smooth muscle actin were significantly reduced with MHY2013 treatment. Using PPAR transfection, we found that PPARγ played a major role in blocking fibroblast activation. In addition, MHY2013 significantly reduced LPS-induced NF-κB activation and chemokine expression mainly through PPARß activation. Taken together, our results suggest that administration of the PPAR pan agonist effectively prevented renal fibrosis in both in vitro and in vivo models of kidney fibrosis, implicating the therapeutic potential of PPAR agonists against chronic kidney diseases.

Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis.

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation, aberrant differentiation of keratinocytes, and dysregulated immune responses. WW domain-containing oxidoreductase (WWOX) is a non-classical tumor suppressor gene that regulates multiple cellular processes, including proliferation, apoptosis, and migration. This study aimed to explore the possible role of WWOX in the pathogenesis of psoriasis. Immunohistochemical analysis showed that the expression of WWOX was increased in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model. Immortalized human epidermal keratinocytes were transduced with a recombinant adenovirus expressing microRNA specific for WWOX to downregulate its expression. Inflammatory responses were detected using Western blotting, real-time quantitative reverse transcription polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay. In human epidermal keratinocytes, WWOX knockdown reduced nuclear factor-kappa B signaling and levels of proinflammatory cytokines induced by polyinosinic: polycytidylic acid [(poly(I:C)] in vitro. Furthermore, calcium chelator and protein kinase C (PKC) inhibitors significantly reduced poly(I:C)-induced inflammatory reactions. WWOX plays a role in the inflammatory reaction of epidermal keratinocytes by regulating calcium and PKC signaling. Targeting WWOX could be a novel therapeutic approach for psoriasis in the future.

Development of Polymersomes Co-Delivering Doxorubicin and Melittin to Overcome Multidrug Resistance.

Multidrug resistance (MDR) is one of the major barriers in chemotherapy. It is often related to the overexpression of efflux receptors such as P-glycoprotein (P-gp). Overexpressed efflux receptors inhibit chemotherapeutic efficacy by pumping out intracellularly delivered anticancer drugs. In P-gp-mediated MDR-related pathways, PI3K/Akt and NF-kB pathways are commonly activated signaling pathways, but these pathways are downregulated by melittin, a main component of bee venom. In this study, a polymersome based on a poly (lactic acid) (PLA)-hyaluronic acid (HA) (20k-10k) di-block copolymer and encapsulating melittin and doxorubicin was developed to overcome anticancer resistance and enhance chemotherapeutic efficacy. Through the simultaneous delivery of doxorubicin and melittin, PI3K/Akt and NF-κB pathways could be effectively inhibited, thereby downregulating P-gp and successfully enhancing chemotherapeutic efficacy. In conclusion, a polymersome carrying an anticancer drug and melittin could overcome MDR by regulating P-gp overexpression pathways.