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Type 2 diabetes is a chronic disease characterized by insulin resistance and often worsened by obesity. Effective management involves the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to assist with glycemic control and weight management. However, these drugs must be administered subcutaneously due to their low oral bioavailability. We developed an oral liraglutide (LRG) formulation by electrostatic complexation of GLP-1 RA with bile acid derivatives and nanomicelle (NM) formation, with non-ionic surfactant n-dodecyl-β-d-maltoside (DDM). The optimized formulation, LDD[1:2:4]-NM, had a mean particle size of 75.9 ± 5.60 nm and a permeability 1347 % higher than that of unformulated LRG when tested in Caco-2/HT29-MTX-E12 cell monolayers. In rats, oral bioavailability was 4.63-fold higher than that of unformulated LRG (1.11 ± 0.20 % vs. 5.14 ± 0.63 %). The absorption mechanism included clathrin-mediated endocytosis, macropinocytosis, and an ASBT-mediated pathway. A 12-week oral treatment consisting of a daily dose of 20 mg LDD[1:2:4]-NM/kg significantly reduced glycohemoglobin levels, a marker of diabetic control, and the HOMA-IR index, a marker of insulin resistance. The weight of epididymal and inguinal white adipose tissue and brown adipose tissue (BAT) was also reduced. Moreover, LDD[1:2:4]-NM had a greater impact on BAT activation, pro-inflammatory gene expression, and lipid metabolism than subcutaneous LRG. This study showed that an oral NM formulation can efficiently deliver LRG. Long-term treatment led to improved hyperglycemic effects, insulin resistance, and modulated lipid metabolism. LDD[1:2:4]-NM is thus a promising oral therapeutic option for the management of type 2 diabetes, potentially transforming treatment paradigms based on the availability of a more convenient administration route., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Mesenchymal stem cells (MSCs) offer a promising avenue for cartilage regeneration; however, their therapeutic efficacy requires substantial improvement. Cell priming using electrical stimulation (ES) is a promising approach to augmenting the therapeutic potential of MSCs and has shown potential for various regenerative applications. This study aimed to promote the ES-mediated chondrogenic differentiation of human MSCs and facilitate the repair of injured articular cartilage. Methods: MSCs were subjected to ES under various conditions (e.g., voltage, frequency, and number of repetitions) to enhance their capability of chondrogenesis and cartilage regeneration. Chondrogenic differentiation of electrically primed MSCs (epMSCs) was assessed based on gene expression and sulfated glycosaminoglycan production, and epMSCs with hyaluronic acid were transplanted into a rat osteochondral defect model. Transcriptomic analysis was performed to determine changes in gene expression by ES. Results: epMSCs exhibited significantly increased chondrogenic gene expression and sulfated glycosaminoglycan production compared with those in unstimulated controls. Macroscopic and histological results showed that in vivo epMSC transplantation considerably enhanced cartilage regeneration. Furthermore, ES markedly altered the expression of numerous genes of MSCs, including those associated with the extracellular matrix, the Wnt signaling pathway, and cartilage development. Conclusion: ES can effectively prime MSCs to improve articular cartilage repair, offering a promising strategy for enhancing the efficacy of various MSC-based therapies., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 Jongdarm Yi et al.)

Oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are highly prevalent in pancreatic ductal adenocarcinoma (PDAC) and have garnered attention as potential targets for targeted therapies, such as KRAS inhibitors. However, the limited therapeutic efficacy of KRAS allele-specific inhibitors necessitate an efficient pan-KRAS cancer cell killing strategy. Here, we have examined enhanced macropinocytosis pathway in KRAS mutant cancer cells and report improved intracellular delivery of albumin-based therapeutics. We further established an albumin-binding peptide-docetaxel conjugate platform (MPD3), which has a caspase-3 cleavable feature, for macropinocytosis-targeted bystander payload delivery and realization of bystander killing of pan-KRAS cancer cells, complemented with caspase-3 mediated activation of MPD3 to bolster tumoral accumulation of cytotoxic payloads. Utilization of in vitro co-culture system of pan-KRAS cancer cells and pharmacodynamic marker staining revealed potent bystander killing effects of MPD3, highlighting MPD3 as an efficient delivery platform against pan-KRAS cancer. Moreover, MPD3 elicited robust anti-tumor activities in both local and liver metastatic PDAC tumor models in mice. Overall, this work establishes a paradigm for developing translational pan-KRAS cancer treatment and broadens the applicability of albumin binding peptide-drug conjugate against albumin-metabolism enriched cancers., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

In this comprehensive large-scale study, conducted from 2015 to 2019, 7,209 wild boars across South Korea were sampled to assess their exposure to influenza A viruses (IAVs). Of these, 250 (3.5%) were found to be IAV-positive by ELISA, and 150 (2.1%) by the hemagglutination inhibition test. Detected subtypes included 23 cases of pandemic 2009 H1N1, six of human seasonal H3N2, three of classical swine H1N1, 13 of triple-reassortant swine H1N2, seven of triple-reassortant swine H3N2, and seven of swine-origin H3N2 variant. Notably, none of the serum samples tested positive for avian IAV subtypes H3N8, H5N3, H7N7, and H9N2 or canine IAV subtype H3N2. This serologic analysis confirmed the exposure of Korean wild boars to various subtypes of swine and human influenza viruses, with some serum samples cross-reacting between swine and human strains, indicating potential infections with multiple IAVs. The results highlight the potential of wild boar as a novel mixing vessel, facilitating the adaptation of IAVs and their spillover to other hosts, including humans. In light of these findings, we recommend regular and frequent surveillance of circulating influenza viruses in the wild boar population as a proactive measure to prevent potential human influenza pandemics and wild boar influenza epizootics., Competing Interests: Declaration. Conflict of Interest: The authors declare that they have no competing interest., (© 2024. EcoHealth Alliance.)

Despite significant progress in combining cancer immunotherapy with chemotherapy to treat triple negative breast cancer (TNBC), challenges persist due to target depletion and tumor heterogeneity, especially in metastasis. Chemotherapy lacks precise targeting abilities, and targeted therapy is inadequate in addressing the diverse heterogeneity of tumors. To address these challenges, we introduce RGDEVD-DOX as a tumor-specific immunogenic agent, namely TPD1, which targets integrin αvβ3 and gets continuously activated by apoptosis. TPD1 facilitates the caspase-3-mediated in situ amplification that results in tumor-specific accumulation of doxorubicin. This local concentration of doxorubicin induces immunogenic cell death and promotes the recruitment of immune cells to the tumor site. Notably, the tumor-targeting capabilities of TPD1 help bypass the systemic immunotoxicity of doxorubicin. Consequently, this alters the tumor microenvironment, converting it into a 'hot' tumor that is more susceptible to immune checkpoint inhibition. We demonstrated the anti-metastatic and anti-cancer efficacy of this treatment using various xenograft and metastatic models. This study underscores the high potential of caspase-3 cleavable peptide-drug conjugates to be used in conjunction with anti-cancer immunotherapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The auditory brainstem response (ABR) is a noninvasive test that measures neural activity in response to auditory stimuli. Racial differences in head shape have provided strong evidence for specific normative data and accurate device calibration. International standards emphasize the need for standardized procedures and references. This study aimed to outline the standard procedure and related normative ABR values. Standard procedures were performed according to International Electrotechnical Commission (IEC) standards. Five studies from two countries were included to compare the normative values of the ABR. The dataset from the National Standard Reference Data Center (NSRDC) was used as reference. Normative values were described in terms of stimuli, latency, and amplitude. For click stimuli, the latency of the ABR showed different patterns across populations, such as those from Korea and the USA. Although the latencies reported by the NSRDC and for Koreans were relatively short, those reported for USA populations were longer. Using clicks, it was shown that the USA population had the largest ABR amplitude compared to those reported for the other two datasets. For Wave V latency using tone bursts, a similar pattern was identified with click stimuli. Frequency-specific trends were also observed. Although there is a lack of ABR datasets, the information and insights of the present study could be utilized as standard guidelines in research on ABR.

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy., Competing Interests: Declaration of competing interest There are no known competing financial interests or personal relationships that could have potentially influenced the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Oxidative stress caused by reactive oxygen species (ROS) is one of the major causes of senescence. Strategies to reduce ROS are known to be important factors in reversing senescence, but effective strategies have not been found. In this study, we screened substances commonly used as cosmetic additives to find substances with antioxidant effects. Polygonum cuspidatum ( P. cuspidatum ) extract significantly reduced ROS levels in senescent cells. A novel mechanism was discovered in which P. cuspidatum extract reduced ROS, a byproduct of inefficient oxidative phosphorylation (OXPHOS), by increasing OXPHOS efficiency. The reduction in ROS by P. cuspidatum extract restored senescence-associated phenotypes and enhanced skin protection. Then, we identified polydatin as the active ingredient of P. cuspidatum extract that exhibited antioxidant effects. Polydatin, which contains stilbenoid polyphenols that act as singlet oxygen scavengers through redox reactions, increased OXPHOS efficiency and subsequently restored senescence-associated phenotypes. In summary, our data confirmed the effects of P. cuspidatum extract on senescence rejuvenation and skin protection through ROS reduction. This novel finding may be used as a treatment in senescence rejuvenation in clinical and cosmetic fields.

This work shows that various polyurethanes (FPUs) prepared using biomass-derived furan diols can be applied as promising tribopositive materials. The elastic FPUs having appropriate glass transition temperature ( T g ) could be incorporated into polyethylene terephthalate (PET) fabrics to form FPU/PET films. The optimal FPU-4/PET film showed promising triboelectric performance with output voltages ( V p-p ) up to 405 V and a maximum power density ( P max ) of 32 mW cm -2 .

As cellular senescence, reactive oxygen species (ROS) accumulate excessively, causing cellular damage. Flavonoids derived from natural products are known for their antioxidant effects and their ability to delay cellular senescence. Previous studies have attempted to mitigate cellular senescence using flavonoids from natural sources. However, the detailed mechanisms and regulatory targets of some flavonoids exhibiting antioxidant effects have not been fully elucidated. Therefore, we screened a library of flavonoids for antioxidant properties. Isoschaftoside, a glycosidic flavonoid, significantly reduced ROS levels in senescent cells. It was found that mitochondrial function was restored, and dependence on glycolysis was reduced in senescent cells treated with isoschaftoside. Additionally, we identified that isoschaftoside suppresses ROS by reducing the expression of RAC2 and LINC00294 in senescent cells. Taken together, this study establishes a novel mechanism for ROS inhibition and the regulation of cellular senescence by isoschaftoside. Our findings contribute important insights to antioxidant and anti-senescence research.

Extracellular vesicles (EVs) have emerged as a potential delivery vehicle for nucleic-acid-based therapeutics, but challenges related to their large-scale production and cargo-loading efficiency have limited their therapeutic potential. To address these issues, we developed a novel "shock wave extracellular vesicles engineering technology" (SWEET) as a non-genetic, scalable manufacturing strategy that uses shock waves (SWs) to encapsulate siRNAs in EVs. Here, we describe the use of the SWEET platform to load large quantities of KRAS G12C -targeting siRNA into small bovine-milk-derived EVs (sBMEVs), with high efficiency. The siRNA-loaded sBMEVs effectively silenced oncogenic KRAS G12C expression in cancer cells; they inhibited tumour growth when administered intravenously in a non-small cell lung cancer xenograft mouse model. Our study demonstrates the potential for the SWEET platform to serve as a novel method that allows large-scale production of cargo-loaded EVs for use in a wide range of therapeutic applications., (© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Polyunsaturated fatty acids and their metabolites have been reported in which their pathway has potential for the modulation of cancer cell growth. 13-( S )-HODE and 15-( S )-HETE, both of which are main metabolites of 15-LOXs, play an important role as endogenous ligands in biological systems. However, the modification of 13-( S )-HODE and 15-( S )-HETE in pharmaceutical applications has not been explored widely. Herein, we report the stereoselective syntheses of 13-( S )-HODE, 15-( S )-HETE, and its derivatives to enable the synthesis of bioactive fatty acid analogues.

Most triblock copolymer-based physical hydrogels form three-dimensional networks through micellar packing, and formation of polymer loops represents a topological defect that diminishes hydrogel elasticity. This effect can be mitigated by maximizing the fraction of elastically effective bridges in the hydrogel network. Herein, we report hydrogels constructed by complexing oppositely charged multiblock copolymers designed with a sequence pattern that maximizes the entropic and enthalpic penalty of micellization. These copolymers self-assemble into branched and bridge-rich network units (netmers), instead of forming sparsely interlinked micelles. We find that the storage modulus of the netmer-based hydrogel is 11.5 times higher than that of the micelle-based hydrogel. Complementary coarse grained molecular dynamics simulations reveal that in the netmer-based hydrogels, the numbers of charge-complexed nodes and mechanically reinforcing bridges increase substantially relative to micelle-based hydrogels., (© 2024. The Author(s).)

KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers. This PDC is specifically designed to trigger a positive feedback loop through its caspase-3 cleavable characteristic. However, we observe that this loop is hindered by DNA-PK mediated DNA damage repair processes in cancer cells. To counter this impediment, we employ AZD7648, a DNA-PK inhibitor. Interestingly, the combined treatment of MPD1 and AZD7648 resulted in a 100% complete response rate in KRAS-mutant xenograft model. We focus on the synergic mechanism of it. We discover that AZD7648 specifically enhances macropinocytosis in KRAS-mutant cancer cells. Further analysis uncovers a significant correlation between the increase in macropinocytosis and PI3K signaling, driven by AMPK pathways. Also, AZD7648 reinforces the positive feedback loop, leading to escalated apoptosis and enhanced payload accumulation within tumors. AZD7648 possesses broad applications in augmenting nano-sized drug delivery and preventing DNA repair resistance. The promising efficacy and evident synergy underscore the potential of combining MPD1 with AZD7648 as a strategy for treating KRAS-mutant cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Detecting ovarian cancer (OC) early using existing biomarkers, e.g., cancer antigen 125 (CA125), is challenging due to its ubiquitous expression in many tissues. Doppel, a prion-like protein, expresses in male reproductive organ but absent in female reproductive systems and healthy tissues, but plays an important role in neoangiogenesis. Here, we have shown two platforms, soluble Doppel in sera/ascites and Doppel expressed circulating tumor cells ( Dpl+ CTC) in the whole blood, to detect subsets of epithelial OC (EOC). Increased level of Doppel in the sera of OC patients, in three different cohorts, confirm Doppel as OC specific biomarker. Serum Doppel level distinguishes EOC subtypes and early stages HGSOCs from non-cancerous conditions with high sensitivity and specificity. Stratifying the EOCs based on Doppel level, we categorized them into Doppel-high (Dpl hi ) and Doppel-low (Dpl low ) groups. Using ascites-derived organoids and single cell sequencing of whole ascites of Dpl hi and Dpl low patients, we identify that Doppel induces epithelial-mesenchymal transition (EMT) and creates an immunosuppressive microenvironment, respectively. Doppel levels in the sera/ascites correlate with the changes of Dpl+ CTC number in whole blood, highlighting the association of Doppel-induced EMT with CTC dissemination in circulation. Thus, Doppel-based detection of EOC subtypes could be a promising platform as clinical biomarker and link Doppel-axis with OC dissemination.

Background: Few studies have evaluated the comparative efficacy of biologics for asthma. This network meta-analysis aimed to compare the efficacy of biologics., Methods: This study included randomized controlled trials (RCTs) evaluating the efficacy of a biologic compared to a placebo or another biologic in patients with inadequately controlled asthma despite high-intensity treatment, published by January 6, 2022. Two researchers independently searched the PubMed, Embase, Web of Science, and Scopus and assessed the risk of bias using the Cochrane tool. The outcomes of interest were the annual asthma exacerbation rate (AER), forced expiratory volume per second before bronchodilator use (preBD FEV1), the asthma control questionnaire (ACQ), and asthma quality of life questionnaire (AQLQ) results. A frequentist network meta-analysis was conducted, and a random effects model was used to draw pooled incidence rate ratio or standardized mean differences., Results: Twenty-three RCTs with 8376 participants were retrieved. All biologics included in this study were associated with significantly better effects than placebo in AER, preBD FEV1, and ACQ outcomes. Although there were no significant differences between the biologics in the overall study population, patients with eosinophil levels ≥300 cells/μL or eosinophilic asthma showed that dupilumab and tezepelumab were significantly better than anti-IL-5 biologics in improving preBD FEV1. Additionally, in patients with eosinophil levels ≥300 cells/μL, benralizumab, unlike reslizumab, performed significantly better than placebo in improving ACQ and AQLQ outcomes., Conclusion: The comparative effects of biologics can be considered with phenotypes and biomarkers to help clinicians select an appropriate treatment for inadequately controlled asthma., Competing Interests: The authors report no competing interests., (© 2024 The Authors.)

This work demonstrates the low-temperature operation of solid-state lithium metal batteries (LMBs) through the development of a fluorinated and plastic-crystal-embedded elastomeric electrolyte (F-PCEE). The F-PCEE is formed via polymerization-induced phase separation between the polymer matrix and plastic crystal phase, offering a high mechanical strain (≈300%) and ionic conductivity (≈0.23 mS cm -1 ) at -10 °C. Notably, strong phase separation between two phases leads to the selective distribution of lithium (Li) salts within the plastic crystal phase, enabling superior elasticity and high ionic conductivity at low temperatures. The F-PCEE in a Li/LiNi 0.8 Co 0.1 Mn 0.1 O 2 full cell maintains 74.4% and 42.5% of discharge capacity at -10 °C and -20 °C, respectively, compared to that at 25 °C. Furthermore, the full cell exhibits 85.3% capacity retention after 150 cycles at -10 °C and a high cut-off voltage of 4.5 V, representing one of the highest cycling performances among the reported solid polymer electrolytes for low-temperature LMBs. This work attributes the prolonged cycling lifetime of F-PCEE at -10 °C to the great mechanical robustness to suppress the Li-dendrite growth and ability to form superior LiF-rich interphases. This study establishes the design strategies of elastomeric electrolytes for developing solid-state LMBs operating at low temperatures and high voltages., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Detecting aberrant cell-free DNA (cfDNA) methylation is a promising strategy for lung cancer diagnosis. In this study, our aim is to identify methylation markers to distinguish patients with lung cancer from healthy individuals. Additionally, we sought to develop a deep learning model incorporating cfDNA methylation and fragment size profiles. To achieve this, we utilized methylation data collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Then we generated methylated DNA immunoprecipitation sequencing and genome-wide Enzymatic Methyl-seq (EM-seq) form lung cancer tissue and plasma. Using these data, we selected 366 methylation markers. A targeted EM-seq panel was designed using the selected markers, and 142 lung cancer and 56 healthy samples were produced with the panel. Additionally, cfDNA samples from healthy individuals and lung cancer patients were diluted to evaluate sensitivity. Its lung cancer detection performance reached an accuracy of 81.5% and an area under the receiver operating characteristic curve of 0.87. In the serial dilution experiment, we achieved tumor fraction detection of 1% at 98% specificity and 0.1% at 80% specificity. In conclusion, we successfully developed and validated a combination of methylation panel and a deep learning model that can distinguish between patients with lung cancer and healthy individuals., (© 2024. The Author(s).)

π-Conjugated organic semiconductors with tunable electronic structures are new prospective active substrate materials for surface-enhanced Raman scattering (SERS). However, observing higher SERS activity when using organic semiconductors as substrates could be difficult because there is no plasmonic effect of hot electrons. Here, we designed a Ag-reduced graphene oxide (rGO) structure, introduced it into a poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate) (PEDOT:PSS) solution, and spin-coated the solution to obtain a Ag-rGO/PEDOT:PSS (ARPP) film. Our analyses demonstrate that the introduction of this Ag-rGO structure can not only enhance the electromagnetic field effect based on plasmon resonance but also improve the interaction between the target molecule and the substrate in the ARPP film. This innovative approach not only improves the SERS activity of π-conjugated organic polymers but also provides novel ideas for the preparation of other organic semiconductor-based SERS substrates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: For maintenance therapy in type 2 diabetes, glucagon-like peptide-1 agonist (GLP-1A), which exhibits low cardiovascular risk and high efficacy, is a promising peptide therapeutic. However, developing an oral GLP-1A presents challenges due to the analog's poor cellular permeability and gastrointestinal (GI) stability., Methods: To mitigate such limitations, an oral nanoformulation of liraglutide (LG) was designed and achieved by combining LG with bile acid derivatives using the nanoprecipitation method. This strategy allowed the bile acid moieties to localize at the nanoparticle surface, enhancing the binding affinity for apical sodium-dependent bile acid transporter (ASBT) and improving GI stability. The in vitro characteristics, cellular permeability, and absorption mechanisms of the LG nanoformulation (LG/TD-NF) were thoroughly investigated. Furthermore, the in vivo oral absorption in rats and the glucose-lowering effects in a diabetic ( db/db ) mouse model were evaluated., Results: The LG/TD-NF produced neutral nanoparticles with a diameter of 58.7 ± 4.3 nm and a zeta potential of 4.9 ± 0.4 mV. Notably, when exposed to simulated gastric fluid, 65.7 ± 3.6% of the LG/TD-NF remained stable over 120 min, while free LG was fully degraded. Relative to unformulated LG, the Caco-2 cellular permeability of the nanoformulation improved, measuring 10.9 ± 2.1 (× 10 -6 cm/s). The absorption mechanism prominently featured endocytosis simultaneously mediated by both ASBT and epidermal growth factor receptor (EGFR). The oral bioavailability of the LG/TD-NF was determined to be 3.62% at a dosage of 10 mg/kg, which is 45.3 times greater than that of free LG. In a diabetes model, LG/TD-NF at 10 mg/kg/day exhibited commendable glucose sensitivity and reduced HbA1c levels by 4.13% within 28 days, similar to that of subcutaneously administered LG at a dosage of 0.1 mg/kg/day., Conclusion: The oral LG/TD-NF promotes ASBT/EGFR-mediated transcytosis and assures cellular permeability within the GI tract. This method holds promise for the development of oral GLP-1A peptides as an alternative to injections, potentially enhancing patient adherence to maintenance therapy., Competing Interests: The authors declare that there are no conflicts of interest associated with this work., (© 2024 Kweon et al.)

Abstract: Psychological symptomatology and quality of life (QoL) have been studied in older people with HIV (PWH) and those with chronic obstructive pulmonary disease (COPD), respectively, but there is a dearth of studies in older PWH with COPD. Our study compared depressive symptoms, anxiety, and QoL between older PWH with and without COPD using data from an HIV clinic in Birmingham, Alabama, from January 2018 to February 2020. Data on depressive symptoms (Patient Health Questionnaire-9), anxiety (Patient Health Questionnaire-5 Anxiety), and QoL (EuroQoL-5 Dimension) were analyzed. Among 690 PWH aged 50 years or older, 102 individuals (14.8%) had COPD. Significant differences were found between the two groups in depressive symptoms and components of QoL (e.g., mobility, self-care, usual activities, and pain/discomfort), but not in anxiety and general health. Experiencing COPD may worsen depressive symptomatology and QoL in older PWH, highlighting the need for tailored health care and research for this population., (Copyright © 2024 Association of Nurses in AIDS Care.)

The exclusion of social play within an adolescent group interferes with learning and the acquisition of essential social behavior during development and can cause modulations in the social brain areas. However, despite the importance of social play in adolescence, an in-depth explanation of its physiological mechanisms is limited because of the lack of experimental animal models that embody social play exclusion in human society. To determine the mechanism of social play in adolescence, we identified differences in emotional behavior and brain activity in animal models of social play exclusion that mimicked human society. Emotional changes in the social play exclusion and non-exclusion groups were examined by tracking social play-related social interaction behavior, social play-related space preference, social play-related locomotor behavior, and anxiety-like behavior using a behavioral data analysis program. Differences in brain activity among groups were identified using immunohistochemical staining. During the social play exclusion model, the rats preferred the partition zone to the other areas in the test chamber. The exclusion group preferred the partition and the center zone over the non-exclusion group. When comparing before and after the social play exclusion, the exclusion group showed a decrease in mobility and an increase in anxiety-like behavior compared to the non-exclusion group. We found that c-Fos expression in the dentate gyrus (DG) of the exclusion group was lower than that in the non-exclusion group, whereas c-Fos expression in the lateral habenula (LHb) of the exclusion group was higher than that in the non-exclusion group. Taken together, in adolescence, exclusion from social play with peers can increase anxiety-like behavior in the exclusion group and change the neuronal activity of the DG and LHb, suggesting that exclusion from social play is linked to modifications in the DG and LHb, which are regions associated with mood regulation., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sac embolization of abdominal aortic aneurysms (AAAs) remains clinically limited by endoleak recurrences. These recurrences are correlated with recanalization due to the presence of endothelial lining and matrix metalloproteinases (MMPs)-mediated aneurysm progression. This study incorporated doxycycline (DOX), a well-known sclerosant and MMPs inhibitor, into a shear-thinning biomaterial (STB)-based vascular embolizing hydrogel. The addition of DOX was expected to improve embolizing efficacy while preventing endoleaks by inhibiting MMP activity and promoting endothelial removal. The results showed that STBs containing 4.5% w/w silicate nanoplatelet and 0.3% w/v of DOX were injectable and had a 2-fold increase in storage modulus compared to those without DOX. STB-DOX hydrogels also reduced clotting time by 33% compared to untreated blood. The burst release of DOX from the hydrogels showed sclerosing effects after 6 h in an ex vivo pig aorta model. Sustained release of DOX from hydrogels on endothelial cells showed MMP inhibition ( ca . an order of magnitude larger than control groups) after 7 days. The hydrogels successfully occluded a patient-derived abdominal aneurysm model at physiological blood pressures and flow rates. The sclerosing and MMP inhibition characteristics in the engineered multifunctional STB-DOX hydrogels may provide promising opportunities for the efficient embolization of aneurysms in blood vessels., Competing Interests: Conflict of Interest A.K. is the Co-founder of a start-up, Obsidio, Inc., which is based on shear-thinning embolic materials. Now Obsidio is a part of Boston Scientific.

Inositol polyphosphates (IPs) are a group of inositol metabolites that act as secondary messengers for external signalling cues. They play various physiological roles such as insulin release, telomere length maintenance, cell metabolism, and aging. Inositol hexakisphosphate kinase 2 (IP6K2) is a key enzyme that produces 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-IP7), which influences the early stages of glucose-induced exocytosis. Therefore, regulation of IP6Ks may serve as a promising strategy for treating diseases such as diabetes and obesity. In this study, we designed, synthesised, and evaluated flavonoid-based compounds as new inhibitors of IP6K2. Structure-activity relationship studies identified compound 20s as the most potent IP6K2 inhibitor with an IC 50 value of 0.55 μM, making it 5-fold more potent than quercetin, the reported flavonoid-based IP6K2 inhibitor. Compound 20s showed higher inhibitory potency against IP6K2 than IP6K1 and IP6K3. Compound 20s can be utilised as a hit compound for further structural modifications of IP6K2 inhibitors.

Nitrogen-doped carbon dots (CDs) have attracted considerable attention across various research areas and applications due to their enhanced optical properties and photostability. However, the mechanism of nitrogen incorporation in CDs remains elusive, hampering the precise control over nitrogen-incorporated structures and the investigation of the effects of nitrogen on the electronic structure and optical properties of CDs. In this study, we employed a rational design approach, utilizing glucosamine and ethylene glycol as the carbon source and co-reagent, respectively, to synthesize N-doped CDs. Our synthesis strategy involved pinacol rearrangement and iminium ion cyclization reactions, enabling the reliable formation of N-doped CDs. Notably, the resulting CDs exhibited distinctive emissive states attributed to heteroatomic defect structures, including oxygenic and nitrogenic polycyclic aromatic hydrocarbons. To gain further insights into their energy levels and electronic transitions, we conducted comprehensive investigations, employing extended Hückel calculations and pump-probe spectroscopy. The synthesized CDs displayed great promise as bioimaging and photodynamic therapy agents, highlighting their potential for biomedical applications. Moreover, our study significantly contributes valuable insights into the rational design of N-doped CDs with controllable chemical and electronic structures, thereby paving the way for advancements in their diverse range of applications., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT)., Methods: In silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated., Results: In silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 μg/kg) lowered the glucose level more than bD-G1A (50 μg/kg) compared with the control (35.5% vs. 26.4%)., Conclusion: GLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment., (© 2023. The Korean Society for Biomaterials.)

Background: The term, "multiple chronic diseases" (MCD), describes a patient with two or more chronic conditions simultaneously at the same time. Compared with general chronic diseases, it is linked to poorer health outcomes, more difficult clinical management, and higher medical expenses. Several existing MCD guidelines support a healthy lifestyle including regular physical activities but do not include specific exercise therapy recommendations. This study aimed to understand the prevalence and model of MCD in middle-aged and elderly South Koreans by comparing MCD characteristics with exercise habits, to provide a theoretical basis for the implementation of exercise therapy in these patients., Methods: The data of 8477 participants aged > 45 years from the "2020 Korean Health Panel Survey" were used to analyze the current status of MCD in the middle-aged and elderly. The Chi-square test for categorical variables and the t-test for continuous variables. the used software was IBM SPSS Statistics 26.0 and IBM SPSS Modeler 18.0., Results: In this study, the morbidity rate of MCD was 39.1%. Those with MCD were more likely to be female (p < 0.001), seniors over 65 years of age (p < 0.001), with low education level, no regular exercise behavior (p < 0.01). Chronic renal failure (93.9%), depression (90.4%), and cerebrovascular disease (89.6%) were the top three diseases identified in patients with MCD. A total of 37 association rules were identified for the group of individuals who did not engage in regular exercise. This equated to 61% more than that of the regular exercise group, who showed only 23 association rules. In the extra association rules, cardiovascular diseases (150%), spondylosis (143%), and diabetes (125%) are the three chronic diseases with the highest frequency increase., Conclusions: Association rule analysis is effective in studying the relationship between various chronic diseases in patients with MCD. It also effectively helps with the identification of chronic diseases that are more sensitive to regular exercise behaviors. The findings from this study may be used to formulate more appropriate and scientific exercise therapy for patients with MCD., (© 2023. The Author(s).)

Background: Bacterial infection is common in acute cholecystitis (AC). To identify appropriate empirical antibiotics, we investigated AC-associated microorganisms and their susceptibilities to antibiotics. We also compared preoperative clinical findings of patients grouped according to specific microorganisms., Methods: Patients who underwent laparoscopic cholecystectomy for AC between 2018 and 2019 were enrolled. Bile cultures and antibiotic susceptibility tests were performed, and clinical findings of patients were noted., Results: A total of 282 patients were enrolled (147 culture-positive and 135 culture-negative). The most frequent microorganisms were Escherichia (n = 53, 32.7%), Enterococcus (n = 37, 22.8%), Klebsiella (n = 28, 17.3%), and Enterobacter (n = 18, 11.1%). For Gram-negative microorganisms, second-generation cephalosporin (cefotetan: 96.2%) was more effective than third-generation cephalosporin (cefotaxime: 69.8%). Vancomycin and teicoplanin (83.8%) were the most effective antibiotics for Enterococcus. Patients with Enterococcus had higher rates of CBD stones (51.4%, p = 0.001) and biliary drainage (81.1%, p = 0.002), as well as higher levels of liver enzymes, than patients with other microorganisms. Patients with ESBL-producing bacteria had higher rates of CBD stones (36.0% vs. 6.8%, p = 0.001) and biliary drainage (64.0% vs. 32.4%, p = 0.005) than those without., Discussion: Preoperative clinical findings of AC are related to microorganisms in bile samples. Periodic antibiotic susceptibility tests should be conducted to select appropriate empirical antibiotics., Competing Interests: Conflicts of interest None declare., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: Despite increasing evidence for the potential association between atopic dermatitis (AD) and cardiovascular diseases (CVDs), results have still remained controversial. Therefore, this study investigated the association between AD and subsequent CVDs in adults newly diagnosed with AD., Methods: Datasets from the National Health Insurance Service-National Sample Cohort in South Korea from 2002 to 2015 were analyzed. The primary outcome was new-onset CVD, which included angina pectoris, myocardial infarction, stroke, or any revascularization procedure. The crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated in the AD group compared with the matched control group using the Cox proportional hazards regression models., Results: A total of 40,512 individuals with AD were matched with 40,512 control subjects without AD. The overall incidence of CVDs was 2,235 (5.5%) and 1,640 (4.1%) in the AD and matched control groups, respectively. In the adjusted model, AD was associated with an increased risk of CVDs (HR, 1.42; 95% CI, 1.33-1.52), angina pectoris (adjusted HR, 1.49; 95% CI, 1.36-1.63), myocardial infarction (adjusted HR, 1.40; 95% CI, 1.15-1.70), ischemic stroke (adjusted HR, 1.34; 95% CI, 1.20-1.49), and hemorrhagic stroke (adjusted HR, 1.26; 95% CI, 1.05-1.52). Most of the subgroup and sensitivity analysis results were consistent with those of the main analysis., Conclusions: The current study found that adult patients newly diagnosed with AD were at significantly increased risk for subsequent CVDs, suggesting the need to consider early prevention strategies for CVDs targeting patients with AD., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2023 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Senescence is a phenomenon defined by alterations in cellular organelles and is the primary cause of aging and aging-related diseases. Recent studies have shown that oncogene-induced senescence is driven by activation of serine/threonine protein kinases (AKT1, AKT2 and AKT3). In this study, we evaluated twelve AKT inhibitors and revealed GDC0068 as a potential agent to ameliorate senescence. Senescence-ameliorating effect was evident from the finding that GDC0068 yielded lysosomal functional recovery as observed by reduction in lysosomal mass and induction in autophagic flux. Furthermore, GDC0068-mediated restoration of lysosomal function activated the removal of dysfunctional mitochondria, resulting in restoration of mitochondrial function. Together, our findings revealed a unique mechanism by which senescence is recovered by functional restoration of lysosomes and mitochondria through modulation of AKT activity., Competing Interests: Competing interest The authors declare no competing financial interests., (Copyright © 2023. Published by Elsevier Inc.)

Adiponectin and leptin are major adipocytokines that control crosstalk between adipose tissue and other organ systems. Hypoadiponectinemia and hypoleptinemia are associated with human metabolic diseases. Compounds with adipocytokine biosynthesis-stimulating activities could be developed as therapeutics against diverse metabolic conditions. In phenotypic screening with human bone marrow mesenchymal stem cells (hBM-MSCs), (E)-4-hydroxy-3-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-6-methyl-2H-pyran-2-one (1) was identified to increase adiponectin biosynthesis during adipogenesis and simultaneously to stimulate leptin production. Using the compound 1 structure, the structure-activity relationship study was performed to discover more potent compounds stimulating both adiponectin and leptin production. (E)-3-(3-(2-fluoropyridin-4-yl)acryloyl)-4-hydroxy-6-methyl-2H-pyran-2-one (11) exhibited the most potent adiponectin (EC 50 , 2.87 μM) and leptin (EC 50 , 2.82 μM) biosynthesis-stimulating activities in hBM-MSCs. In a target identification study, compound 11 was characterized as a dual modulator binding to both peroxisome proliferator-activated receptor (PPAR) γ and glucocorticoid receptor (GR). This study provides a novel pharmacophore for PPARγ/GR dual modulators with therapeutic potential against human metabolic diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Purpose: In general, bile is normally sterile. However, there are reports bactibilia may occur in certain instances, though the causal factors are unclear. We analyzed possible preoperative predictors of bactibilia upon cholecystectomy., Methods: Bile samples were collected during cholecystectomies from November 2018 to November 2019. A total of 428 open or laparoscopic cholecystectomies were performed. Preoperative, intraoperative, and postoperative variables were compared between the culture-positive and culture-negative groups., Results: One hundred fifty-seven patients (36.7%) were culture-positive. Gram-negative bacteria (95 [61.0%]) were more common. Escherichia coli (38 [40.0%]) and Enterobacter (22 [23.2%]) were the most common species. In univariate analysis, age of ≥70 years (P < 0.001), male sex (P < 0.001), high American Society of Anesthesiologists physical status grades (P = 0.001), diabetes mellitus (P = 0.002), jaundice (P = 0.007), high Tokyo Guideline grades (P = 0.008), percutaneous transhepatic gallbladder drainage (PTGBD; P < 0.001), endoscopic retrograde cholangiopancreatography (ERCP; P < 0.001) were identified as a risk factors for bactibilia. In multivariate analysis, age of ≥70 years (hazard ratio [HR], 2.874; 95% confidence interval [CI], 1.769-4.670; P = 0.001), ERCP (HR, 9.001; 95% CI, 4.833-16.75; P < 0.001), and PTGBD (HR, 2.866; 95% CI, 1.440-4.901; P = 0.002) were independent risk factors for bactibilia., Conclusion: Among patients who underwent cholecystectomy, those who were elderly, symptomatic, and underwent preoperative drainage were more likely to have bactibilia. In such cases, surgeons should take care to prevent bile leakage during surgery and consider administering appropriate antibiotics., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2023, the Korean Surgical Society.)

Background/purpose: The current study aimed to develop a prediction model using a multi-marker panel as a diagnostic screening tool for pancreatic ductal adenocarcinoma., Methods: Multi-center cohort of 1991 blood samples were collected from January 2011 to September 2019, of which 609 were normal, 145 were other cancer (colorectal, thyroid, and breast cancer), 314 were pancreatic benign disease, and 923 were pancreatic ductal adenocarcinoma. The automated multi-biomarker Enzyme-Linked Immunosorbent Assay kit was developed using three potential biomarkers: LRG1, TTR, and CA 19-9. Using a logistic regression model on a training data set, the predicted values for pancreatic ductal adenocarcinoma were obtained, and the result was classification into one of the three risk groups: low, intermediate, and high. The five covariates used to create the model were sex, age, and three biomarkers., Results: Participants were categorized into four groups as normal (n = 609), other cancer (n = 145), pancreatic benign disease (n = 314), and pancreatic ductal adenocarcinoma (n = 923). The normal, other cancer, and pancreatic benign disease groups were clubbed into the non-pancreatic ductal adenocarcinoma group (n = 1068). The positive and negative predictive value, sensitivity, and specificity were 94.12, 90.40, 93.81, and 90.86, respectively., Conclusions: This study demonstrates a significant diagnostic performance of the multi-marker panel in distinguishing pancreatic ductal adenocarcinoma from normal and benign pancreatic disease states, as well as patients with other cancers., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

The purinergic P2X7 receptor (P2X7R) is an adenosine triphosphate (ATP)- gated cation channel protein. Although extracellular ATP (eATP) is maintained at the nanomolar concentration range under normal conditions, it is elevated to micromolar levels in response to cell stress or damage, resulting in activation of P2X7R in the brain. The binding of eATP to P2X7R in glial cells in the brain activates the NLRP3 inflammasome and releases pro-inflammatory cytokines, such as IL-1β, IL-6, IL-18, and TNFα. Depression has been demonstrated to be strongly associated with neuroinflammation activated by P2X7R. Therefore, P2X7R is an attractive therapeutic target for depression. Multinational pharmaceutical companies, including AstraZeneca, GlaxoSmithKline, Janssen, Lundbeck, and Pfizer, have developed CNS-penetrating P2RX7 antagonists. Several of these have been evaluated in clinical trials. This review summarizes the recent development of P2X7R antagonists as novel antidepressant agents in terms of structural optimization, as well as in vitro/in vivo evaluation and physicochemical properties of representative compounds., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

One of the biggest obstacles in cancer treatment is the development of chemoresistance. To overcome this, attempts have been made to screen novel anticancer substances derived from natural products. The purpose of this study is to find new anticancer candidates in the mycelium culture extract of mushrooms belonging to Polyporus . Here, we used a high-throughput screening to find agents capable of inhibiting cancer cell proliferation. The culture extract of Polyporus Parvovarius mycelium in DY medium (pp-DY) was effective. pp-DY inhibited cancer cell proliferation by inducing apoptosis and S-phase arrest. The anticancer property of pp-DY was not only effective against one type of cancer, but also against another type of cancer. Compound fractionation was performed, and the active ingredient exhibiting anticancer effects in pp-DY was identified as 3,4-dihydroxybenzaldehyde (Protocatechualdehyde, PCA). PCA, like pp-DY, inhibited the proliferation of cancer cells by inducing apoptosis and S-phase arrest. Furthermore, unlike conventional anticancer drugs, PCA did not increase the proportion of the side population that plays the most important role in the development of chemoresistance. Taken together, our data revealed the novel mycelium culture extract that exhibited anticancer property, and identified active ingredients that did not activate a proportion of the side population. These novel findings may have clinical applications in the treatment of cancer, particularly chemo-resistant cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Pancreatic resection has higher postoperative mortality and morbidity rates than other abdominal operations. Some centers have reported remarkable postoperative outcomes of minimally invasive surgery. This study investigated the chronological trends of pancreatectomies by analyzing a large-scale database., Methods: The medical records of 5175 patients who underwent pancreatic resection between 1961 and 2019 at a single institution were reviewed. To investigate the chronological change in survival outcomes of periampullary cancer, the survival data of 3,108 patients were analyzed., Results: Patient age and the proportion with pancreatic cancer have increased over time. From 2015 to 2019, pancreatic cancer was the most common cause for resection (35.9%), followed by pancreatic cysts (24.8%) and common bile duct cancer (13.4%). The incidence of postoperative complications tended to decrease over time (26.0% from 2000 to 2004; 20.8% from 2015 to 2019). A comparison of survival outcomes of periampullary malignancies by period revealed that patients with pancreatic cancer significantly improved (5-year survival rate: 14.4% before 2000% vs 15.2% from 2000 to 2009% vs 29.0% after 2009, P < .001)., Conclusions: Postoperative outcomes of pancreatic resection have improved over the past few decades. To improve outcomes in the future, an active multidisciplinary approach and postoperative management are required., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Inositol hexakisphosphate kinase (IP6K) is an important mammalian enzyme involved in various biological processes such as insulin signalling and blood clotting. Recent analyses on drug metabolism and pharmacokinetic properties on TNP ( N 2 -( m -trifluorobenzyl), N 6 -( p -nitrobenzyl)purine), a pan-IP6K inhibitor, have suggested that it may inhibit cytochrome P450 (CYP450) enzymes and induce unwanted drug-drug interactions in the liver. In this study, we confirmed that TNP inhibits CYP3A4 in type I binding mode more selectively than the other CYP450 isoforms. In an effort to find novel purine-based IP6K inhibitors with minimal CYP3A4 inhibition, we designed and synthesised 15 TNP analogs. Structure-activity relationship and biochemical studies, including ADP-Glo kinase assay and quantification of cell-based IP7 production, showed that compound 9 dramatically reduced CYP3A4 inhibition while retaining IP6K-inhibitory activity. Compound 9 can be a tool molecule for structural optimisation of purine-based IP6K inhibitors.

Oncogene-induced senescence (OIS), characterized by irreversible cell cycle arrest by oncogene activation, plays an important role in the pathogenesis of aging and age-related diseases. Recent research indicates that OIS is driven by activation of mitogen-activated protein kinase (MAPK). However, it is not apparent whether MAPK inhibition helps to recover senescence. In our previous study, we uncovered p38 MAPK inhibitor, SB203580, as an effective agent to reduce reactive oxygen species and increase proliferation in premature senescent cells. In this study, we evaluated whether SB203580 could ameliorate senescence in normal senescent cells. The senescence-improving effect was observed in the results that SB203580 treatment restored lysosomal function, as evidenced by a decrease in lysosomal mass and an increase in autophagic vacuoles. Then, SB203580-mediated lysosomal function restoration triggered the clearance of damaged mitochondria, leading to metabolic reprogramming necessary for amelioration of senescence. Indeed, p38 MAPK inhibition by SB203580 improved key senescent phenotypes. Our findings suggest a novel mechanism by which modulation of p38 MAPK activity leads to senescence improvement through functional restoration of lysosome and mitochondria.

Atorvastatin (ATV) has attracted considerable attention as a potential therapeutic agent for cancer because it inhibits cancer cell proliferation by suppressing the mevalonate pathway. However, because of its low oral absorption, high doses of ATV are required for chemotherapeutic applications. In this study, we constructed ATV-loaded nanoemulsions (ATV-NEs) containing multivalent intestinal transporter-targeting lipids to improve the oral bioavailability of ATV. ATV-NEs were prepared via oil-in-water emulsification for transporter-targeted delivery, and contained the following anchors: an ionic complex of deoxycholic acid (DOCA) with the cationic lipid 1,2-dioleyl-3-trimethylammonium propane (DOTAP) (DOCA-DOTAP), a biotin-conjugated lipid (Biotinyl PE), and d-alpha-tocopherol polyethylene glycol succinate (TPGS) to allow bile acid- and multivitamin transporter-mediated permeation of ATV without P-glycoprotein (P-gp)-mediated efflux. The optimized formulation (ATV-NE#6) had 1,091% higher oral bioavailability than free ATV. Finally, treatment of 4T1 cell-bearing mice with oral ATV-NE#6 (equivalent to 40 mg/kg ATV) significantly suppressed tumor growth; the maximum tumor growth reduction was 2.44-fold that of the control group. The results thus suggest that ATV-NEs allow for effective oral chemotherapy by enhancing the oral bioavailability of ATV.

The straightforward and rapid incorporation of a thiazolidinedione scaffold into prefunctionalized (hetero)aromatic compounds is in demand for the development of antidiabetic glitazones and other pharmaceuticals. Herein, we report the unprecedented N- and O-directed C-H alkylation of various (hetero)arenes with methylene thiazolidinediones under rhodium(III) catalysis. The applicability of the developed protocol in challenging contexts is exhibited by the late-stage installation of a methylene thiazolidinedione moiety on the C-H bond of commercially available drug molecules. Combined mechanistic investigations aided the elucidation of a plausible reaction mechanism.

Coxsackievirus B3 (CVB3) is a single-stranded RNA virus that belongs to the Enterovirus genus. CVB3 is a human pathogen associated with serious conditions such as myocarditis, dilated cardiomyopathy, and pancreatitis. However, there are no therapeutic interventions to treat CVB3 infections. In this study, we found that CVB3 induced metabolic alteration in host cells through increasing glycolysis level, as indicated by an increase in the extracellular acidification rate (ECAR). CVB3-mediated metabolic alteration was confirmed by metabolite change analysis using gas chromatography-mass spectrometry (GC-MS). Based on findings, a strategy to inhibit glycolysis has been proposed to treat CVB3 infection. Indeed, glycolysis inhibitors (2-Deoxy-D-glucose, sodium oxide) significantly reduced CVB3 titers after CVB3 infection, indicating that glycolysis inhibitors can be used as effective antiviral agents. Taken together, our results reveal a novel mechanism by which CVB3 infection is controlled by regulation of host cell metabolism., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Abstract: People with HIV (PWH) are living longer and healthier lives; thanks to combination antiretroviral therapy. As many PWH age, they find themselves providing care to family members and friends, just as their counterparts without HIV. The literature indicates that becoming a caregiver creates conditions that compromise one's cognitive function. Additionally, nearly 45% of all PWH experience HIV-associated neurocognitive disorder and are already vulnerable to cognitive impairment due to HIV, aging, and accompanying health conditions, and lifestyle factors. Given what is known, we assert that caregivers with HIV, especially as they age, are at additional risk for developing cognitive impairments. The purpose of this commentary was to briefly examine the juxtaposition between cognitive vulnerability of caregiving and the cognitive vulnerability of aging with HIV. Potential factors contributing to impaired cognition include stress, lack of social support, stigma, lifestyle, and comorbidities. Implications for clinical practice and research are provided., (Copyright © 2022 Association of Nurses in AIDS Care.)

Objective: This study evaluated the associated factors and prognosis according to pathology and margin after surgical resection of intraductal papillary mucinous neoplasms (IPMN)., Background: There is limited information on recurrence patterns according to pathology and margin in IPMN., Methods: Total 577 patients who underwent operation for IPMN at a tertiary center were included. Factors associated with recurrence, survival, and recurrence outcomes according to pathology and margin were analyzed., Results: Among 548 patients analyzed, 353 had low-grade dysplasia (LGD), 78 had high-grade dysplasia (HGD), and 117 had invasive IPMN. Total 50 patients developed recurrences, with 4 resection margins, 10 remnant pancreas, 11 locoregional, and 35 distant recurrences. Invasive IPMN showed worse 5-year cumulative recurrence risk (LGD vs HGD vs invasive: 0.7% vs 4.3% vs 37.6%, P < 0.001) and 5-year survival rate (89.0% vs 84.0% vs 48.4%, P < 0.001). Recurrence risk increased after 5 years, even in LGD and HGD. Malignant margin (HGD and invasive) had worse 5-year cumulative recurrence rate (R0 vs LGD vs malignant: 8.3% vs 5.9% vs 50.6%, P < 0.001) and 5-year survival rate (80.7% vs 83.0% vs 30.8%, P < 0.001). Carbohydrate antigen 19-9 >37 ( P = 0.003), invasive IPMN ( P < 0.001), and malignant margin ( P = 0.036) were associated with recurrence., Conclusions: Invasive IPMN developed more recurrences and had worse survival than LGD or HGD, indicating the need for more efficient postoperative treatment strategies. Patients with LGD and HGD also need regular follow-up for recurrence after 5 years. Malignant margins need additional resection to achieve negative or at least LGD margin., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Among various prognostic factors of pancreatic cancer, preoperative clinical information is obtained by imaging modality. This study aimed to evaluate clinical usefulness of preoperative carbohydrate antigen and preoperative standard uptake value in 18F-fluorodeoxyglucose positron emission tomography as predictive biological markers for resectable pancreatic ductal adenocarcinoma., Methods: A total of 189 patients with PDAC who underwent preoperative PET-computed tomography were evaluated. Patients underwent neoadjuvant chemotherapy, and R2 resection was excluded. The correlation between SUVmax and clinicopathologic parameters was analyzed. The C-tree statistical method was used to estimate cutoff values of logCA19-9 and SUVmax for survival rate. A multivariate analysis was conducted to identify prognostic factors for overall survival., Results: The median duration of OS was 26 months, and the 5-year survival rate was 22.4%. The optimal cutoff values for CA19-9 level was 150 U/mL and SUVmax was 5.5. When subjects were divided into three groups according to the combination of CA19-9 level and SUVmax from C-tree (high-risk group, CA19-9 > 150 U/mL and SUVmax > 5.5; intermediate-risk group, CA19-9 ≤ 150 U/mL and SUVmax > 5.5 or CA19-9 > 150 U/mL and SUVmax ≤ 5.5; and low-risk group, CA19-9 ≤ 150 U/mL and SUVmax ≤ 5.5), there was a significant 5YSR difference (5.6%, 24.3%, and 36.5%, P < .001). The multivariate analysis revealed high SUVmax, high preoperative CA19-9 level, venous invasion, and adjuvant chemotherapy were prognostic factors of OS., Conclusions: CA19-9 and SUVmax are strong prognostic biological factors in resectable PDAC. Moreover, patients with high CA19-9 level and SUVmax are not indicated for upfront surgery., (© 2020 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect. Albumin metabolism-mediated apoptosis triggered expression of caspase-3 allows the continuous activation of the PDC, accumulation of payloads, sustained upregulation of tumoral caspase-3, and intensified in-situ apoptosis. Importantly, PDC strategy exerts potent therapeutic efficacy against PTEN-loss metastatic triple-negative breast cancer, the highly aggressive and heterogenous nature of which remains a challenge conventional targeted therapies need to overcome. This study thus presents a conceptually novel approach to treat PTEN-loss cancer and creates new translational perspectives of exploiting PTEN-loss for providing an avenue to advance current targeted therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neoadjuvant treatment (NAT) followed by surgery is the primary treatment for borderline resectable pancreatic cancer (BRPC). However, there is limited high-level evidence supporting the efficacy of NAT in BRPC. PubMed was searched to identify studies that compared the survival between BRPC patients who underwent NAT and those who underwent upfront surgery (UFS). The overall survival (OS) was compared using intention-to-treat (ITT) analysis. A total of 1204 publications were identified, and 19 publications with 21 data sets (2906 patients; NAT, 1516; UFS, 1390) were analyzed. Two randomized controlled trials and two prospective studies were included. Thirteen studies performed an ITT analysis, while six presented the data of resected patients. The NAT group had significantly better OS than the UFS group in the ITT analyses (HR: 0.63, 95% CI = 0.53-0.76) and resected patients (HR: 0.68, 95% CI = 0.60-0.78). Neoadjuvant chemotherapy with gemcitabine or S-1 and FOLFIRINOX improved the survival outcomes. Among the resected patients, the R0 resection and node-negativity rates were significantly higher in the NAT group. NAT improved the OS, R0 resection rate, and node-negativity rate compared with UFS. Standardizing treatment regimens based on high-quality evidence is fundamental for developing an optimal protocol.

Hepsin, a cell surface serine protease, is a potential biomarker for the detection of prostate cancer due to its high expression in prostate cancer but not in normal prostate. This study aimed to develop a radioligand for positron emission tomography (PET) imaging of hepsin. Six leucine-arginine (Leu-Arg) dipeptide derivatives (two diastereomers for each of three ligands) were synthesized and evaluated for their binding affinities and selectivity for hepsin. Based on the binding assay, a nat Cu-1,4,7,10-tetraazacyclododecane- N , N ', N ″, N ‴-tetraacetic acid (DOTA)-conjugated ligand ( 3B ) was selected for the development of a PET radioligand. [ 64 Cu] 3B was synthesized by labeling the DOTA-conjugated compound 11B with [ 64 Cu]CuCl 2 at 80 ° C for 20 min. The radioligand was evaluated for prostate cancer cell binding and PET imaging in a prostate tumor mouse model. The results demonstrated that [ 64 Cu] 3B exhibited high binding to LNCaP cells, intermediate binding to 22Rv1 cells, and low binding to PC3 cells. PET studies of [ 64 Cu] 3B in mice, implanted with 22Rv1 and PC3 cells on each flank, revealed that the radioligand uptake was high and persistent in the 22Rv1 tumors over time, whereas it was low in PC3 tumors. The results of this study suggest that [ 64 Cu] 3B is a promising PET radioligand for hepsin imaging.

Background: Bismuth-Corlette type IV Klatskin tumors have conventionally been considered unresectable. This retrospective study aimed to demonstrate the survival improvement of patients with type IV Klatskin tumors when resected and suggest possible radiological features for R0 resectability., Methods: Data on type IV Klatskin tumors diagnosed between 2008 and 2019 were reviewed retrospectively. Patients with distant metastasis, concomitant other cancers at the initial state, extensive vascular invasions, poor liver function, and poor general condition were excluded. The survival outcomes of patients and radiologic parameters of bile duct tumors were compared between the curative resection (R0, 1 resection) and non-resection groups., Results: The demographic findings of patients with curative resection (n = 48) and non-resection (n = 111) were comparable. Both were potentially resectable in the initial state. The postoperative morbidity was 22.9% and the 90-day mortality 4.2%. There was a significant difference in the median survival among the curative-intended resection, palliative treatment, and supportive care groups (35, 16, and 12 months, respectively; P < 0.001)., Discussion: In patients with type IV Klatskin tumor without extensive tumor invasion into adjacent tissues, including major vessels, surgical resection can be considered for better survival., Clinical Registration Number: IRB No. 2009-100-1157., (© 2022. The Society for Surgery of the Alimentary Tract.)