Optic atrophy 1 (OPA1)‐related mitochondrial fusion and mitophagy are vital to sustain mitochondrial homeostasis under stress conditions. However, no study has confirmed whether OPA1‐related ...mitochondrial fusion/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial stress in the setting of cardiac ischemia‐reperfusion (I/R) injury. Our results indicated that OPA1, mitochondrial fusion, and mitophagy were significantly repressed by I/R injury, accompanied by infarction area expansion, heart dysfunction, myocardial inflammation, and cardiomyocyte oxidative stress. However, melatonin treatment maintained myocardial function and cardiomyocyte viability, and these effects were highly dependent on OPA1‐related mitochondrial fusion/mitophagy. At the molecular level, OPA1‐related mitochondrial fusion/mitophagy, which was normalized by melatonin, substantially rectified the excessive mitochondrial fission, promoted mitochondria energy metabolism, sustained mitochondrial function, and blocked cardiomyocyte caspase‐9‐involved mitochondrial apoptosis. However, genetic approaches with a cardiac‐specific knockout of OPA1 abolished the beneficial effects of melatonin on cardiomyocyte survival and mitochondrial homeostasis in vivo and in vitro. Furthermore, we demonstrated that melatonin affected OPA1 stabilization via the AMPK signaling pathway and that blockade of AMPK repressed OPA1 expression and compromised the cardioprotective action of melatonin. Overall, our results confirm that OPA1‐related mitochondrial fusion/mitophagy is actually modulated by melatonin in the setting of cardiac I/R injury. Moreover, manipulation of the AMPK‐OPA1‐mitochondrial fusion/mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I/R injury.
Mitochondrial fusion is linked to heart and liver ischemia‐reperfusion (IR) insult. Unfortunately, there is no report to elucidate the detailed influence of mitochondrial fusion in renal IR injury. ...This study principally investigated the mechanism by which mitochondrial fusion protected kidney against IR injury. Our results indicated that sirtuin 3 (Sirt3) was inhibited after renal IR injury in vivo and in vitro. Overexpression of Sirt3 improved kidney function, modulated oxidative injury, repressed inflammatory damage, and reduced tubular epithelial cell apoptosis. The molecular investigation found that Sirt3 overexpression attenuated IR‐induced mitochondrial damage in renal tubular epithelial cells, as evidenced by decreased reactive oxygen species production, increased antioxidants sustained mitochondrial membrane potential, and inactivated mitochondria‐initiated death signaling. In addition, our information also illuminated that Sirt3 maintained mitochondrial homeostasis against IR injury by enhancing optic atrophy 1 (OPA1)‐triggered fusion of mitochondrion. Inhibition of OPA1‐induced fusion repressed Sirt3 overexpression‐induced kidney protection, leading to mitochondrial dysfunction. Further, our study illustrated that OPA1‐induced fusion could be affected through ERK; inhibition of ERK abolished the regulatory impacts of Sirt3 on OPA1 expression and mitochondrial fusion, leading to mitochondrial damage and tubular epithelial cell apoptosis. Altogether, our results suggest that renal IR injury is closely associated with Sirt3 downregulation and mitochondrial fusion inhibition. Regaining Sirt3 and/or activating mitochondrial fission by modifying the ERK‐OPA1 cascade may represent new therapeutic modalities for renal IR injury.
Altogether, our results suggest that renal ischemia‐reperfusion (IR) injury is closely associated with sirtuin 3 (Sirt3) downregulation and mitochondrial fusion inhibition. Regaining Sirt3 and/or activating mitochondrial fission by modifying the ERK‐OPA1 cascade may represent new therapeutic modalities for renal IR injury.
Abstract To explore the differences of vaginal microbes in women with preterm birth (PTB), and to construct prediction model. We searched for articles related to vaginal microbiology in preterm women ...and obtained four 16S rRNA-sequence datasets. We analyzed that for species diversity and differences, and constructed a random forest model with 20 differential genera. We introduce an independent whole genome-sequencing (WGS) data for validation. In addition, we collected vaginal and cervical swabs from 33 pregnant women who delivered spontaneously full-term and preterm infants, performed WGS in our lab to further validate the model. Compared to term birth (TB) samples, PTB women vagina were characterized by a decrease in Firmicutes , Lactobacillus , and an increase in diversity accompanied by the colonization of pathogenic bacteria such as Gardnerella , Atopobium and Prevotella . Twenty genus markers, including Lactobacillus , Prevotella , Streptococcus , and Gardnerella performed well in predicting PTB, with study-to-study transfer validation and LODO validation, different gestation validation showing good results, and in two independent cohorts (external WGS cohorts and woman samples WGS cohorts) in which the accuracy was maintained. PTB women have unique vaginal microbiota characteristics. A predictive model of PTB was constructed and its value validated from multiple perspectives.
The aim of this study was to evaluate probiotic properties of ten
Streptococcus thermophilus
strains (st1 to st10) isolated from pickles in China. These strains all had β-galactosidase activity, ...which laid foundation for studying their probiotic properties. In this study, the bile salt hydrolase activity, lysozyme resistance, tolerance to simulated gastric juice, bile salt tolerance, and bacterial adhesion capacity to the Caco-2 cells of these selected strains were detected in vitro conditions. The results indicated that the bile salt hydrolase activities of st2, st6, and st9 were higher than that for other strains. St10 showed the greatest lysozyme resistance (> 80% survival), followed by st9, st8, st7, st5, and st6. As for the tolerance to simulated gastric juice, st5 possessed the highest survival rate (35%), followed by st6 (30%). St6 was the best performer in both bile salt tolerance and bacterial adhesion capacity to the Caco-2 cells. The results of fluorescence microscope and electron microscope further confirmed previous studies and more intuitively demonstrated the st6 strain's tolerance to harsh environments. Overall, these strains were expected to possess beneficial properties and have the potentiality to be probiotics.
Breast cancer is the most common cancer in women and the second leading cause of cancer‐related deaths after lung cancer. Metastasis of the central nervous system is a terrible event for breast ...cancer patients, affecting their survival and quality of life. Compared with hormone receptor‐positive/human epidermal growth factor receptor 2‐negative breast cancer patients, brain metastases are more likely to affect patients with triple‐negative breast cancer and human epidermal growth factor receptor 2‐positive breast cancer. The treatment of breast cancer has improved greatly in the last two decades. However, brain metastases from breast cancer remain the leading cause of morbidity and mortality. Patients with breast cancer brain metastasis have been in an inferior position due to the lack of clinical research in this field, and they are often explicitly excluded from almost all clinical trials. The occurrence and progression of brain metastases will result in severe cognitive impairment and adverse physical consequences, so we must have a good understanding of the molecular mechanisms of breast cancer brain metastasis. In this article, we have retrieved the latest literature of molecules and pathways associated with breast cancer brain metastasis, summarized common therapy strategies, and discussed the prospects and clinical implications of targeting the molecules involved.
A portion of cells at the primary site acquired invasive properties by EMT. Invasive cancer cells intravasate into the bloodstream, survive, and arrest the circulatory system. Then these cells extravasate through transendothelial migration, colonize, and form metastatic brain lesions. BBB plays a critical role in ensuring normal brain function. However, as the development of primary or metastatic tumors in the brain, BBB becomes disrupted, and is altered to BTB. At last, new, and aberrant vessels grow during tumor progression.
Triple-negative breast cancer (TNBC), as a highly aggressive and metastatic tumor, can still not contain the medical needs. It has become an urgent problem to develop prognostic markers further and ...realize precision medicine. The predictive and prognostic significance of peripheral blood lymphocytes, as well as the clinicopathological factors affecting them, were explored in the present study.
The clinicopathological data of 278 patients with TNBC were collected and analyzed retrospectively. Peripheral blood lymphocytes (pBL) and blood routine indexes before treatment were quantified by flow cytometry analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier curve and Cox hazard proportion regression model. The associations between hematologic parameters and treatment response and clinicopathological characteristics were estimated by the Mann-Whitney test and Spearman test.
Compared with all blood routine indexes, only a significant correlation between better treatment efficacy and higher peripheral CD4 +/CD8 + ratio of TNBC patients was observed (P=0.059), particularly those treated with chemotherapy combined with immune checkpoint inhibitors (P=0.048). Among the pBL subsets, CD4 + T lymphocyte was the only independent factor that could predict the prognosis of metastatic TNBC. Patients presenting higher values of peripheral CD4 + T lymphocytes showed longer PFS (median PFS 9 months vs. 5 months; HR =0.65, 95%CI: 0.440-0.973, P = 0.032) and OS (median OS 31 months vs. 16 months; HR=0 .63, 95%CI: 0.417-0.940, P< 0.01). Especially CD4+ was found predictive for prognosis in TNBC patients who received chemotherapy (P<0.05). Finally, the older age, higher clinical stage, and more advanced treatment lines were related to the lower level of CD4 +. The older age and having received neoadjuvant therapy were related to the lower CD4 +/CD8 + ratio (P<0.05).
The baseline CD4+/CD8+ cell ratio in peripheral blood is associated with therapeutic response, especially for chemotherapy combined with immunotherapy. Peripheral CD4+ cells can steadily predict all clinical outcomes for patients with mTNBC, and this clinical prognosis prediction is significantly related to chemotherapy. Peripheral CD4+ and CD4+/CD8+ are both closely associated with clinicopathological parameters.
The importance of astrocytic K
+
uptake for extracellular K
+
(K
+
e
) clearance during neuronal stimulation or pathophysiological conditions is increasingly acknowledged. It occurs by preferential ...stimulation of the astrocytic Na
+
,K
+
-ATPase, which has higher K
m
and V
max
values than its neuronal counterpart, at more highly increased K
+
e
with additional support of the cotransporter NKCC1. Triggered by a recent DiNuzzo et al. paper, we used administration of the glycogenolysis inhibitor DAB to primary cultures of mouse astrocytes to determine whether K
+
uptake required K
+
-stimulated glycogenolysis. KCl was increased by either 5 mM (stimulating only the Na
+
,K
+
-ATPase) or 10 mM (stimulating both transporters) in glucose-containing saline media prepared to become iso-osmotic after the addition. DAB completely inhibited both uptakes, the Na
+
,K
+
-ATPase-mediated by preventing Na
+
uptake for stimulation of its intracellular Na
+
-activated site, and the NKCC1-mediated uptake by inhibition of depolarization- and L-channel-mediated Ca
2+
uptake. Drugs inhibiting the signaling pathways involved in either of these processes also abolished K
+
uptake. Assuming similar in vivo characteristics, partly supported by literature data, K
+
-stimulated astrocytic K
+
uptake must discontinue after normalization of extracellular K
+
. This will allow Kir1.4-mediated release and reuptake by the less powerful neuronal Na
+
,K
+
-ATPase.
Aroma compounds in fruits and related products are known to occur in free and glycosidically bound forms. In this study, free and bound volatiles in juices and wines of two kiwifruit cultivars,
...Actinidia deliciosa
‘Hayward’ and
A. chinensis
‘Hort16A’, were analyzed by solid-phase microextraction-gas chromatography-mass spectrometry. Results showed that 67 free and 79 bound volatiles were found in juices and wines. Alcohols were the most abundant free volatiles, while the most representative bound volatiles were terpenoids.
β-
Damascenone and 4-methyl-3-penten-2-one released from aroma precursors were found in ‘Hort16A’ juice for the first time. Fruity, floral, and sweet flavors appeared to be the characteristic aroma in kiwifruit juices and wines. Principal component analysis showed that kiwifruit wines had a great aroma potential. Cluster analysis revealed that juices and wines had different profile of free volatiles, while similar bound volatile compositions were found. Moreover, abundant bound volatiles were discovered in these two kiwifruit pomace for the first time, indicating their potential applications in food and cosmetics industry.
Primary neuroendocrine carcinoma of the breast (NECB) is characterized with heterogeneity, rarity, and poor differentiation, which is probably an underestimated subtype of breast cancer, including ...small cell NECs and large cell NECs. The diagnostic criteria for NECB have been constantly updated as the disease changes and the understanding increases. According to the latest WHO Classification, primary neuroendocrine neoplasm (NEN) of the breast consists of well-differentiated neuroendocrine tumors (NET), extremely aggressive neuroendocrine carcinomas (NEC) as well as invasive breast cancers of no special type (IBCs-NST) with neuroendocrine differentiation. The accurate diagnosis of NECB remains a challenge for its low incidence, which needs multi-disciplinary methods. For the rarity of the disease, there is a lack of large samples and prospective clinical research. For these invasive tumors, there are no standardized therapeutic guidelines or norms, and the treatment often refers to nonspecific breast cancer. In addition, the prognosis of such patients remains unknown. In 2003, the World Health Organization (WHO) listed NECB as an independent entity for the first time, while few features of NECB were clarified. In this review, it presents the WHO Classification, clinicopathologic characteristics, diagnosis, treatment, and prognosis of these patients. In addition, it summarizes the latest studies on molecular features of NECB, aiming to provide new therapeutic perspectives for the disease.
The relationship between gut microbiota (GM) and mental health is one of the focuses of psychobiology research. In recent years, the microbial-gut-brain axis (MGBA) concept has gradually formed about ...this bidirectional communication between gut and brain. But how the GM is involved in regulating brain function and how they affect emotional disorders these mechanisms are tenuous and limited to animal research, and often controversial. Therefore, in this review, we attempt to summarize and categorize the latest advances in current research on the mechanisms of GM and depression to provide valid information for future diagnoses and therapy of mental disorders. Finally, we introduced some antidepressant regimens that can help restore gut dysbiosis, including classic antidepressants, Chinese materia medica (CMM), diet, and exogenous strains. These studies provide further insight into GM's role and potential pathways in emotion-related diseases, which holds essential possible clinical outcomes for people with depression or related psychiatric disorders. Future research should focus on clarifying the causal role of GM in disease and developing microbial targets, applying these findings to the prevention and treatment of depression.
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