RESUMO
Cancer vaccines have been developed as a promising way to boost cancer immunity. However, their clinical potency is often limited due to the imprecise delivery of tumor antigens. To overcome this problem, we conjugated an endogenous Toll-like receptor (TLR)2/6 ligand, UNE-C1, to human papilloma virus type 16 (HPV-16)-derived peptide antigen, E7, and found that the UNE-C1-conjugated cancer vaccine (UCV) showed significantly enhanced antitumor activity in vivo compared with the noncovalent combination of UNE-C1 and E7. The combination of UCV with PD-1 blockades further augmented its therapeutic efficacy. Specifically, the conjugation of UNE-C1 to E7 enhanced its retention in inguinal draining lymph nodes, the specific delivery to dendritic cells and E7 antigen-specific T cell responses, and antitumor efficacy in vivo compared with the noncovalent combination of the two peptides. These findings suggest the potential of UNE-C1 derived from human cysteinyl-tRNA synthetase 1 as a unique vehicle for the specific delivery of cancer antigens to antigen-presenting cells via TLR2/6 for the improvement of cancer vaccines.
RESUMO
Hepatocellular carcinoma (HCC) is characterized by high incidence and fatality rates worldwide. In our exploration of prognostic factors in HCC, the 26s proteasome subunit, non-ATPase 1 (PSMD1) protein emerged as a significant contributor, demonstrating its potential as a therapeutic target in this aggressive cancer. PSMD1 is a subunit of the 19S regulatory particle in the 26S proteasome complex; the 19S particle controls the deubiquitination of ubiquitinated proteins, which are then degraded by the proteolytic activity of the complex. Proteasome-targeting in cancer therapy has received significant attention because of its practical application as an established anticancer agent. We investigated whether PSMD1 plays a critical role in cancer owing to its prognostic significance. PSMD1 depletion induced cell cycle arrest in G2/M phase, DNA damage and apoptosis of cancer cells, irrespective of the p53 status. PSMD1 depletion-mediated cell death was accompanied by an increase in overall protein ubiquitination. These phenotypes occurred exclusively in cancer cells, with no effects observed in normal cells. These findings indicate that PSMD1 depletion-mediated ubiquitination of cellular proteins induces cell cycle arrest and eventual death in cancer cells, emphasizing PSMD1 as a potential therapeutic target in HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Apoptose/genética , Carcinoma Hepatocelular/genética , Dano ao DNA , Neoplasias Hepáticas/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) causes a chronic and progressive granulomatous enteritis and economic losses in dairy cattle in subclinical stages. Subclinical infection in cattle can be detected using serum MAP antibody enzyme-linked immunosorbent assay (ELISA) and fecal polymerase chain reaction (PCR) tests. OBJECTIVES: To investigate the differences in blood parameters, according to the detection of MAP using serum antibody ELISA and fecal PCR tests. METHODS: We divided 33 subclinically infected adult cattle into three groups: seronegative and fecal-positive (SNFP, n = 5), seropositive and fecal-negative (SPFN, n = 10), and seropositive and fecal-positive (SPFP, n = 18). Hematological and serum biochemical analyses were performed. RESULTS: Although the cows were clinically healthy without any manifestations, the SNFP and SPFP groups had higher platelet counts, mean platelet volumes, plateletcrit, lactate dehydrogenase levels, lactate levels, and calcium levels but lower mean corpuscular volume concentration than the SPFN group (p < 0.017). The red blood cell count, hematocrit, monocyte count, glucose level, and calprotectin level were different according to the detection method (p < 0.05). The SNFP and SPFP groups had higher red blood cell counts, hematocrit and calprotectin levels, but lower monocyte counts and glucose levels than the SPFN group, although there were no significant differences (p > 0.017). CONCLUSIONS: The cows with fecal-positive MAP status had different blood parameters from those with fecal-negative MAP status, although they were subclinically infected. These findings provide new insights into understanding the mechanism of MAP infection in subclinically infected cattle.
Assuntos
Doenças dos Bovinos , Mycobacterium avium subsp. paratuberculosis , Paratuberculose , Feminino , Bovinos , Animais , Paratuberculose/diagnóstico , Doenças dos Bovinos/microbiologia , Ensaio de Imunoadsorção Enzimática/veterinária , Ensaio de Imunoadsorção Enzimática/métodos , Fezes/microbiologia , Complexo Antígeno L1 Leucocitário , GlucoseRESUMO
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.
Assuntos
Proteínas de Ligação a DNA , Neoplasias , Humanos , Proteínas de Ligação a DNA/genética , Neoplasias/genética , Mutações Sintéticas Letais , Medicina de Precisão , Fatores de Transcrição/genética , Peptídeos , Diester Fosfórico Hidrolases/genéticaRESUMO
Atopic dermatitis is a chronic inflammatory skin condition that is characterized by skin inflammation, itching, and redness. Although various treatments can alleviate symptoms, they often come with side effects, highlighting the need for new treatments. Here, we discovered a new peptide-based therapy using the intra-dermal delivery technology (IDDT) platform developed by Remedi Co., Ltd (REMEDI). The platform screens and identifies peptides derived from proteins in the human body that possess cell-penetrating peptide (CPP) properties. We screened over 1000-peptides and identified several derived from the Speckled protein (SP) family that have excellent CPP properties and have anti-inflammatory effects. We assessed these peptides for their potential as a treatment for atopic dermatitis. Among them, the RMSP1 peptide showed the most potent anti-inflammatory effects by inhibiting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling pathways while possessing CPP properties. To further improve efficacy and stability, we developed a palmitoylated version called Pal-RMSP1. Formulation studies using liposomes (Pal-RMSP1 LP) and micelles (Pal-RMSP1 DP) demonstrated improved anti-inflammatory effects in vitro and enhanced therapeutic effects in vivo. Our study indicates that nano-formulated Pal-RMSP1 could have the potential to become a new treatment option for atopic dermatitis.
Assuntos
Dermatite Atópica , Nanopartículas , Humanos , Dermatite Atópica/tratamento farmacológico , NF-kappa B/metabolismo , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Anti-Inflamatórios/farmacologiaRESUMO
Background and Objectives: Patients experience severe pain after surgical correction of ankle fractures. Although their exact mechanism is unknown, dexamethasone and epinephrine increase the analgesic effect of anesthetics in peripheral nerve blocks. This study aimed to compare the postoperative pain control efficacy of peripheral nerve blocks with ropivacaine combined with dexamethasone/epinephrine and peripheral nerve blocks with only ropivacaine and added patient-controlled analgesia in patients with ankle fractures. Materials and Methods: This randomized, controlled prospective study included patients aged 18-70 years surgically treated for ankle fractures between December 2021 and September 2022. The patients were divided into group A (n = 30), wherein pain was controlled using patient-controlled analgesia after lower extremity peripheral nerve block, and group B (n = 30), wherein dexamethasone/epinephrine was combined with the anesthetic solution during peripheral nerve block. In both groups, ropivacaine was used as the anesthetic solution for peripheral nerve block, and this peripheral nerve block was performed just before ankle surgery for the purpose of anesthesia for surgery. Pain (visual analog scale), patient satisfaction, and side effects were assessed and compared between the two groups. Results: The patients' demographic data were similar between groups. Pain scores were significantly lower in group B than in group A postoperatively. Satisfaction scores were significantly higher in group B (p = 0.003). There were no anesthesia-related complications in either group. Conclusions: Dexamethasone and epinephrine as adjuvant anesthetic solutions can effectively control pain when performing surgery using peripheral nerve blocks for patients with ankle fractures.
Assuntos
Fraturas do Tornozelo , Bloqueio Nervoso , Humanos , Ropivacaina/uso terapêutico , Anestésicos Locais/uso terapêutico , Estudos Prospectivos , Fraturas do Tornozelo/cirurgia , Fraturas do Tornozelo/complicações , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/etiologia , Bloqueio Nervoso/métodos , Nervos Periféricos , Epinefrina/uso terapêutico , Dexametasona/uso terapêuticoRESUMO
The applicability of a polyether ether ketone locking compression plate (PEEK LCP) fabricated using FDM (fused deposition modeling)-based 3D printing to treat actual patients was studied. Three different tests-bending, axial compression, and axial torsion-were conducted on tibial non-osteoporotic comminuted diaphyseal fracture samples fixed with the commercial titanium alloy LCP and 3D-printed PEEK LCP. Comparing the outcomes of these tests revealed that the commercial titanium alloy LCP underwent plastic deformation in the bending and axial torsion tests, though the LCP did not fail even when an external force greater than the maximum allowable load of the tibia fixture of the LCP was applied. Elastic deformation occurred in the 3D-printed PEEK LCP in the bending and axial torsion tests. However, deformation occurred even under a small external force, and its stiffness was 10% compared to commercial titanium alloy LCP. Thus, 3D-printed PEEK LCP can be applied to the fracture conditions in non-weight-bearing regions. The experimental results reveal detailed insights into the treatment of actual patients by considering the stiffness and high toughness of 3D-printed PEEK LCP.
RESUMO
Anti-pigmentation peptides have been developed as alternative skin-lightening agents to replace conventional chemicals that have adverse effects on the skin. However, the maximum size of these peptides is often limited by their low skin and cell penetration. To address this issue, we used our intra-dermal delivery technology (IDDT) platform to identify peptides with hypo-pigmenting and high cell-penetrating activity. Using our cell-penetrating peptides (CPPs) from the IDDT platform, we identified RMNE1 and its derivative RMNE3, "DualPep-Shine", which showed levels of α-Melanocyte stimulating hormone (α-MSH)-induced melanin inhibition comparable to the conventional tyrosinase inhibitor, Kojic acid. In addition, DualPep-Shine was delivered into the nucleus and regulated the gene expression levels of melanogenic enzymes by inhibiting the promoter activity of microphthalmia-associated transcription factor-M (MITF-M). Using a 3D human skin model, we found that DualPep-Shine penetrated the lower region of the epidermis and reduced the melanin content in a dose-dependent manner. Furthermore, DualPep-Shine showed high safety with little immunogenicity, indicating its potential as a novel cosmeceutical ingredient and anti-pigmentation therapeutic agent.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Peptídeos Penetradores de Células , Melaninas , Melanócitos , Fator de Transcrição Associado à Microftalmia , Proteínas do Tecido Nervoso , Preparações Clareadoras de Pele , Pigmentação da Pele , Transcrição Gênica , Melaninas/antagonistas & inibidores , Pigmentação da Pele/efeitos dos fármacos , Fator de Transcrição Associado à Microftalmia/genética , Transcrição Gênica/efeitos dos fármacos , alfa-MSH/antagonistas & inibidores , alfa-MSH/metabolismo , Humanos , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Preparações Clareadoras de Pele/química , Preparações Clareadoras de Pele/farmacologia , Melanoma Experimental , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/metabolismoRESUMO
Drug repositioning has gained significant attention over the past several years. The anti-rheumatoid arthritis drug auranofin has been investigated for the treatment of other diseases, including liver fibrosis. Because auranofin is rapidly metabolized, it is necessary to identify the active metabolites of auranofin that have detectable levels in the blood and reflect its therapeutic effects. In the present study, we investigated whether aurocyanide as an active metabolite of auranofin, can be used to evaluate the anti-fibrotic effects of auranofin. Incubation of auranofin with liver microsomes showed that auranofin was susceptible to hepatic metabolism. Previously, we found that the anti-fibrotic effects of auranofin are mediated via system xc--dependent inhibition of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Therefore, we tried to identify active metabolites of auranofin based on their inhibitory effects on system xc- and NLRP3 inflammasome in bone marrow-derived macrophages. Among the seven candidate metabolites, 1-thio-ß-D-glycopyrano-sato-S-(triethyl-phosphine)-gold(I) and aurocyanide potently inhibited system xc- and NLRP3 inflammasome. A pharmacokinetics study on mice detected significant plasma levels of aurocyanide after auranofin administration. Oral administration of aurocyanide significantly prevented thioacetamide-induced liver fibrosis in mice. Moreover, the in vitro anti-fibrotic effects of aurocyanide were assessed in LX-2 cells, where aurocyanide significantly decreased the migratory ability of the cells. In conclusion, aurocyanide is metabolically stable and detectable in plasma, and has inhibitory effects on liver fibrosis, suggesting that it is a potential marker of the therapeutic effects of auranofin.
Assuntos
Auranofina , Inflamassomos , Camundongos , Animais , Auranofina/farmacologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos Endogâmicos NOD , Ouro , Cirrose Hepática/tratamento farmacológicoRESUMO
The indication for the surgical treatment of ankle fractures that involve a posterior malleolar fragment remains controversial. This cadaver study assessed the biomechanical results of rotation stiffness of Haraguchi type 1 posterior malleolar fragments with or without cannulated screw fixation. Twelve anatomic lower-extremity specimens from 6 cadavers were tested. Six right legs were subjected to posterior malleolus osteotomy (Haraguchi type I) followed with (group A; n = 3) or without (group B; n = 3) fixation using a cannulated screw. Ankle joint stability was measured under both external rotation force and axial loading, and the passive resistive torque was measured in both groups. The mean torque value in group A was 0.1093 Nm/º, while that in group B was 0.0537 Nm/º. There was a significant intergroup difference (p = .004). In group B, the torque value was further increased in the latter rotation period (about 40-60 degrees). Group A proved more stable under experimental conditions than group B. Fixation in type I posterior malleolar fragments produced improved stability in ankle rotation, even for posterior malleolar fragments involving <25% of the articular surface, and has been considered an effective aid in treatment.
Assuntos
Fraturas do Tornozelo , Fraturas Ósseas , Humanos , Fixação Interna de Fraturas/métodos , Fraturas Ósseas/cirurgia , Articulação do Tornozelo/cirurgia , Tornozelo , Cadáver , Fraturas do Tornozelo/diagnóstico por imagem , Fraturas do Tornozelo/cirurgiaRESUMO
Background: Comorbid chronic obstructive pulmonary disease (COPD) is increasingly common and may have an adverse impact on outcomes in patients undergoing total joint arthroplasty (TJA) of lower extremity. The purpose of this meta-analysis is to compare the postoperative complications between COPD and non-COPD patients undergoing primary TJA including total hip and knee arthroplasty. Methods: PubMed, EMBASE, and Cochrane Library were systematically searched for relevant studies published before December 2021. Postoperative outcomes were compared between patients with COPD versus those without COPD as controls. The outcomes were mortality, re-admission, pulmonary, cardiac, renal, thromboembolic complications, surgical site infection (SSI), periprosthetic joint infection (PJI), and sepsis. Results: A total of 1,002,779 patients from nine studies were finally included in this meta-analysis. Patients with COPD had an increased risk of mortality (OR [odds ratio] = 1.69, 95% confidence interval [CI] 1.42-2.02), re-admission (OR = 1.54, 95% CI 1.38-1.71), pulmonary complications (OR = 2.73, 95% CI 2.26-3.30), cardiac complications (OR = 1.40, 95% CI 1.15-1.69), thromboembolic complications (OR = 1.21, 95% CI 1.15-1.28), renal complications (OR = 1.50, 95% CI 1.14-1.26), SSI (OR = 1.23, 95% CI 1.18-1.30), PJI (OR = 1.26, 95% CI 1.15-1.38), and sepsis (OR = 1.36, 95% CI 1.22-1.52). Conclusion: Patients with comorbid COPD showed an increased risk of mortality and postoperative complications following TJA compared with patients without COPD. Therefore, orthopedic surgeons can use the study to adequately educate these potential complications when obtaining informed consent. Furthermore, preoperative evaluation and medical optimization are crucial to minimizing postoperative complications from arising in this difficult-to-treat population. Level of evidence: Level III. Registration: None. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-022-00794-2.
RESUMO
Extracellular vesicles (EVs) have emerged as vehicles that mediate diverse cell-cell communication. However, in-depth understanding of these vesicles is hampered by a lack of a reliable isolation method to separate different types of EVs with high levels of integrity and purity. Here, we developed a nanoporous and ultra-thin membrane structure (NUTS) that warrants the size-based isolation of EVs without cake formation, minimizing the sample loss during the filtration process. By utilizing the micro-electro-mechanical systems (MEMS) technique, we could also control the pore size in nanoscale. We validated the performance of this membrane to separate EVs according to their size range.
RESUMO
G protein-coupled receptors (GPCRs) are a diverse family of cell surface receptors implicated in various physiological functions, making them common targets for approved drugs. Many GPCRs are abnormally activated in cancers and have emerged as therapeutic targets for cancer. Neuropeptide FF receptor 2 (NPFFR2) is a GPCR that helps regulate pain and modulates the opioid system; however, its function remains unknown in cancers. Here, we found that NPFFR2 is significantly up-regulated in liver cancer and its expression is related to poor prognosis. Silencing of NPFFR2 reduced the malignancy of liver cancer cells by decreasing cell survival, invasion, and migration, while its overexpression increased invasion, migration, and anchorage-independent cell growth. Moreover, we found that the malignant function of NPFFR2 depends on RhoA and YAP signaling. Inhibition of Rho kinase activity completely restored the phenotypes induced by NPFFR2, and RhoA/F-Actin/YAP signaling was controlled by NPFFR2. These findings demonstrate that NPFFR2 may be a potential target for the treatment of hepatocellular carcinoma.
RESUMO
Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancers have the worst prognosis due to their higher recurrence rate, higher probability of developing metastases and higher chemoresistance compared to those of other molecular subtypes. Pharmacologically actionable somatic mutations are rarely found in EMT-subtype gastric cancers, limiting the utility of targeted therapies. Here, we conducted a high-throughput chemical screen using 37 gastric cancer cell lines and 48,467 synthetic smallmolecule compounds. We identified YK-135, a small-molecule compound that showed higher cytotoxicity toward EMT-subtype gastric cancer cell lines than toward non-EMT-subtype gastric cancer cell lines. YK-135 exerts its cytotoxic effects by inhibiting mitochondrial complex I activity and inducing AMP-activated protein kinase (AMPK)-mediated apoptosis. We found that the lower glycolytic capacity of the EMT-subtype gastric cancer cells confers synthetic lethality to the inhibition of mitochondrial complex I, possibly by failing to maintain energy homeostasis. Other well-known mitochondrial complex I inhibitors (e.g., rotenone and phenformin) mimic the efficacy of YK-135, supporting our results. These findings highlight mitochondrial complex I inhibitors as promising therapeutic agents for EMT-subtype gastric cancers and YK-135 as a novel chemical scaffold for further drug development. [BMB Reports 2022; 55(12): 645-650].
Assuntos
Antineoplásicos , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Transição Epitelial-MesenquimalRESUMO
Exosomes, which are well-known nanoscale extracellular vesicles, are multifunctional biomaterials derived from endosomes and perform various functions. The exosome is a critical material in cell-cell communication. In addition, it regulates the pathophysiological conditions of the tumor microenvironment in particular. In the tumor microenvironment, exosomes play a controversial role in supporting or killing cancer by conveying biomaterials derived from parent cells. Innate immunity is a crucial component of the host defense mechanism, as it prevents foreign substances, such as viruses and other microbes and tumorigenesis from invading the body. Early in the tumorigenesis process, the innate immunity explicitly recognizes the tumor via Ags and educates the adaptive immunity to eliminate it. Recent studies have revealed that exosomes regulate immunity in the tumor microenvironment. Tumor-derived exosomes regulate immunity against tumor progression and metastasis. Furthermore, tumor-derived exosomes regulate polarization, differentiation, proliferation, and activation of innate immune cells. Exosomes produced from innate immune cells can inhibit or support tumor progression and metastasis via immune cell activation and direct cancer inhibition. In this study, we investigated current knowledge regarding the communication between tumor-derived exosomes and innate immune cell-derived exosomes (from macrophages, dendritic cells, NK cells, and neutrophils) in the tumor microenvironment. In addition, we discussed the potential development of exosomal immunotherapy using native or engineered exosomes against cancer.
RESUMO
BACKGROUND: Autophagy is elevated in metastatic tumors and is often associated with active epithelial-to-mesenchymal transition (EMT). However, the extent to which EMT is dependent on autophagy is largely unknown. This study aimed to identify the mechanisms by which autophagy facilitates EMT. METHODS: We employed a liquid chromatography-based metabolomic approach with kirsten rat sarcoma viral oncogene (KRAS) and liver kinase B1 (LKB1) gene co-mutated (KL) cells that represent an autophagy/EMT-coactivated invasive lung cancer subtype for the identification of metabolites linked to autophagy-driven EMT activation. Molecular mechanisms of autophagy-driven EMT activation were further investigated by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting analysis, immunoprecipitation, immunofluorescence staining, and metabolite assays. The effects of chemical and genetic perturbations on autophagic flux were assessed by two orthogonal approaches: microtubule-associated protein 1A/1B-light chain 3 (LC3) turnover analysis by Western blotting and monomeric red fluorescent protein-green fluorescent protein (mRFP-GFP)-LC3 tandem fluorescent protein quenching assay. Transcription factor EB (TFEB) activity was measured by coordinated lysosomal expression and regulation (CLEAR) motif-driven luciferase reporter assay. Experimental metastasis (tail vein injection) mouse models were used to evaluate the impact of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) or ATP citrate lyase (ACLY) inhibitors on lung metastasis using IVIS luciferase imaging system. RESULTS: We found that autophagy in KL cancer cells increased acetyl-coenzyme A (acetyl-CoA), which facilitated the acetylation and stabilization of the EMT-inducing transcription factor Snail. The autophagy/acetyl-CoA/acetyl-Snail axis was further validated in tumor tissues and in autophagy-activated pancreatic cancer cells. TFEB acetylation in KL cancer cells sustained pro-metastatic autophagy in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner. Pharmacological inhibition of this axis via CAMKK2 inhibitors or ACLY inhibitors consistently reduced the metastatic capacity of KL cancer cells in vivo. CONCLUSIONS: This study demonstrates that autophagy-derived acetyl-CoA promotes Snail acetylation and thereby facilitates invasion and metastasis of KRAS-LKB1 co-mutated lung cancer cells and that inhibition of the autophagy/acetyl-CoA/acetyl-Snail axis using CAMKK2 or ACLY inhibitors could be a potential therapeutic strategy to suppress metastasis of KL lung cancer.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Fatores de Transcrição da Família Snail/metabolismo , Acetilcoenzima A/farmacologia , Acetilação , Animais , Autofagia/genética , Neoplasias Pulmonares/genética , Mamíferos , Camundongos , Processos Neoplásicos , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: One in five patients with mechanical alignment (MA) after total knee arthroplasty (TKA) was reportedly dissatisfied. As constitutional varus knees are common, restoring the patients' natural residual varus (RV) alignment is as an appealing alternative to neutral MA. This meta-analysis aimed to evaluate the effects of RV alignment on the functional outcomes compared with those of MA in TKA for the knees with varus osteoarthritis. METHODS: The MEDLINE/PubMed, Cochrane Library, and EMBASE databases were comprehensively searched for papers comparing the effects of RV alignment and MA on the functional outcomes from the time of inception of the databases to July 2020. Studies comparing the functional outcomes in the knees subjected to TKA with RV alignment (case group) and MA (control group) were included. The Knee Society knee and functional scores (KSKS and KSFS, respectively), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Oxford knee score (OKS), and forgotten joint score (FJS) were compared. RESULTS: Seven studies were finally included; all studies showed a low risk of selection bias and provided detailed demographic data. The pooled mean difference in the KSKS (0.06, 95% confidence interval [CI]: -0.14 to 0.27; p = 0.55) and KSFS (0.08, 95% CI: -0.08 to 0.35; p = 0.56) between RV alignment and MA did not significantly differ. The pooled mean differences in the WOMAC (-0.25, 95% CI: -0.57 to 0.07; p = 0.12), OKS (0.06, 95% CI: -0.15 to 0.27; p = 0.56), and FJS (0.41, 95% CI: -0.18 to 1.00; p = 0.18) between the groups were not significant. CONCLUSION: The beneficial effects of RV alignment on the functional outcomes are limited compared to those of MA in TKA for varus osteoarthritis to date. Currently, TKA with neutral MA should be considered as the gold standard.
Assuntos
Artroplastia do Joelho , Prótese do Joelho , Osteoartrite do Joelho , Humanos , Joelho/cirurgia , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/cirurgiaRESUMO
Knowledge of the impact of the gut microbiota on human health has increased, and modulation of the bacterial community is now considered a therapeutic target for various diseases. Certain novel bacterial species have probiotic properties associated with improvement in obesity and related metabolic disorders. The relative abundance of Butyricimonas spp. is correlated with metabolic parameters; however, the physiological role of Butyricimonas in metabolic improvement is unclear. In this study, live and heat-killed Butyricimonas virosa were administered to mice with high-fat diet (HFD)-induced obesity. Both live and heat-killed B. virosa ameliorated HFD-impaired body weight, serum glucose level, insulin resistance, and liver steatosis. Moreover, activation of the glucagon-like peptide-1 receptor (GLP-1R) and peroxisome proliferator-activated receptor α (PPARα) was observed in the liver, and the expression levels of insulin receptor substrate (IRS)-1, IRS-2, Toll-like receptor 5 (TLR5), and zonula occludens-1 (ZO-1) were upregulated in the ileum. Finally, we demonstrated that the effect of B. virosa treatment on glucose regulation may be linked to the upregulation of GLP-1R in the liver and is not a result of colonization of the gut by B. virosa or B. virosa-produced butyrate. Our results provide a rationale for the development of Butyricimonas spp.-based therapeutics and prophylactics for hyperglycemia.
RESUMO
Interactive metronome training may be effective for improving motor performances through timing. In this systematic review and meta-analysis, 18 prospective studies met our eligibility criteria, and we summarized the effects of interactive metronome training protocols on motor functioning. We estimated effect sizes by quantifying differences in altered motor functions between participants in interactive metronome training and control groups. Two additional subgroup analyses determined whether the positive effects on motor function improvements were different among (a) three types of participants (i.e., athletes, healthy individuals, and patients with neurological disorders) and (b) two different training protocols (i.e., interactive metronome training only and interactive metronome training combined with an additional motor program). Random-effects model meta-analysis revealed moderate positive effects of interactive metronome training on motor function, with interactive metronome treatment effects significant across athletes, healthy individuals, and patients with neurological disorders. Interactive metronome training combined with additional motor programs showed comparable effects to those obtained after interactive metronome training alone. These findings suggest motor improvement benefits to strengthening or capitalizing on an individual's motor timing.