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OBJECTIVE: To evaluate the physiological and psychological changes in cancer survivors who engage in repeated forest therapy in a living environment. METHODS: This study included stay-based forest therapy for female cancer survivors aged ≥40 years. The program was conducted in two cycles, each spanning 3 weeks and consisting of a 2-night, 3-day stay, followed by daily life integration. The cycles were repeated from July 2, 2022, to August 18, 2022. Participant assessment included standard physical health parameters and a questionnaire on general characteristics, lifestyle habits, stress levels, and health status. RESULTS: Thirty-seven female cancer survivors participated in the forest healing program, 56.8% of whom had a history of breast cancer. The median body mass index (BMI) was 23.80 kg/m2 (range, 21.00-25.60). More than half of the patients reported mild-to-moderate fatigue, chronic pain, and mild-to-moderate depression (81%, 65%, and 73%, respectively). After two cycles of forest therapy, no significant differences were observed in terms of fatigue, pain, or BMI levels. However, significant improvements were found in quality of life measures, particularly the psychological quality of life (mean score 12.54 at baseline vs. 13.48 after cycle 2; P=0.007). Positive improvements were also observed in terms of stress (mean score 17.03 vs. 13.76; P=0.002) and depression (mean score 8.35 vs. 6.11; P=0.002) levels. CONCLUSION: Our forest-healing program demonstrated that nature-based therapies improve the mental health and quality of life of female cancer survivors, suggesting the need for further research on nature-based interventions to better support cancer survivors.
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Trained immunity, an innate immune response characterized by enhanced cellular responsiveness, exhibits a profound memory akin to adaptive immunity. This phenomenon involves intricate metabolic and epigenetic reprogramming triggered by stimuli such as ß-glucan and BCG, shaping innate immune memory. Following elucidation of the background on trained immunity, it is important to explore its multifaceted roles in various pathological contexts. In this review, we delve into the specific contributions of trained immunity in the intricate landscape of viral infections, tumorigenesis, and diverse inflammatory diseases, shedding light on its potential as a therapeutic target, and offering comprehensive understanding of its broader immunological implications.
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Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1-deficient mice are resistant to metastasis and further protected by combined immune-checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF-ß1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK-target cell responses, which is dysregulated and hijacked by tumors during metastatic progression.
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Progressão da Doença , Células Matadoras Naturais , Melanoma , Células Matadoras Naturais/imunologia , Animais , Camundongos , Melanoma/genética , Melanoma/patologia , Melanoma/imunologia , Humanos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Modelos Animais de Doenças , Metástase Neoplásica , Linhagem Celular TumoralRESUMO
Transmembrane protein 135 (TMEM135) is a 52 kDa protein with five predicted transmembrane domains that is highly conserved across species. Previous studies have shown that TMEM135 is involved in mitochondrial dynamics, thermogenesis, and lipid metabolism in multiple tissues; however, its role in the inner ear or the auditory system is unknown. We investigated the function of TMEM135 in hearing using wild-type (WT) and Tmem135 FUN025/FUN025 ( FUN025 ) mutant mice on a CBA/CaJ background, a normal-hearing mouse strain. Although FUN025 mice displayed normal auditory brainstem response (ABR) at 1 month, we observed significantly elevated ABR thresholds at 8, 16, and 64 kHz by 3 months, which progressed to profound hearing loss by 12 months. Consistent with our auditory testing, 13-month-old FUN025 mice exhibited a severe loss of outer hair cells and spiral ganglion neurons in the cochlea. Our results using BaseScope in situ hybridization indicate that TMEM135 is expressed in the inner hair cells, outer hair cells, and supporting cells. Together, these results demonstrate that the FUN025 mutation in Tmem135 causes progressive sensorineural hearing loss, and suggest that TMEM135 is crucial for maintaining key cochlear cell types and normal sensory function in the aging cochlea.
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Natural killer (NK) cells are key effectors in cancer immunosurveillance, eliminating a broad spectrum of cancer cells without major histocompatibility complex (MHC) specificity and graft-versus-host diseases (GvHD) risk. The use of allogeneic NK cell therapies from healthy donors has demonstrated favorable clinical efficacies in treating diverse cancers, particularly hematologic malignancies, but it requires cytokines such as IL-2 to primarily support NK cell persistence and expansion. However, the role of IL-2 in the regulation of activating receptors and the function of NK cells expanded for clinical trials is poorly understood and needs clarification for the full engagement of NK cells in cancer immunotherapy. Here, we demonstrated that IL-2 deprivation significantly impaired the cytotoxicity of primary expanded NK cells by preferentially downregulating NKp30 but not NKp46 despite their common adaptor requirement for expression and function. Using NK92 and IL-2-producing NK92MI cells, we observed that NKp30-mediated cytotoxicity against myeloid leukemia cells such as K562 and THP-1 cells expressing B7-H6, a ligand for NKp30, was severely impaired by IL-2 deprivation. Furthermore, IL-2 deficiency-mediated NK cell dysfunction was overcome by the ectopic overexpression of an immunostimulatory NKp30 isoform such as NKp30a or NKp30b. In particular, NKp30a overexpression in NK92 cells improved the clearance of THP-1 cells in vivo without IL-2 supplementation. Collectively, our results highlight the distinct role of IL-2 in the regulation of NKp30 compared to that of NKp46 and suggest NKp30 upregulation, as shown here by ectopic overexpression, as a viable modality to harness NK cells in cancer immunotherapy, possibly in combination with IL-2 immunocytokines.
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Citotoxicidade Imunológica , Interleucina-2 , Células Matadoras Naturais , Receptor 3 Desencadeador da Citotoxicidade Natural , Humanos , Receptor 3 Desencadeador da Citotoxicidade Natural/imunologia , Receptor 3 Desencadeador da Citotoxicidade Natural/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Interleucina-2/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Células K562 , Células THP-1 , Antígenos B7/genética , Antígenos B7/metabolismo , Antígenos B7/imunologiaRESUMO
The Indian Ocean Dipole (IOD) is a major climate variability mode that substantially influences weather extremes and climate patterns worldwide. However, the response of IOD variability to anthropogenic global warming remains highly uncertain. The latest IPCC Sixth Assessment Report concluded that human influences on IOD variability are not robustly detected in observations and twenty-first century climate-model projections. Here, using millennial-length climate simulations, we disentangle forced response and internal variability in IOD change and show that greenhouse warming robustly suppresses IOD variability. On a century time scale, internal variability overwhelms the forced change in IOD, leading to a widespread response in IOD variability. This masking effect is mainly caused by a remote influence of the El Niño-Southern Oscillation. However, on a millennial time scale, nearly all climate models show a long-term weakening trend in IOD variability by greenhouse warming. Our results provide compelling evidence for a human influence on the IOD.
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The cytotoxic mycotoxin deoxynivalenol (DON) reportedly has adverse effects on oocyte maturation and embryonic development in pigs. Recently, the interplay between cell apoptosis and endoplasmic reticulum (ER) stress has garnered increasing attention in embryogenesis. However, the involvement of the inositol-requiring enzyme 1 (IRE1)/c-jun N-terminal kinase (JNK)/C/EBP homologous protein (CHOP) pathways of unfolded protein response (UPR) signaling in DON-induced apoptosis in porcine embryos remains unknown. In this study, we revealed that exposure to DON (0.25 µM) substantially decreased cell viability until the blastocyst stage in porcine embryos, concomitant with initiation of cell apoptosis through the IRE1/JNK/CHOP pathways in response to ER stress. Quantitative PCR confirmed that UPR signaling-related transcription factors were upregulated in DON-treated porcine blastocysts. Western blot analysis showed that IRE1/JNK/CHOP signaling was activated in DON-exposed porcine embryos, indicating that ER stress-associated apoptosis was instigated. The ER stress inhibitor tauroursodeoxycholic acid protected against DON-induced ER stress in porcine embryos, indicating that the toxic effects of DON on early developmental competence of porcine embryos can be prevented. In conclusion, DON exposure impairs the developmental ability of porcine embryos by inducing ER stress-mediated apoptosis via IRE1/JNK/CHOP signaling.
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Apoptose , Estresse do Retículo Endoplasmático , Fator de Transcrição CHOP , Tricotecenos , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Fator de Transcrição CHOP/metabolismo , Fator de Transcrição CHOP/genética , Suínos , Tricotecenos/toxicidade , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Blastocisto/efeitos dos fármacos , Blastocisto/metabolismo , FemininoRESUMO
BACKGROUND: Evidence on the association between obesity parameters, including body mass index (BMI) and waist circumference (WC), and osteoarthritis is limited. This study aimed to investigate these associations in Korean adults. METHODS: This nationwide cross-sectional study used data from 24,101 adults aged ≥19 years who participated in the Korea National Health and Nutrition Examination Survey 2016-2020. Odds ratios (ORs) and 95% confidence intervals (CIs) for osteoarthritis according to BMI and WC were analyzed using multivariable logistic regression analyses. RESULTS: The prevalence of osteoarthritis was higher in individuals with general (10.0%) and abdominal obesity (12.8%) compared with those without. Greater BMI and WC were associated with a higher prevalence (P<0.001) and risk of osteoarthritis (Model 3, P for trend <0.001). Individuals with general and abdominal obesity were associated with a 1.50-fold (OR, 1.50; 95% CI, 1.35-1.67) and 1.64-fold (OR, 1.64; 95% CI, 1.47-1.84) increased risk of osteoarthritis, compared with those without. Similar associations were observed in subgroups according to age, sex, smoking status, and presence of diabetes mellitus. The odds of osteoarthritis 1.73-fold increased (OR, 1.73; 95% CI, 1.53-1.95) in individuals with both general and abdominal obesity compared with those without any of them. CONCLUSION: Greater BMI, WC, and general and abdominal obesity were associated with an increased risk of osteoarthritis in Korean adults. Appropriate management of abdominal and general obesity may be important to reduce the risk of osteoarthritis.
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Ochratoxin A (OTA), a mycotoxin found in foods, has a deleterious effect on female reproduction owing to its endocrine-disrupting activity mediated through endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production. However, the mechanisms of OTA-induced ER stress in pig embryos during in vitro culture (IVC) are not yet fully understood. In the present study, porcine embryos were cultured for two days in an IVC medium supplemented with 0.5, 1.0, and 5.0 µM OTA, which led to an OTA-induced reduction in the developmental rate of blastocysts. The mRNA-seq transcriptome analysis revealed that the reduced blastocyst development ability of OTA-exposed porcine embryos was caused by ER stress, ultimately resulting in the accumulation of ROS and the occurrence of apoptosis. The expression levels of some UPR/PERK signaling-related genes (DDIT3, EIF2AK3, EIF2S1, NFE2L2, ATF4, EIF2A, and KEAP1) were found to differ in OTA-exposed pig embryos. OTA induces DNA damage by triggering an increase in RAD51/γ-H2AX levels and suppressing p-NRF2 activity. This effect is mediated through intracellular ROS and superoxide accumulation in the nuclei of porcine embryos. The cytotoxicity of OTA increased the activation of the PERK signal pathways (p-PERK, PERK, p-eIF2α, eIF2α, ATF4, and CHOP) in porcine embryos, with abnormal distribution of the ER observed around the nucleus. Collectively, our findings indicate that ER stress is a major cause of decline in the development of porcine embryos exposed to OTA. Therefore, OTA exposure induces ER stress and DNA damage via oxidative stress by disrupting PERK/NRF2 signaling activity in the developmental competence of porcine embryos during IVC.
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Estresse do Retículo Endoplasmático , Fator 2 Relacionado a NF-E2 , Ocratoxinas , Feminino , Animais , Suínos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Dano ao DNA , ApoptoseRESUMO
Background and Objectives: Hand grip strength (HGS) and osteoporosis are known to be closely related to the health condition of the elderly, respectively. Comprehensive studies including adults over middle age were insufficient. This study aimed to investigate the relationship between HGS with osteoporosis and health-related quality of life (HRQoL) in adults aged >40 years. Materials and Methods: This cross-sectional analysis included data from 13,966 people aged >40 years between 2015 to 2018 provided by the Korea National Health and Nutrition Examination Survey. The HGS was divided into strong and weak quartiles, defined as the highest and lowest quartiles, respectively. We used the European Quality of Life Scale-Five dimensions (EQ-5D) for HRQoL. We performed multiple logistic regression and post hoc analysis to confirm the relationship between the four groups and HRQoL. Results: Osteoporotic patients with weak HGS showed the lowest EQ-5D index (0.87 ± 0.01) among all groups and had a significantly impaired HRQoL in all EQ-5D dimensions, at least 1.75 times more than healthy individuals with strong HGS (0.95 ± 0.00). Osteoporotic patients with weak HGS showed, notably, 2.68 times more impaired mobility compared to healthy individuals with strong HGS among all five dimensions of the EQ-5D. In self-care, significant sex differences in impaired HRQoL were observed (males 6.03, 2.23-16.35; females 2.51, 1.70-3.71). Conclusions: Weak HGS and the presence of osteoporosis were associated with low HRQoL, respectively. Middle-aged and older adults with both weak HGS and osteoporosis showed poorer HRQoL compared to healthy middle-aged and older adults. This suggests that HGS is a possible factor for predicting poor HRQoL in adults aged >40 years with or without osteoporosis. It is necessary to assess the risk of low HRQoL by measuring HGS and confirming whether osteoporosis is accompanied in adults over middle age.
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Osteoporose , Qualidade de Vida , Idoso , Pessoa de Meia-Idade , Humanos , Masculino , Feminino , Inquéritos Nutricionais , Força da Mão , Estudos Transversais , Osteoporose/complicações , Osteoporose/epidemiologia , Inquéritos e QuestionáriosRESUMO
Juvenile gangrenous vasculitis is characterized by the abrupt onset of scrotal ulcerations in young males, preceded by fever and pharyngeal symptoms. The etiology of this disease is poorly understood. The course is benign and self-limiting within a few weeks with no relapse. Because of its rare incidence, physicians often confuse it with Fournier's gangrene, which progresses rapidly to severe systemic symptoms requiring urgent surgical intervention. Herein, we report a rare case of juvenile gangrenous vasculitis of the scrotum and emphasize the importance of awareness of this diagnosis to avoid unnecessary invasive surgical intervention. A 17-year-old boy presented with painful and tender, diffuse erythema and swelling with a necrotic lesion on the scrotum for three days. Preceding the cutaneous manifestations, he had a fever and sore throat. Physical examination showed an about 2 cm-sized well-demarcated necrotic lesion on the anterior scrotum. Laboratory findings revealed neutrophilic leukocytosis with an elevated C-reactive protein and erythrocyte sedimentation rate. On scrotal ultrasonography, only edematous skin thickening and an increase in vascularity were observed. Histopathological examination showed epidermal necrosis and dermal neutrophilic infiltration. Empirical antibiotic treatment with ampicillin/sulbactam and clindamycin was administered and a prompt clinical resolution was observed.
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Papillary thyroid cancer (PTC) is the most common type of endocrine cancer worldwide. Generally, PTC has an excellent prognosis; however, lymph node metastases and recurrences occur frequently. Over the last decade, circular RNAs (circRNAs), a large class of noncoding RNAs (ncRNAs), have emerged as key regulators of various tumor progression pathways. Here, we aimed to identify novel circRNAs as PTC biomarkers. Differentially expressed circRNAs and mRNAs were analyzed using public datasets from the Gene Expression Omnibus and Cancer Genome Atlas. In addition, we screened for target miRNAs using online prediction databases. Based on these results, we established a circRNA-miRNA-mRNA regulatory network associated with PTC, in which protein-protein interaction networks led to the identification of hub genes. Functional enrichment and survival analyses were performed to gain insights into the biological mechanisms of circRNA involvement. As a result, we found that two circRNAs (hsa_circ_0041829 and has_circ_0092299), four miRNAs (miR-369, miR-486, miR-574, and miR-665), and nine hub genes (BBC3, E2F1, FYN, MAG, SDC1, SDC3, SNAP25, TK1, and TYMS) play significant roles in PTC progression. This study provides a novel framework for understanding the roles of circRNA-miRNA-mediated gene regulation in PTC. It also introduces potential therapeutic targets and prognostic biomarkers, which may serve as a basis for developing targeted therapeutic interventions for PTC.
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Ceramide induces autophagy upon starvation via downregulation of nutrient transporters. To elucidate the mechanism by which starvation regulates autophagy in mouse embryos, the present study investigated nutrient transporter expression and the effect of C2-ceramide on in vitro embryo development, apoptosis, and autophagy. The transcript levels of the glucose transporters Glut1 and Glut3 were high at the 1- and 2-cell stages, and gradually decreased at the morula and blastocyst (BL) stages. Similarly, expression of the amino acid transporters L-type amino transporter-1 (LAT-1) and 4F2 heavy chain (4F2hc) gradually decreased from the zygote to the BL stage. Upon ceramide treatment, expression of Glut1, Glut3, LAT-1, and 4F2hc was significantly reduced at the BL stage, while expression of the autophagy-related genes Atg5, LC3, and Gabarap and synthesis of LC3 were significantly induced. Ceramide-treated embryos exhibited significantly reduced developmental rates and total cell numbers per blastocyst, and increased levels of apoptosis and expression of Bcl2l1 and Casp3 at the BL stage. Ceramide treatment significantly decreased the average mitochondrial DNA copy number and mitochondrial area at the BL stage. In addition, ceramide treatment significantly decreased mTOR expression. These results suggest that ceramide-induced autophagy promotes apoptosis by following downregulation of nutrient transporters during mouse embryogenesis.
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Ceramidas , Desenvolvimento Embrionário , Gravidez , Feminino , Camundongos , Animais , Ceramidas/farmacologia , Ceramidas/metabolismo , Transportador de Glucose Tipo 1 , Transportador de Glucose Tipo 3 , Desenvolvimento Embrionário/genética , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Membrana Transportadoras/farmacologia , Autofagia/genéticaRESUMO
Salivary gland dysfunction worsens the quality of life, but treatment for restoration of salivary gland function is limited. Although previous reports have demonstrated the therapeutic potentials of extracellular vesicles (EVs) in different preclinical models, the role of EVs in salivary glands remains elusive. Furthermore, little is known about the roles of salivary gland-derived EVs in tissue repair or regeneration compared to other EVs. In this study, EVs secreted from salivary gland-derived mesenchymal stem cells (sgMSCs) were comparatively analyzed with those from Wharton's jelly-derived MSC (wjMSCs). sgMSCs secreted more significant amounts of EVs than wjMSCs, and salivary gland epithelial cells showed a more efficient uptake of sgMSC-EVs than wjMSC-EVs. The possibility of immune regulation was tested via macrophage polarization and LPS-induced epithelial inflammation, resulting in an M1-to-M2 shift and reversal of acinar-to-ductal metaplasia by sgMSC-EV. Furthermore, the roles of sgMSC-EV-mediated immune regulation and tissue repair were clarified in vivo via retroductal delivery of sgMSC-EVs in a mouse model of obstructive sialadenitis. Collectively, our data demonstrate the superior role of sgMSC-EVs in the recovery from salivary gland inflammation and injury and suggest EVs as therapeutic tools for salivary gland dysfunction.
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Vesículas Extracelulares , Células-Tronco Mesenquimais , Sialadenite , Camundongos , Animais , Qualidade de Vida , Células-Tronco Mesenquimais/fisiologia , Sialadenite/terapia , Inflamação/terapiaRESUMO
PURPOSE: The purpose of this study was to identify the main keywords, network properties, and main topics of news articles related to artificial intelligence technology in the field of nursing. METHODS: After collecting artificial intelligence-and nursing-related news articles published between January 1, 1991, and July 24, 2022, keywords were extracted via preprocessing. A total of 3,267 articles were searched, and 2,996 were used for the final analysis. Text network analysis and topic modeling were performed using NetMiner 4.4. RESULTS: As a result of analyzing the frequency of appearance, the keywords used most frequently were education, medical robot, telecom, dementia, and the older adults living alone. Keyword network analysis revealed the following results: a density of 0.002, an average degree of 8.79, and an average distance of 2.43; the central keywords identified were 'education,' 'medical robot,' and 'fourth industry.' Five topics were derived from news articles related to artificial intelligence and nursing: 'Artificial intelligence nursing research and development in the health and medical field,' 'Education using artificial intelligence for children and youth care,' 'Nursing robot for older adults care,' 'Community care policy and artificial intelligence,' and 'Smart care technology in an aging society.' CONCLUSION: The use of artificial intelligence may be helpful among the local community, older adult, children, and adolescents. In particular, health management using artificial intelligence is indispensable now that we are facing a super-aging society. In the future, studies on nursing intervention and development of nursing programs using artificial intelligence should be conducted.
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Inteligência Artificial , Pesquisa em Enfermagem , Criança , Humanos , Idoso , AdolescenteRESUMO
Rapamycin induces autophagosome formation and activity during oocyte maturation, improved fertilization ability of matured oocytes, and early embryonic developmental competence. However, potential changes in mitochondrial fission and mitophagy via regulation of autophagy in early porcine embryonic development have not been previously studied. Here, we investigated embryonic developmental ability and quality of porcine embryos 2 days after in vitro fertilization and following treatment with 1 and 10 nM rapamycin. As a results, 1 nM rapamycin exposure significantly improved (p < 0.05) blastocyst developmental competence compared to that in nontreated embryos (nontreated: 26.2 ± 5.7% vs. 1 nM rapamycin: 35.3 ± 5.1%). We observed autophagic (LC3B) and mitochondrial fission protein expression (dynamin-related protein-1 [DRP1] and pDRP1-Ser616) at the cleavage stage of 1 and 10 nM rapamycin-treated porcine embryos, using Western blot and immunofluorescence analyses. Interestingly, 1 nM rapamycin treatment significantly improved autophagy formation, mitochondrial activation, and mitochondrial fission protein levels (p < 0.05; p-DRP1 [Ser616]) at the cleavage stage of porcine embryos. Additionally, mitophagy was significantly increased in blastocysts treated with 1 nM rapamycin. In conclusion, our results suggest that rapamycin promotes blastocyst development ability in porcine embryos through mitochondrial fission, activation, and mitophagy in in vitro culture.
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Técnicas de Maturação in Vitro de Oócitos , Dinâmica Mitocondrial , Gravidez , Feminino , Suínos , Animais , Técnicas de Maturação in Vitro de Oócitos/métodos , Mitofagia , Sirolimo/farmacologia , Desenvolvimento Embrionário , Oócitos/metabolismo , Blastocisto/metabolismo , Fertilização in vitroRESUMO
AIMS: Mdivi-1 (Md-1) is a well-known inhibitor of mitochondrial fission and mitophagy. The mitochondrial superoxide scavenger Mito-TEMPO (MT) exerts positive effects on the developmental competence of pig embryos. This study aimed to explore the adverse effects of Md-1 on developmental capacity in porcine embryos and the protective effects of MT against Md-1-induced injury. MAIN METHODS: We exposed porcine embryos to Md-1 (10 and 50 µM) for 2 days after in vitro fertilization (IVF). MT (0.1 µM) treatment was applied for 4 days after exposing embryos to Md-1. We assessed blastocyst development, DNA damage, mitochondrial superoxide production, and mitochondrial distribution using TUNEL assay, Mito-SOX, and Mito-tracker, respectively. Subsequently, the expression of PINK1, DRP1, and p-DRP1Ser616 was evaluated via immunofluorescence staining and Western blot analysis. KEY FINDINGS: Md-1 compromised the developmental competence of blastocysts. Apoptosis and mitochondrial superoxide production were significantly upregulated in 50 µM Md-1-treated embryos, accompanied by a downregulation of p-DRP1Ser616, PINK1, and LC3B levels and lower mitophagy activity at the blastocyst stage. We confirmed the protective effects of MT against the detrimental effect of Md-1 on blastocyst developmental competence, mitochondrial fission, and DRP1/PINK1-mediated mitophagy activation. Eventually, MT recovered DRP1/PINK1-mediated mitophagy and mitochondrial fission by inhibiting superoxide production in Md-1-treated embryos. SIGNIFICANCE: MT protects against detrimental effects of Md-1 on porcine embryos by suppressing superoxide production. These findings expand available scientific knowledge on improving outcomes of IVF.
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Mitofagia , Superóxidos , Suínos , Animais , Superóxidos/metabolismo , Dinâmica Mitocondrial , Apoptose , Blastocisto/metabolismo , Mitomicina/farmacologia , Proteínas Quinases/metabolismo , Dinaminas/metabolismoRESUMO
This study investigated the effect of the flavonoid-based compound isorhamnetin (ISO) on maturation and developmental competence in oxidative stress-exposed porcine oocytes in vitro. Treatment with 2 µM ISO (2 ISO) increases the developmental rate of oxidative stress-exposed porcine oocytes during in vitro maturation (IVM). The glutathione level and mRNA expression of antioxidant-related genes (NFE2L2 and SOD2) were increased in the 2 ISO-treated group, whereas the reactive oxygen species level was decreased. Treatment with 2 ISO increased mRNA expression of a cumulus cell expansion-related gene (SHAS2) and improved chromosomal alignment. mRNA expression of maternal genes (CCNB1, MOS, BMP15 and GDF9) and mitogen activated protein kinase (MAPK) activity were increased in the 2 ISO-treated group. The total cell number per blastocyst and percentage of apoptotic cells were increased and decreased in the 2 ISO-treated group, respectively. Treatment with 2 ISO increased mRNA expression of development-related genes (SOX2, NANOG, and POU5F1) and anti-apoptotic genes (BCL2L1 and BIRC5) and decreased that of pro-apoptotic genes (CASP3 and FAS). These results demonstrate that 2 ISO improves the quality of porcine oocytes by protecting them against oxidative stress during IVM and enhances subsequent embryo development in vitro. Therefore, we propose that ISO is a useful supplement for IVM of porcine oocytes.
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Desenvolvimento Embrionário , Técnicas de Maturação in Vitro de Oócitos , Oócitos , Estresse Oxidativo , Animais , Blastocisto/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Técnicas de Maturação in Vitro de Oócitos/métodos , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , SuínosRESUMO
Regulatory T (Treg) cells have an immunosuppressive function and highly express the immune checkpoint receptor PD-1 in the tumor microenvironment; however, the function of PD-1 in tumor-infiltrating (TI) Treg cells remains controversial. Here, we showed that conditional deletion of PD-1 in Treg cells delayed tumor progression. In Pdcd1fl/flFoxp3eGFP-Cre-ERT2(+/-) mice, in which both PD-1-expressing and PD-1-deficient Treg cells coexisted in the same tissue environment, conditional deletion of PD-1 in Treg cells resulted in impairment of the proliferative and suppressive capacity of TI Treg cells. PD-1 antibody therapy reduced the TI Treg cell numbers, but did not directly restore the cytokine production of TI CD8+ T cells in TC-1 lung cancer. Single-cell analysis indicated that PD-1 signaling promoted lipid metabolism, proliferation and suppressive pathways in TI Treg cells. These results suggest that PD-1 ablation or inhibition can enhance antitumor immunity by weakening Treg cell lineage stability and metabolic fitness in the tumor microenvironment.
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Neoplasias , Linfócitos T Reguladores , Animais , Camundongos , Linfócitos T CD8-Positivos , Expressão Gênica , Linfócitos do Interstício Tumoral , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Microambiente TumoralRESUMO
PURPOSE: This study aimed to analyze the efficacy of psychosocial interventions for improving pregnancy rates in infertile women undergoing in vitro fertilization (IVF) treatment through a systematic review and meta-analysis. METHODS: Twelve studies were included in the meta-analysis. To estimate the effect size, a meta-analysis of the studies was performed using RevMan 5.3. The possibility of publication bias was evaluated using funnel plots and Egger's method. RESULTS: A statistically significant effect size (standardized mean difference [SMD] = 1.39; 95% confidence interval [CI] = 1.11-1.71; p = 0.004; I2 = 19%) was found for the 12 studies that investigated the effects of psychosocial interventions on clinical pregnancy rates. The psychosocial interventions that had a significant effect on pregnancy rates were mind-body interventions (SMD = 1.37; 95% CI = 1.01-1.85; p = 0.040; I2 = 0%) and cognitive behavioral therapy (SMD = 2.19; 95% CI = 1.17-4.13; p = 0.010). CONCLUSIONS: The results suggest that psychosocial interventions affect pregnancy rates. Moreover, they indicate that mind-body interventions and cognitive behavioral therapy are beneficial for improving the pregnancy outcome in infertile women undergoing IVF.