General physiology and biophysics最新文献

Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by excessive accumulation of surfactant components in alveolar macrophages, alveoli, and peripheral airways. The accumulation of surfactant is associated with only a minimal inflammatory response but can lead to the development of pulmonary fibrosis. Three clinical forms of PAP are distinguished - primary, secondary and congenital. In recent years, significant findings have helped to clarify the ethiology and pathogenesis of the disease. Apart from impaired surfactant protein function, a key role in the development of PAP is played by signal pathway of granulocyte and macrophage colonies stimulating growth factor (GM-CSF) which is necessary for the functioning of alveolar macrophages and for surfactant homeostasis. Surfactant is partially degraded by alveolar macrophages that are stimulated by GM-CSF. The role of GM-CSF has been shown especially in primary PAP, which is currently considered an autoimmune disease involving the development of GM-CSF neutralising autoantibodies. Clinically, the disease may be silent or manifest with dyspnoeic symptoms triggered by exertion and cough. However, there is a 10 to 15% rate of patients who develop respiratory failure. Total pulmonary lavage is regarded as the standard method of treatment. In addition, recombinant human GM-CSF has been studied as a prospective therapy for the treatment of PAP.

Cerebral ischemia-reperfusion (I/R) is a serious complication in patients with ischemic stroke. Senkyunolide A (SenA) can alleviate neuronal cell damage induced by cerebral I/R; however, the exact action mechanism remains unclear. An in vitro cellular injury model was established by inducing PC-12 cells with OGD/R. The viability of SenA-treated PC-12 cells with or without OGD/R induction was detected with CCK-8 assay while the cell apoptosis was detected using TUNEL. The secretion of inflammatory cytokines, the activity of ROS, mitochondrial membrane potential and mtROS level were measured with ELISA, ROS assay kits, JC-1 staining and MitoSOX Red assay, respectively. The level of Fe2+ was detected with Fe2+ assay kits and lipid peroxidation was detected with TBARS assay. The expressions of lipid peroxides were measured using corresponding assay kits. Western blot was used to measure the expressions of NLRP3, apoptosis-, and ferroptosis-related proteins. The transfection efficiency of OV-NLRP3 was also detected using Western blot. The present study showed that SenA could attenuate viability damage, inflammatory response, oxidative stress, apoptosis and ferroptosis in OGD/R-induced PC-12 cells and it was identified that the cytoprotective effects of SenA on PC-12 cells stimulated by OGD/R may be associated with the inhibition of NLPR3. Collectively, SenA protects neuronal cells against cerebral I/R injury through the inhibition of NLRP3-mediated ferroptosis.

Senescence, a crucial yet paradoxical phenomenon in cellular biology, acts as a barrier against cancer progression while simultaneously promoting aging and age-related pathologies. This duality underlines the importance of precise monitoring of senescence response, especially with regard to the proposed use of drugs selectively removing senescent cells. In particular, little is known about the role of senescence in neurons and in neurodegenerative diseases. Our study investigates the senescence response in neuroblastoma SH-SY5Y cells and human neural progenitor ReNcell VM cells exposed to doxorubicin, a chemotherapeutic agent known to induce DNA damage and subsequent senescence. Through a comprehensive analysis employing the most robust senescence markers, we characterized the senescence-associated patterns in these neural cell lines including cellular morphological changes, SA-beta-gal, γH2A.X, p21Waf1/Cip1 and p16Ink4a. Our findings indicate that ReNcell VM cells exhibit greater senescence-associated response at lower doxorubicin concentrations compared to SH-SY5Y cells. Additionally, we observed cell-type-specific differences in timing and levels of the expression of key cell cycle regulators during senescence. Our results emphasize the necessity of cell-type-specific strategies in senescence research with regard to implications as well as limitations for translation into aging and neurodegenerative disorders.

Small nucleolar RNAs may serve as new potential biomarkers for the diagnosis and treatment of liver cancer. The purpose of our study was to reveal the mechanism small nucleolar RNA 42 (SNORA42) affects the proliferation and migration of liver cancer cells. Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of SNORA42 and its host gene. Cell proliferation and migration were measured using the CCK-8 and Transwell assays, respectively. Western blotting was performed to measure the expression of the proteins affected by SNORA42. SNORA42 overexpression could reinforce the proliferation of hepatocellular carcinoma (HCC) cells, and promote the migration of hepatocellular carcinoma cells. In addition, SNORA42 did not affect the expression of host genes KIAA0907. SNORA42 is one of the most important components of the PI3K/Akt signaling pathway. SNORA42 augmented phospho-Akt expression, which was reversed by PI3K and Akt inhibitors. Our study displayed that SNORA42 may affect the proliferation and migration of HCC cells by interfering with the PI3K/Akt signaling pathway. Thus, SNORA42 may be a new target for detecting or treating HCC.

Intervertebral disc degeneration (IVDD) is a common contributor for low back pain, which is featured by loss of extracellular matrix and nucleus pulposus cells (NPCs). Hence, our current study is undertaken to explore the potential mechanism of NPC apoptosis during IVDD. Transcription factor Dp-1 (TFDP1) expression in degenerative and non-degenerative intervertebral disc tissues was analyzed by bioinformatics. After transfection as needed, viability and apoptosis of NPCs were evaluated by cell counting kit-8 assay and flow cytometry, respectively. Western blot or quantitative real-time reverse transcription polymerase chain reaction was applied to assess expressions of TFDP1, matrix metallopeptidase 9 (MMP9), a disintegrin and metalloproteinase 15 (ADAM15), and apoptosis-associated proteins. TFDP1 expression was upregulated in degenerative intervertebral disc tissues. TFDP1 overexpression repressed viability, promoted apoptosis, increased expressions of Bax, Cleaved caspase 3, MMP9 and ADAM15, and decreased Bcl-2 expression in NPCs, while TFDP1 silencing did conversely. ADAM15 silencing promoted viability, inhibited apoptosis, increased Bcl-2 expression, and decreased Bax, Cleaved caspase 3, and MMP9 expressions in NPCs, which were reversed by TFDP1 overexpression. TFDP1 overexpression promotes apoptosis of NPCs in IVDD through regulating ADAM15/MMP9 axis, highlighting its role as a molecular target for the treatment of low back pain.

Bronchopulmonary dysplasia (BPD) is a serious complication in premature infants. This study aimed to investigate the mechanism of mitogen-activated protein 3 kinase 7 (Map3k7) affecting BPD by regulating caspase-1 mediated pyroptosis. The morphology of the lung tissue was observed using hematoxylin-eosin staining. TUNEL staining was performed to detect tissue apoptosis. RNA-seq and protein-protein interaction (PPI) network were performed to identify hub genes. Cell viability and apoptosis was analyzed using the CCK-8 assay and flow cytometry, respectively. Pyroptosis-related factors, inflammatory factors, oxidative stress indicators, and pathway-related proteins were detected using ELISA, qRT-PCR, and Western blotting. Hyperoxia-induced neonatal rats showed alveolar simplification with increased alveolar lumen, and decreased density of secondary alveolar cristae, demonstrating the successful BPD model. Map3k7 was identified as the crucial gene that was upregulated in BPD. Silencing Map3k7 promoted cell proliferation and suppressed apoptosis, inflammation, oxidative stress, and pyroptosis in hyperoxia-induced AEC-II, and alleviated BPD progression in hyperoxia-induced rats. Furthermore, silencing Map3k7 inhibited the TGF-β1/Smad3 pathway, and SRI-011381, the TGF-β pathway activator, weakened the inhibitory effects of silencing Map3k7 on hyperoxia-induced AEC-II. Silencing Map3k7 suppressed pyroptosis to alleviate BPD through inhibiting the TGF-β1/Smad3 pathway, providing a direction for the treatment of BPD in premature infants.

Dysfunction of astrocytes has a crucial role in the pathology of depression. Here, we aimed to define the exact action of the ubiquitous transcription factor (TF) Yin Yang-1 (Yy1) in depression pathogenesis and astrocytic dysfunction. A chronic unpredictable mild stress (CUMS) mouse model was generated. Primary mouse astrocytes were exposed to lipopolysaccharide (LPS). Cell growth was determined by CCK-8 and EdU assays. The direct interaction of Yy1 and the Trem1 promoter was validated by chromatin immunoprecipitation (ChIP) and luciferase assays. In CUMS mice, the levels of Yy1 and inflammatory cytokines were augmented and oxidative stress was enhanced. Functionally, disruption of Yy1 or triggering receptor expressed on myeloid cell 1 (Trem1) relieved LPS-triggered pro-growth, pro-inflammation, and pro-oxidative stress effects in mouse astrocytes. Mechanistically, Yy1 directly promoted the transcription and expression of Trem1 by binding to the Trem1 promoter. Yy1 disruption exerted regulatory impacts in LPS-induced mouse astrocytes via down-regulation of Trem1. Additionally, the Yy1/Trem1 cascade could modulate the activation of the NF-κB signaling in mouse astrocytes. Our study defines that Yy1 disruption relieves LPS-triggered neuroinflammation and oxidative stress in mouse astrocytes via the NF-κB pathway by down-regulating Trem1, providing possible strategies for depression treatment.

The study aimed to evaluate the basic pharmacological effects of modified phenyl carbamic acid derivates with a basic part made of N-phenylpiperazine (compounds 6a, 6b, 6c, 6d) in Wistar rats. The compounds were evaluated for their ability to decrease the phenylephrine-induced contraction of the aortic strips of rats after repeated administration of the compounds and their ability to inhibit the positive chronotropic effect of isoproterenol on spontaneously beating rat atria. The ability to inhibit the vasoconstriction effect of phenylephrine was confirmed in all compounds in the range from 10.39 % to 13.65 %. The most significant vasoconstriction was achieved in compound 6d (86.35%, p < 0.001). None of the compounds reached the effect of carvedilol. All compounds proved an antagonistic ability to the positive chronotropic effect of isoproterenol. The highest value of the anti-isoproterenol effect was identified for the compound 6c (pA2 = 8.21 ± 0.56; p < 0.05). Only compound 6a decreased heart rate significantly (by 3.17%, p < 0.05), so we can indicate its potential negative chronotropic effect. The obtained results showed that the evaluated compounds confirmed the basic characteristics of beta-blockers with additional α-adrenolytic properties.

Sevoflurane is considered an effective neuroprotector in cerebral ischemia/reperfusion injury (CIRI). Sevoflurane preconditioning in CIRI, however, remains unknown precisely by its molecular mechanism. The middle cerebral artery occlusion reperfusion (MCAO/R) rat model was established, and neurological function was evaluated by Zea-Longa score. Cerebral water content was determined to assess cerebral edema. Brain pathological condition was observed by hematoxylin and eosin staining, the intact changes of rat neurons were observed by Nissl staining, and neuronal apoptosis was measured by TUNEL staining. In addition, miR-192-5p and DICER1 levels were detected by RT-qPCR or Western blot, and the targeting relationship between miR-192-5p and DICER1 was verified by bioinformatics analysis and luciferase reporting experiment. miR-192-5p was up-regulated and DICER1 was down-regulated in MCAO/R rats. Sevoflurane preconditioning could decrease miR-192-5p and promote DICER1 expression. Sevoflurane preconditioning could alleviate brain tissue injury and neuronal apoptosis in MCAO/R rats. DICER1 expression was negatively regulated by targeting miR-192-5p. Elevating miR-192-5p or suppressing DICER1 rescued the protective effect of sevoflurane preconditioning on MCAO/R rats. Sevoflurane alleviates brain injury in MCAO/R rats via miR-192-5p/DICER1 axis.

Anisodine hydrobromide injection has shown promising therapeutic effects in treating patients with cerebral infarction, improving recovery of neurological function during the post-cerebral infarction period. However, the effects of anisodine hydrobromide on brain recovery and neuroplasticity are unclear. This study explores the therapeutic effects and underlying mechanisms of anisodine hydrobromide in mice experiencing the chronic phase of an ischemia stroke. The electrocautery method established a distal middle cerebral artery occlusion (MCAO) model in healthy male C57BL/6 mice. Neurological deficits were evaluated using Golgi and immunofluorescence staining to measure the effects of anisodine hydrobromide on neural proliferation, migration and remodeling. DAPT (dipeptidic γ-secretase-specific inhibitor) was employed to explore the involvement of the Notch signaling pathway post-anisodine hydrobromide treatment. Compared to the control and MCAO groups, mice treated with anisodine hydrobromide showed improved post-stroke neurological function, increased neurite intersections, and dendritic spine density in the peri-infarct cortex. Anisodine hydrobromide also promoted neural cell regeneration which is dendritic and axonal structures and synaptic vesicle protein restructuring. Gap43, NGF, Notch1, and Hes1 protein level increased significantly in the ANI group provided inhibitor DAPT was absent. Anisodine hydrobromide can promote neurological function, neurotrophic factors, and neuroplasticity. Notch signaling pathways also impact the effects of anisodine hydrobromide on neural plasticity in ischemia stroke.