Immunostimulating effects of ulvan type polysaccharide isolated from Korean Ulva pertusa in cyclophosphamide-induced immunosuppressed BALB/c mice.

This study aimed to determine the immunostimulatory activities of ulvan type polysaccharides isolated from Ulva pertusa. First, U. pertusa polysaccharide (UPP) mainly consists of rhamnose, glucuronic acid, iduronic acid, and xylose, which are typical ulvan type monosaccharides. UPP induced phosphorylation of the mitogen-activated protein kinase and nuclear factor-kappa B pathways in macrophages, subsequently triggering cytokine release and phagocytosis. The effects were closely associated with pattern recognition receptors such as dectin-1, mannose receptor, CD11b, CD14, and Toll-like receptors 2 and 4. Moreover, prophylactic administration of UPP was found to protect against body weight loss and lymphatic organ damage in cyclophosphamide-induced immunosuppressed mice. In addition, UPP demonstrated significant stimulatory effects on various immunocytes, such as T cells, B cells, macrophages, and natural killer cells derived from the spleen. These effects were closely related to the mitogen-activated protein kinase and nuclear factor-kappa B pathways, and significant secretion of immunostimulatory cytokines such as IL-6, -12, and TNF-α was noted in both blood and spleen samples. Impairment of the short-chain fatty acid balance in the cecum was prevented by UPP administration in a dose-dependent manner. Consequently, these results suggest that the UPP isolated from U. pertusa contributes to immune system activation.

Germanium and Tin Precursors for Chalcogenide Materials Containing N-Alkoxy Thioamide Ligands.

This study describes the synthesis of germanium and tin complexes Ge(mdpaS)2 (1), Ge(edpaS)2 (2), Ge(bdpaS)2 (3), Ge(empaS)2 (4), Sn(mdpaS)2 (5), Sn(edpaS)2 (6), Sn(bdpaS)2 (7), and Sn(empaS)2 (8) (mdpaSH = (Z)-N-methoxy-2,2-dimethylpropanimidothioic acid; edpaSH = (Z)-N-ethoxy-2,2-dimethylpropanimidothioic acid; bdpaSH = (Z)-N-(tert-butoxy)-2,2-dimethylpropanimidothioic acid; empaSH = (Z)-N-ethoxy-2-methylpropanimidothioic acid), using newly designed N-alkoxy thioamide ligands as precursors for metal chalcogenide materials. All complexes were characterized using various analytical techniques, and the single-crystal structures of complexes 5 and 7 revealed a distorted seesaw geometry in the monomeric SnL2 form. Thermogravimetric (TG) curves showed differences between Ge compounds, which exhibited single-step weight losses, and Sn compounds, which exhibited multistep weight losses. As a result, we suggest that the synthesized complexes 1-8 are potential precursors for group IV metal chalcogenide materials.

Gastric Metastasis Mimicking Early Gastric Cancer from Invasive Ductal Carcinoma of the Breast: Case Report and Literature Review.

Backgound and Objectives: Gastric metastasis from invasive ductal breast cancer (BC) is rare. It mainly occurs in patients with lobular BC. The occurrence of multiple metastases is typically observed several years after the primary diagnosis. Endoscopic findings of gastric metastasis of the BC were usually the linitis plastic type. Case presentation: A 72-year-old women who underwent right modified radical mastectomy (MRM) 10 month ago was referred after being diagnosed with early gastric cancer (EGC) during systemic chemotherapy. EGC type I was found at gastric fundus, and pathologic finding showed poorly differentiated adenocarcinoma. Metachronous double primary tumor EGC was considered. Management and Outcome: A laparoscopic total gastrectomy was performed, and postoperative pathology revealed submucosa invasion and two lymph node metastases. A pathologic review that focused on immunohistochemical studies of selected antibodies such as GATA binding protein 3 (GATA3), gross cystic disease fluid protein-15 (GCDFP-15), cytokeratin 7 (CK7) was performed again, comparing previous results. As a result, gastric metastasis from BC was diagnosed. After totally laparoscopic total gastrectomy, palliative first-line chemotherapy with paclitaxel/CDDP was performed. Two months after gastrectomy, she was diagnosed with para-aortic lymph node metastasis and multiple bone metastases. She expired six months after gastrectomy. Conclusions: Gastric metastasis from invasive ductal carcinoma of the breast, which is clinically manifested as EGC, is a very rare condition. If there is a history of BC, careful pathological review will be required.

NJK14047 inhibition of p38 MAPK ameliorates inflammatory immune diseases by suppressing T cell differentiation.

p38 MAPK has been implicated in the pathogenesis of rheumatoid arthritis and psoriasis. To assess the therapeutic efficacy of the p38 MAPK inhibitor NJK14047 in the treatment of rheumatoid arthritis and psoriasis, we developed mouse models of collagen-induced rheumatoid arthritis (CIA) and imiquimod-induced psoriasis (IIP). NJK14047 was found to suppress arthritis development and psoriasis symptoms and also suppressed histopathological changes induced by CIA and IIP. Furthermore, we established that CIA and IIP evoked increases in the mRNA expression levels of Th1/Th17 inflammatory cytokines in the joints and skin, which was again suppressed by NJK14047. NJK14047 reversed the enlargement of spleens induced by CIA and IIP as well as increases in the levels of inflammatory cytokine in spleens following induction by CIA and IIP. In human SW982 synovial cells, NJK14047 was found to suppress lipopolysaccharide-induced increases in the mRNA expression of proinflammatory cytokines. NJK14047 inhibition of p38 MAPK suppressed the differentiation of naïve T cells to Th17 and Th1 cells. Our findings in this study provide convincing evidence indicating the therapeutic efficacy of the p38 MAPK inhibitor NJK14047 against CIA and IIP, which we speculate could be associated with the suppression on T-cell differentiation.

Synthesis of 2,3-Benzotropones via Palladium(II)-Catalyzed Aerobic Dehydrogenation from 1-Benzosuberones and Sequential Diels-Alder Reaction to Yield Benzobicyclo[3.2.2]nonenones.

An approach to 2,3-benzotropone from 1-benzosuberone via palladium(II)-catalyzed aerobic dehydrogenation was developed. This method first provided a catalytic route to various 2,3-benzotropones from their corresponding 1-benzosuberones in good yields. In addition, the reaction could be applied to a one-pot Diels-Alder reaction with maleimide, providing a complex benzobicyclo[3.2.2]nonenone in ≤90% yield. Kinetic analysis supporting our proposed mechanism was also performed, underscoring the robustness of the developed synthetic pathway.

Hollow Ru/RuO2 nanospheres with nanoparticulate shells for high performance electrocatalytic oxygen evolution reactions.

This work shows that hollow Ru/RuO2 nanoparticles having nanoparticulate shells (HN-Ru/RuO2) can be prepared using hollow microporous organic polymers with Ru species (H-MOP-Ru) as precursors. Using silica spheres as templates, H-MOPs were prepared through the Sonogashira-Hagihara coupling of 1,3,5-triethynylbenzene with 2,3-ethoxymethylenedioxy-1,4-diiodobenzene. Acid hydrolysis of cyclic ethyl orthoformate protecting groups generated catechol moieties to form H-MOP-Cat. Then, H-MOP-Ru was obtained by incorporating Ru species into H-MOP-Cat. Heat-treatment of H-MOP-Ru under air induced the formation of HN-Ru/RuO2 with a diameter of 61 nm and shells consisting of 6-7 nm nanoparticles. Due to the hollow structure and nanoparticulate shells, HN-Ru/RuO2 showed a high surface area of 80 m2 g-1 and a pore volume of 0.18 cm3 g-1. The HN-Ru/RuO2 showed enhanced electrocatalytic performance for the oxygen evolution reaction (OER) with an overpotential of 295 mV @ 10 mA cm-2 and a Tafel slope of 46 mV dec-1 in alkaline electrolyte, compared with control RuO2 such as commercial Ru/RuO2 nanoparticles (A-Ru/RuO2) and home-made Ru/RuO2 nanoparticles (N-Ru/RuO2) prepared via the same synthetic procedure as HN-Ru/RuO2. While HN-Ru/RuO2 inevitably contained Pd originated from coupling catalysts, it showed superior performance to Ru/RuO2 nanoparticles with the same Pd content (N1-Ru/RuO2), indicating that the efficient electrocatalytic performance of HN-Ru/RuO2 is attributable to its hollow structure and nanoparticulate shells.

Biomass- and Carbon Dioxide-Derived Polyurethane Networks for Thermal Interface Material Applications.

Recent environmental concerns have increased demand for renewable polymers and sustainable green resource usage, such as biomass-derived components and carbon dioxide (CO2). Herein, we present crosslinked polyurethanes (CPUs) fabricated from CO2- and biomass-derived monomers via a facile solvent-free ball milling process. Furan-containing bis(cyclic carbonate)s were synthesized through CO2 fixation and further transformed to tetraols, denoted FCTs, by aminolysis and utilized in CPU synthesis. Highly dispersed polyurethane-based hybrid composites (CPU-Ag) were also manufactured using a similar ball milling process. Due to the malleability of the CPU matrix, enabled by transcarbamoylation (dynamic covalent chemistry), CPU-based composites are expected to present very low interfacial thermal resistance between the heat sink and heat source. The characteristics of the dynamic covalent bond (i.e., urethane exchange reaction) were confirmed by the results of dynamic mechanical thermal analysis and stress relaxation analysis. Importantly, the high thermal conductivity of the CPU-based hybrid material was confirmed using laser flash analysis (up to 51.1 W/m·K). Our mechanochemical approach enables the facile preparation of sustainable polymers and hybrid composites for functional application.

Epithelioid angiomyolipoma of the liver in a patient with Li-Fraumeni syndrome: a case report.

BACKGROUND: Epithelioid angiomyolipoma (EAML) is a rare variant of angiomyolipoma that predominantly consists of epithelioid cells and belongs to the perivascular epithelioid cell neoplasm (PEComa) family. The majority of EAMLs arise in the kidneys, and primary hepatic EAML appears to be much less common than renal EAML. Most PEComas arise sporadically, but may be associated with tuberous sclerosis complex (TSC), an autosomal dominant genetic disorder characterized by germline mutations in the TSC1 or TSC2 genes. However, PEComas have previously been reported in five patients with Li-Fraumeni syndrome (LFS), which is an inherited cancer susceptibility disorder resulting from germline mutations in the TP53 tumor suppressor gene. CASE PRESENTATION: We report a 49-year-old female patient with hepatic EAML and pancreatic cancer. Because she had previously been diagnosed with bilateral breast cancer at the age of 30, we performed a comprehensive genetic analysis to identify genetic alterations associated with any cancer predisposition syndrome. Whole-exome sequencing of a blood sample identified a heterozygous germline variant of TP53 (NM_000546.5):c.708C>A, and targeted next-generation sequencing of liver EAML and pancreatic cancer tissue samples demonstrated the same TP53 (NM_000546.5):c.708C>A variant in both. This, plus the patient's history of early-onset breast cancer, met the 2015 version of the Chompret criteria for diagnosis of LFS. CONCLUSIONS: There have been very few case reports regarding the presence of PEComa in LFS, and to the best of our knowledge, this is the first report of EAML of the liver in a patient with LFS.

Identification of intracellular activation mechanism of rhamnogalacturonan-I type polysaccharide purified from Panax ginseng leaves in macrophages and roles of component sugar chains on activity.

This study aimed to investigate the mechanisms underlying intracellular signaling pathways in macrophages in relation to the structural features of rhamnogalacturonan (RG) I-type polysaccharide (PGEP-I) purified from Panax ginseng leaves. For this investigation, we used several specific inhibitors and antibodies against mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and pattern recognition receptors (PRRs). Furthermore, we investigated the roles of component sugar chains on immunostimulating activity through a sequential enzymatic and chemical degradation steps. We found that PGEP-I effectively induced the phosphorylation of several MAPK- and NF-κB-related proteins, such as p38, cJun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p65. Particularly, immunocytochemistry analysis confirmed the PGEP-I-induced translocation of p65 into the nucleus. Furthermore, the breakdown of PGEP-I side chains and main chain during sequential enzymatic and chemical degradation reduced the PGEP-I-induced macrophage cytokine secretion activity. IL-6, TNF-α, and NO secreted by macrophages are associated with several signaling pathway proteins such as ERK, JNK, and NF-κB and several PRRs such as dectin-1, CD11b, CD14, TLR2, TLR4, and SR. Thus, these findings suggest that PGEP-I exerts potent macrophage-activating effects, which can be attributed to its typical RG-I structure comprising arabinan, type II arabinogalactan, and rhamnose-galacturonic acid repeating units in the main chain.

Amidoxime-Containing Zr and Hf Atomic Layer Deposition Precursors for Metal Oxide Thin Films.

In this article, we discuss the synthesis of eight novel zirconium and hafnium complexes containing amidoxime ligands as potential precursors for atomic layer deposition (ALD). Two amidoximes, viz., (E)-N'-hydroxy-N,N-dimethylacetimidamide (mdaoH) and (Z)-N'-hydroxy-N,N-dimethylpivalimidamide (tdaoH), along with their Zr and Hf homoleptic complexes, Zr(mdao)4 (1), Hf(mdao)4 (2), Zr(tdao)4 (3), and Hf(tdao)4 (4) were prepared. We further synthesized heteroleptic compounds with different physical properties by introducing cyclopentadienyl (Cp) ligand, namely, CpZr(mdao)3 (5), CpHf(mdao)3 (6), CpZr(tdao)3 (7), and CpHf(tdao)3 (8). Thermogravimetric analysis was used for the assessment of the evaporation characteristics of complexes 1, 2, 5, and 6, and it revealed multistep weight losses with high residues. On the other hand, the thermogravimetric analysis curves of complexes 3, 4, 7, and 8 comprising tdao ligands revealed single-step weight losses with moderate residues. Single-crystal X-ray diffraction studies of complexes 1, 3, and 7 showed that all of the complexes have monomeric molecular structures. Complex 7 exhibited a low melting point (75 °C), good volatility, and high thermal stability compared with other complexes. Therefore, an atomic layer deposition process for the growth of ZrO2 was developed by using ZrCp(tdao)3 (7) as a novel precursor.

Asian variant intravascular large B-cell lymphoma with highly suspected central nervous system involvement: A case report.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal lymphoma. In particular, the Asian variant of IVLBCL is characterized by hemophagocytic lymphohistiocytosis along with bone marrow involvement. However, central nervous system (CNS) involvement is uncommon in this variant compared to the Western variant. Here, we report a case of typical Asian variant IVLBCL with highly suspected CNS involvement and discuss the nature of the disease and its genetic aberration. CASE SUMMARY: A 67-year-old female patient complained of gradually worsening cognitive impairment. While hospitalized, she developed a high fever and showed marked bicytopenia. Intracranial imaging revealed a suspected leptomeningeal disease. Although no malignant cells were found in the cerebrospinal fluid (CSF), the protein and lactate dehydrogenase levels in CSF were increased. Bone marrow examination revealed an increased number of hemophagocytic histiocytes, and 18F-fluorodeoxyglucose (FDG) positron emission tomography with computerized tomography scan revealed increased FDG uptake in both adrenal glands, the liver, and the right ethmoid sinus. A tissue biopsy showed atypical large lymphoid cells with prominent nucleoli in the vessels, and the tumor cells were positive for CD20, BCL2, BCL6, and IRF4/MUM1. In addition, targeted sequencing identified MYD88, TET2, and PIM1 mutations. Consequently, we diagnosed the patient with the Asian variant of IVLBCL with highly suspected CNS involvement. CONCLUSION: Suspicion of IVLBCL and immediate diagnosis lead to timely treatment. Moreover, careful CNS examination at diagnosis is recommended.

Validation of the Korean Ankylosing Spondylitis Quality of Life Questionnaire.

Background: Measuring accurate and reliable scores of quality of life in patients with ankylosing spondylitis (AS) is important in both decision-making and treatment planning for the disease. Questionnaire, The ankylosing spondylitis quality of life (ASQoL), is one of the representative tools for assessing how seriously AS patients view their disease severity, activity, as well as their overall health. To make these types of questionnaires readable and understandable, local language translation of surveys should be required. A Korean version of the ASQoL questionnaire has accordingly been developed. This study assessed the Korean version of the ASQoL survey to evaluate the reliability and validity of it. Methods: Translation and reverse translation of the English ASQoL survey were conducted. A total of 120 consecutive AS patients received a mail including the Korean-translated 36-Item Short Form Survey (SF-36), the ASQoL survey, and the visual analog scale (pain). The coefficient of intraclass correlation and Cronbach's alpha were computed, and factor analysis, as well as reliability assessments utilizing the kappa agreement statistics for each item, was undertaken. By analyzing the responses to SF-36 and ASQoL questionnaire utilizing Pearson's correlation coefficient, construct validity was calculated. Results: Factor analysis was performed regarding pain, physical function, and mental function. The kappa statistic of agreement was larger than 0.6 for all items. The ASQoL questionnaire had adequate test and re-test reliability (0.814). Furthermore, Cronbach'sα, the internal consistency, was very good (0.877). The Korean-translated ASQoL questionnaire demonstrated a significantly strong correlation between the single domain and total SF-36 scores. Conclusions: The Korean version of the ASQoL questionnaire showed acceptable properties of measurement and successful translation. Thus, it can be said that the questionnaire is appropriate for evaluating the outcomes of Korean patients with AS.

New Heteroleptic Germanium Precursors for GeO2 Thin Films by Atomic Layer Deposition.

This study describes the synthesis of 12 new germanium complexes containing ß-diketonate and/or N-alkoxy carboxamidate-type ligands as precursors for GeO2 through atomic layer deposition (ALD). A series of Ge(ß-diketonate)Cl complexes such as Ge(acac)Cl (1) and Ge(tmhd)Cl (2) were synthesized by using acetylacetone (acacH) and 2,2,6,6-tetramethyl-3,5-heptanedione (tmhdH). N-Alkoxy carboxamidate-type ligands such as N-methoxypropanamide (mpaH), N-methoxy-2,2-dimethylpropanamide (mdpaH), N-ethoxy-2-methylpropanamide (empaH), N-ethoxy-2,2-dimethylpropanamide (edpaH), and N-methoxybenzamide (mbaH) were used to afford further substituted complexes Ge(acac)(mpa) (3), Ge(acac)(mdpa) (4), Ge(acac)(empa) (5), Ge(acac)(edpa) (6), Ge(acac)(mba) (7), Ge(tmhd)(mpa) (8), Ge(tmhd)(mdpa) (9), Ge(tmhd)(empa) (10), Ge(tmhd)(edpa) (11), and Ge(tmhd)(mba) (12), respectively. Thermogravimetric analysis curves, which mostly exhibited single-step weight losses, were used to determine the evaporation properties of complexes 1-12. Interestingly, liquid complex 2 has no residue at 198 °C and therefore exhibits excellent vaporization properties and high volatility. Single-crystal X-ray diffraction studies of 1 and 7 demonstrated that the complexes had monomeric molecular structures with germanium chelated by the oxygen atoms of one or two bidentate ligands, respectively. An ALD process was developed for the growth of GeO2 using Ge(tmhd)Cl (2) as a new precursor and H2O2 as an oxidant. This study demonstrates the achievement of self-limiting growth of GeO2 films by varying the duration of injection/purge, with an observed ALD window at deposition temperatures ranging from 300 to 350 °C. The saturated growth per cycle of the GeO2 film was determined as 0.27 Å/cycle at a deposition temperature of 300 °C. The deposited films were observed to be amorphous consisting of GeO2.

Postoperative peritoneal inflammatory granuloma mimicking peritoneal metastasis in a patient with breast cancer: a case report.

Peritoneal metastasis from breast cancer is a relatively rare life-threatening condition. The gold standard for diagnosing peritoneal metastasis is a direct peritoneal biopsy. In this report, we describe an interesting case of peritoneal inflammation mimicking peritoneal metastasis in a patient with breast cancer, as confirmed by laparoscopic peritoneal biopsy. A 45-year-old woman with a history of right breast cancer presented with a peritoneal wall mass seen on an abdominal computed tomography (CT) in routine follow-up. She underwent right skin-sparing mastectomy with sentinel lymph node biopsy with direct to implant reconstruction 6 years prior and underwent right salpingo-oophorectomy 2 years before. Positron emission tomography-computed tomography (PET-CT) and abdominopelvic CT showed multiple enhancing nodules in small bowel mesentery and right peritoneal wall with a small amount of ascites, which led to a strong suspicion of peritoneal metastasis. After a multidisciplinary conference, the possibility of peritoneal seeding became doubtful. Laparoscopic biopsy was performed, and peritoneal wall mass biopsy was subsequently performed. Pathologic results showed no evidence of peritoneal metastasis of breast cancer. The peritoneal biopsy specimen revealed postoperative fibrosis and inflammation with some meal content. Although rare in breast cancer, peritoneal metastasis can produce a devastating outcome if left undiagnosed. Despite the imaging findings strongly suggesting metastasis, biopsy confirmation for the suspected lesion was necessary. This not only verifies true metastasis but also determines the treatment options available for the patient and thus unnecessary treatment can be avoided.

Loss of Cutibacterium is responsible for chronic kidney disease-associated pruritus in patients on dialysis.

Background: Chronic kidney disease (CKD)-associated pruritus is a severe distressing condition that frequently occurs in patients undergoing dialysis. In this study, the profile of the skin microbiome was analyzed to understand the underlying etiology and potential treatments. Methods: Seventy-six end-stage kidney disease (ESKD) patients (hemodialysis, 40; peritoneal dialysis, 36) and 15 healthy controls were enrolled and swabbed at three sites: back, antecubital fossa, and shin. The pruritus severity of the enrolled subjects was validated by the Worst Itch Numeric Rating Scale (WI-NRS), 5-D itch scale, and Uremic Pruritus in Dialysis Patients (UP-Dial). The 16S gene-based metagenomics method was applied to skin microbiome analysis. Results: In the comparison of bacterial communities of ESKD patients and the control group, there was a significant difference on back. Specifically, the average composition ratio of the Cutibacterium in the back samples was significantly lower in ESKD patients than in healthy controls (p < 0.01). In further analysis of ESKD patients, Cutibacterium was significantly lower in the high pruritus group than in the low pruritus group (p < 0.05), even though other clinical parameters such as age, calcium-phosphorus product, and intact parathyroid hormone showed no significance difference between the groups. Conclusion: In ESKD patients, the skin microbiome of the back was significantly altered, and the severity of itching was related to the reduction of Cutibacterium. This research reveals the relationship between skin microbiota and CKD-associated pruritus in multiple skin sites for the first time. The results of this study suggest a potential data basis for the diagnosis and treatment of CKD-associated pruritus.

A Cell-Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer-Specific Synthetic Lethality.

Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof-of-principle evidence is presented that a cell-penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene-addicted cancer cells through transcription activity-independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2-p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome-wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C-resistant cancers. This study enhances the understanding of ACP52C-induced cancer-specific apoptosis induction and supports the use of ACP52C in anticancer drug development.

Vasomotion in human arteries and their regulations based on ion channel regulations: 10 years study.

Vasomotion is the oscillation of vascular tone which gives rise to flow motion of blood into an organ. As is well known, spontaneous contractile organs such as heart, GI, and genitourinary tract produce rhythmic contraction. It imposes or removes pressure on their vessels alternatively for exchange of many substances. It was first described over 150 years ago, however the physiological mechanism and pathophysiological implications are not well understood. This study aimed to elucidate underlying mechanisms and physiological function of vasomotion in human arteries. Conventional contractile force measurement, immunohistochemistry, and Western blot analysis were employed to study human left gastric artery (HLGA) and uterine arteries (HUA). RESULTS: Circular muscle of HLGA and/or HUA produced sustained tonic contraction by high K+ (50 mM) which was blocked by 2 µM nifedipine. Stepwise stretch and high K+ produced nerve-independent spontaneous contraction (vasomotion) (around 45% of tested tissues). Vasomotion was also produced by application of BayK 8644, 5-HT, prostagrandins, oxytocin. It was blocked by nifedipine (2 µM) and blockers of intracellular Ca2+ stores. Inhibitors of Ca2+ -activated Cl- channels (DIDS and/or niflumic acid) and ATP-sensitive K+ (KATP ) channels inhibited vasomotion reversibly. Metabolic inhibition by sodium cyanide (NaCN) and several neuropeptides also regulated vasomotion in KATP channel-sensitive and -insensitive manner. Finally, we identified TMEM16A Ca2+ -activated Cl- channels and subunits of KATP channels (Kir 6.1/6.2 and sulfonylurea receptor 2B [SUR2B]), and c-Kit positivity by Western blot analysis. We conclude that vasomotion is sensitive to TMEM16A Ca2+ -activated Cl- channels and metabolic changes in human gastric and uterine arteries. Vasomotion might play an important role in the regulation of microcirculation dynamics even in pacemaker-related autonomic contractile organs in humans.

MicroRNA 29a therapy for CEACAM6-expressing lung adenocarcinoma.

BACKGROUND: Non-coding microRNAs (miRNAs) play critical roles in tumor progression and hold great promise as therapeutic agents for multiple cancers. MicroRNA 29a (miR-29a) is a tumor suppressor miRNA that inhibits cancer cell growth and tumor progression in non-small cell lung cancer. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), which plays an important role in lung cancer progression, has been identified as a target of miR-29a. Here, we evaluated the therapeutic efficacy of a peptide vector capable of delivering miR-29a intracellularly using the acidic tumor microenvironment in a lung adenocarcinoma xenograft mouse model. METHODS: A miRNA delivery vector was constructed by tethering the peptide nucleic acid form of miR-29a to a peptide with a low pH-induced transmembrane structure (pHLIP) to enable transport of the miRNAs across the plasma membrane. Tumor suppressive effects of pHLIP-miR29a on lung adenocarcinoma development in vivo were assessed using a BALB/c xenograft model injected with A549 cells. RESULTS: Incubation of A549 cells with pHLIP-miR-29a at an acidic pH downregulated endogenous CEACAM6 expression and reduced cell viability. Intravenous injection of the mice with pHLIP-miR-29a inhibited tumor growth by up to 18.1%. Intraperitoneal injection of cisplatin reduced tumor volume by 29.9%. Combined pHLIP-miR-29a + cisplatin treatment had an additive effect, reducing tumor volume up to 39.7%. CONCLUSIONS: Delivery of miR-29a to lung adenocarcinoma cells using a pHLIP-mediated method has therapeutic potential as a unique cancer treatment approach.

Improved prediction of protein-protein interactions by a modified strategy using three conventional docking software in combination.

Proteins play a crucial role in many biological processes, where their interaction with other proteins are integral. Abnormal protein-protein interactions (PPIs) have been linked to various diseases including cancer, and thus targeting PPIs holds promise for drug development. However, experimental confirmation of the peculiarities of PPIs is challenging due to their dynamic and transient nature. As a complement to experimental technologies, multiple computational molecular docking (MD) methods have been developed to predict the structures of protein-protein complexes and their dynamics, still requiring further improvements in several issues. Here, we report an improved MD method, namely three-software docking (3SD), by employing three popular protein-peptide docking software (CABS-dock, HPEPDOCK, and HADDOCK) in combination to ensure constant quality for most targets. We validated our 3SD performance in known protein-peptide interactions (PpIs). We also enhanced MD performance in proteins having intrinsically disordered regions (IDRs) by applying the modified 3SD strategy, the three-software docking after removing random coiled IDR (3SD-RR), to the comparable crystal PpI structures. At the end, we applied 3SD-RR to the AlphaFold2-predicted receptors, yielding an efficient prediction of PpI pose with high relevance to the experimental data regardless of the presence of IDRs or the availability of receptor structures. Our study provides an improved solution to the challenges in studying PPIs through computational docking and has the potential to contribute to PPIs-targeted drug discovery. SIGNIFICANCE STATEMENT: Protein-protein interactions (PPIs) are integral to life, and abnormal PPIs are associated with diseases such as cancer. Studying protein-peptide interactions (PpIs) is challenging due to their dynamic and transient nature. Here we developed improved docking methods (3SD and 3SD-RR) to predict the PpI poses, ensuring constant quality in most targets and also addressing issues like intrinsically disordered regions (IDRs) and artificial intelligence-predicted structures. Our study provides an improved solution to the challenges in studying PpIs through computational docking and has the potential to contribute to PPIs-targeted drug discovery.