Insights into the defensive roles of lncRNAs during Mycoplasma pneumoniae infection.

Mycoplasma pneumoniae causes respiratory tract infections, affecting both children and adults, with varying degrees of severity ranging from mild to life-threatening. In recent years, a new class of regulatory RNAs called long non-coding RNAs (lncRNAs) has been discovered to play crucial roles in regulating gene expression in the host. Research on lncRNAs has greatly expanded our understanding of cellular functions involving RNAs, and it has significantly increased the range of functions of lncRNAs. In lung cancer, transcripts associated with lncRNAs have been identified as regulators of airway and lung inflammation in a process involving protein complexes. An excessive immune response and antibacterial immunity are closely linked to the pathogenesis of M. pneumoniae. The relationship between lncRNAs and M. pneumoniae infection largely involves lncRNAs that participate in antibacterial immunity. This comprehensive review aimed to examine the dysregulation of lncRNAs during M. pneumoniae infection, highlighting the latest advancements in our understanding of the biological functions and molecular mechanisms of lncRNAs in the context of M. pneumoniae infection and indicating avenues for investigating lncRNAs-related therapeutic targets.

Effective Descriptor for Screening Single-Molecule Conductance Switches.

The adsorption-type molecular switch exhibits bistable states with an equivalently long lifetime at the organic/inorganic interface, promising reliable switching behavior and superior assembly ability in the electronic circuits at the molecular scale. However, the number of reported adsorption-type molecular switches is currently less than 10, and exploring these molecular switches poses a formidable challenge due to the intricate interplay occurring at the interface. To address this challenge, we have developed a model enabling the identification of diverse molecular switches on metal surfaces based on easily accessible physical characteristics. These characteristics primarily include the metal valency electron concentration, the work function of metal surfaces, and the electronegativity difference of molecules. Using this model, we identified 56 new molecular switches. Employing the gradient descent algorithm and statistical linear discriminant analysis, we constructed an explicit descriptor that establishes a relationship between the interfacial structure and chemical environment and the stability of molecular switches. The model's accuracy was validated through density functional theory calculations, achieving a 90% accuracy for aromatic molecular switches. The conductive switching behaviors were further confirmed by nonequilibrium Green's function transport calculations.

Evidence for widespread existence of functional novel and non-canonical human transcripts.

BACKGROUND: Fraction of functional sequence in the human genome remains a key unresolved question in Biology and the subject of vigorous debate. While a plethora of studies have connected a significant fraction of human DNA to various biochemical processes, the classical definition of function requires evidence of effects on cellular or organismal fitness that such studies do not provide. Although multiple high-throughput reverse genetics screens have been developed to address this issue, they are limited to annotated genomic elements and suffer from non-specific effects, arguing for a strong need to develop additional functional genomics approaches. RESULTS: In this work, we established a high-throughput lentivirus-based insertional mutagenesis strategy as a forward genetics screen tool in aneuploid cells. Application of this approach to human cell lines in multiple phenotypic screens suggested the presence of many yet uncharacterized functional elements in the human genome, represented at least in part by novel exons of known and novel genes. The novel transcripts containing these exons can be massively, up to thousands-fold, induced by specific stresses, and at least some can represent bi-cistronic protein-coding mRNAs. CONCLUSIONS: Altogether, these results argue that many unannotated and non-canonical human transcripts, including those that appear as aberrant splice products, have biological relevance under specific biological conditions.

A non-thermal modification method to promote the interaction of zein-alginate oligosaccharides composites for better encapsulation and stability-Cold plasma.

This current research explored the application of cold plasma (CP) treatment to modify zein-alginate oligosaccharide (zein-AOS) composites in an ethanol-water solution. Anti-solvent method was used to prepare zein-AOS nanoparticles (NPs), and the objective was to investigate the mechanism by which CP promotes interaction between protein and saccharides. Characterization results indicated that CP treatment improved hydrogen bonding and electrostatic interaction between zein and AOS. The CP zein-AOS NPs underwent dispersion and rearrangement, resulting in smaller aggregates with better dispersibility. Among the various induction conditions tested, the zein-AOS85 NPs (induced at 85 W for 2 min) exhibited superior performance as delivery wall materials, with smaller particle size (234.67 nm), larger specific surface area (9.443 m2/g), and higher surface charge (-35.43 mV). In addition, zein-AOS85 showed high stability when used as delivery wall material, providing more binding sites and self-assembly dynamics for nutrients. Curcumin was used as the nutrient model in this study, and CP was found to enhance hydrogen bonding, electrostatic interaction, and hydrophobic interaction between zein, AOS, and nutrients, resulting in increased encapsulation efficiency (EE) from 63.80 % to 85.17 %. The delivery system also exhibited good pH, ionic strength, storage, and dispersion stability.

Single-Nucleus Transcriptome Profiling of Locally Advanced Cervical Squamous Cell Cancer Identifies Neural-Like Progenitor Program Associated with the Efficacy of Radiotherapy.

Radiotherapy is the first-line treatment for locally advanced cervical squamous cell cancer (CSCC). However, ≈50% of patients fail to respond to therapy and, in some cases, tumors progress after radical radiotherapy. Here, single-nucleus RNA-seq is performed to construct high-resolution molecular landscapes of various cell types in CSCC before and during radiotherapy, to better understand radiotherapy related molecular responses within tumor microenvironment. The results show that expression levels of a neural-like progenitor (NRP) program in tumor cells are significantly higher after radiotherapy and these are enriched in the tumors of nonresponding patients. The enrichment of the NRP program in malignant cells from the tumors of nonresponders in an independent cohort analyzed by bulk RNA-seq is validated. In addition, an analysis of The Cancer Genome Atlas dataset shows that NRP expression is associated with poor prognosis in CSCC patients. In vitro experiments on the CSCC cell line demonstrate that downregulation of neuregulin 1 (NRG1), a key gene from NRP program, is associated with decreased cell growth and increased sensitivity to radiation. Immunohistochemistry staining in cohort 3 validated key genes, NRG1 and immediate early response 3 from immunomodulatory program, as radiosensitivity regulators. The findings reveal that the expression of NRP in CSCC can be used to predict the efficacy of radiotherapy.

SIRT3 regulates mitophagy in liver fibrosis through deacetylation of PINK1/NIPSNAP1.

Damaged mitochondria, a key factor in liver fibrosis, can be removed by the mitophagy pathway to maintain homeostasis of the intracellular environment to alleviate the development of fibrosis. PINK1 (PTEN-induced kinase 1) and NIPSNAP1 (nonneuronal SNAP25-like protein 1), which cooperatively regulate mitophagy, have been predicted to include the sites of lysine acetylation related to SIRT3 (mitochondrial deacetylase sirtuin 3). Our study aimed to discuss whether SIRT3 deacetylates PINK1 and NIPSNAP1 to regulate mitophagy in liver fibrosis. Carbon tetrachloride (CCl4 )-induced liver fibrosis as an in vivo model and LX-2 cells as activated cells were used to simulate liver fibrosis. SIRT3 expression was significantly decreased in mice in response to CCl4 , and SIRT3 knockout in vivo significantly deepened the severity of liver fibrosis, as indicated by increased α-SMA and Col1a1 levels both in vivo and in vitro. SIRT3 overexpression decreased α-SMA and Col1a1 levels. Furthermore, SIRT3 significantly regulated mitophagy in liver fibrosis, as demonstrated by LC3-Ⅱ/Ⅰ and p62 expression and colocalization between TOM20 and LAMP1. Importantly, PINK1 and NIPSNAP1 expression was also decreased in liver fibrosis, and PINK1 and NIPSNAP1 overexpression significantly improved mitophagy and attenuated ECM production. Furthermore, after simultaneously interfering with PINK1 or NIPSNAP1 and overexpressing SIRT3, the effect of SIRT3 on improving mitophagy and alleviating liver fibrosis was disrupted. Mechanistically, we show that SIRT3, as a mitochondrial deacetylase, specifically regulates the acetylation of PINK1 and NIPSNAP1 to mediate the mitophagy pathway in liver fibrosis. SIRT3-mediated PINK1 and NIPSNAP1 deacetylation is a novel molecular mechanism in liver fibrosis.

Salvianolic Acid A Protects against Acetaminophen-Induced Hepatotoxicity via Regulation of the miR-485-3p/SIRT1 Pathway.

The vast majority of drug-induced liver injury is mainly attributed to acetaminophen (APAP) overdose. Salvianolic acid A (Sal A), a powerful water-soluble compound obtained from Salvia miltiorrhiza, has been confirmed to exert hepatoprotective effects. However, the beneficial effects and the exact mechanisms of Sal A on APAP-induced hepatotoxicity remain unclear. In this study, APAP-induced liver injury with or without Sal A treatment was examined in vitro and in vivo. The results showed that Sal A could alleviate oxidative stress and inflammation by regulating Sirtuin 1 (SIRT1). Furthermore, miR-485-3p could target SIRT1 after APAP hepatotoxicity and was regulated by Sal A. Importantly, inhibiting miR-485-3p had a hepatoprotective effect similar to that of Sal A on APAP-exposed AML12 cells. These findings suggest that regulating the miR-485-3p/SIRT1 pathway can alleviate oxidative stress and inflammation induced by APAP in the context of Sal A treatment.

Chinese Medicine Plaster as A New Treatment for Surgical Site Infection in Patients with Cesarean Delivery: A Randomized, Double-Blind, Controlled Trial.

OBJECTIVE: To evaluate the efficacy of Chinese plaster containing rhubarb and mirabilite on surgical site infection (SSI) in patients with cesarean delivery (CD) by performing a randomized controlled trial. METHODS: This randomized controlled trial included 560 patients with CD due to fetal head descent enrolled at a tertiary teaching center between December 31, 2018 and October 31, 2021. Eligible patients were randomly assigned to a Chinese medicine (CM) group (280 cases) or a placebo group (280 cases) by a random number table, and were treated with CM plaster (made by rhubarb and mirabilite) or a placebo plaster, respectively. Both courses of treatment lasted from the day 1 of CD, followed day 2 until discharge. The primary outcome was the total number of patients with superficial, deep and organ/space SSI. The secondary outcome was duration of postoperative hospital stay, antibiotic intake, and unplanned readmission or reoperation due to SSI. All reported efficacy and safety outcomes were confirmed by a central adjudication committee that was unaware of the study-group assignments. RESULTS: During the recovery process after CD, the rates of localized swelling, redness and heat were significantly lower in the CM group than in the placebo group [7.55% (20/265) vs. 17.21% (47/274), P<0.01]. The durution of postoperative antibiotic intake was shorter in the CM group than in the placebo group (P<0.01). The duration of postoperative hospital stay was significantly shorter in the CM group than in the placebo group (5.49 ± 2.68 days vs. 8.96 ± 2.35 days, P<0.01). The rate of postoperative C-reactive protein elevation (≽100 mg/L) was lower in the CM group than in the placebo group [27.6% (73/265) vs. 43.8% (120/274), P<0.01]. However, there was no difference in purulent drainage rate from incision and superficial opening of incision between the two groups. No intestinal reactions and skin allergies were found in the CM group. CONCLUSIONS: CM plaster containing rhubarb and mirabilite had an effect on SSI. It is safe for mothers and imposes lower economic and mental burdens on patients undergoing CD. (Registration No. ChiCTR2100054626).

Exploring variations and influencing factors of illegal adoption: A comparison between child trafficking and informal adoption.

BACKGROUND: Illegal adoption, which mainly includes child trafficking and informal adoption, has long been a prevalent social issue in China. However, the processes and patterns of illegal adoption are not well understood due to the scarcity of data. OBJECTIVE: The findings are expected to provide insightful clues for the government and the public to better understand the two categories of illegal adoption. PARTICIPANTS AND SETTING: This study included 4296 trafficking cases and 4499 informal adoption cases between 1949 and 2018. The data came from the 'Baby Coming Back Home' (https://www.baobeihuijia.com) website, which is the most comprehensive commonweal forum established by nongovernmental volunteers for finding missing persons in China. METHODS: Mathematical statistics and hot spot analysis were used to visualize the spatiotemporal pattern of illegal adoption. RESULTS: Child trafficking and informal adoption show opposite gender preferences and different age gradients. The numbers of both cases peaked in the early 1990s and then dropped. More than 50 % of all trafficked children were male, whereas approximately 83 % cases of informal adoption were female between 1980 and 2000. Hot spots of illegal adoption have shifted from the cities of the Huai River Basin to the southeastern coastal cities over time, 39.40 % of trafficking cases occurred in rural residential areas, and 52.45 % of informal adoption cases were observed in hospitals. CONCLUSIONS: Child trafficking and informal adoption are two different ways of adopting children in China. The combination of the one-child policy and the traditional culture of son preference shaped the different characteristics of the illegal adoption of children during a critical period.

Cold plasma treatment with alginate oligosaccharide improves the digestive stability and bioavailability of nutrient-delivered particles: An in vitro INFOGEST gastrointestinal study.

To improve the stability and bioavailability of the delivered hydrophobic nutrients, the zein-based delivery system was modified by alginate oligosaccharide (AOS), cold plasma (CP) treatments, and synergistically. The digestive behavior of each was investigated in an INFOGEST static in vitro digestion model. The results showed that AOS and CP treatments and their synergistic effects improved the dispersion and stability of the delivery system, leading to a more concentrated particle size distribution and higher particle surface charge. Both CP treatments and AOS increased the release rate of Curcumin (Cur) at small intestine (11.8 % to 20.5 % and 11.8 % to 24.64 %, respectively), and the synergistic effect was higher (11.8 % to 43.84 %). The wall material modified showed a higher encapsulation efficiency of Cur (52.83 % to 85.17 %). Cur release rate measurements showed that the wall material modified could have a positive effect on the slow release of Cur. SDS-page electrophoresis revealed that the slow release was due to the enhanced resistance of wall material to digestive fluids. Thus, treatment with AOS and CP treatments, and the synergism are suitable for modifying zein-based delivery systems for the encapsulation, stabilization, and slow release of hydrophobic nutrients during digestion in the field of functional foods.

Effects of high temperature, high humidity, and cold storage on structure and qualities of whole oat flour noodles during processing.

Gelation and structure of oat starch significantly affect qualities of whole oat flour noodles. During extrusion, the structure of noodles is loose, resulting in high cooking loss and poor texture. Therefore, oat noodles were treated with high temperature, high humidity (HTH), and cold storage (CS), and their structure and qualities were analyzed. The results showed that compared with CS, HTH could reduce the cooking loss of noodles from 10.12% to 6.13%, increase the hardness (65.59 g) and chewiness (20.67) of noodles, and effectively improve the sensory quality of noodles. The change in texture and sensory of noodles was due to HTH by accelerating the retrogradation of starch in noodles, promoting the cross-linking of starch molecules to form an ordered structure, causing an increase in the ordered degree and crystallinity of starch and making the structure of noodles denser. It made the mobility of water in the noodles decrease, and more tightly bound water was transformed into weakly bound water and free water. HTH can be applied to industrial production of whole oat flour noodles. This study could effectively guide the production of high-quality whole oat flour noodles without any food additives.

Outcomes and risk factors for failed trial of labor after cesarean delivery (TOLAC) in women with one previous cesarean section: a Chinese population-based study.

OBJECTIVE: To evaluate the outcomes and risk factors for trial of labor after cesarean delivery (TOLAC) failure in patients in China. METHODS: Consecutive patients who had a previous cesarean delivery (CD) and attempted TOLAC were included from 2014 to 2020. Patients who successfully delivered were classified into the TOLAC success group. Patients who attempted TOLAC but had a repeat CD due to medical issues were classified into the TOLAC failure group. Multiple logistic regression analyses were performed to examine the risk factors for TOLAC failure. RESULTS: In total, 720 women who had a previous CD and attempted TOLAC were identified and included. The success rate of TOLAC was 84.2%(606/720). Seven patients were diagnosed with uterine rupture, none of whom underwent hysterectomy. Multiple logistic regression analysis showed that the induction of labor (OR = 2.843, 95% CI: 1.571-5.145, P < 0.001) was positively associated with TOLAC failure, but the thickness of the lower uterine segment (LUS) (OR = 0.215, 95% CI: 0.103-0.448, P < 0.001) was negatively associated with TOLAC failure. CONCLUSIONS: This study suggested that TOLAC was effective in decreasing CD rates in the Chinese population. The induction of labor was positively associated with TOLAC failure, but the thickness of the LUS was negatively associated with TOLAC failure. Our findings need to be confirmed in larger samples with patients of different ethnicities.

Kurarinone alleviated Parkinson's disease via stabilization of epoxyeicosatrienoic acids in animal model.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by loss of dopaminergic neurons in the substantia nigra (SN), causing bradykinesia and rest tremors. Although the molecular mechanism of PD is still not fully understood, neuroinflammation has a key role in the damage of dopaminergic neurons. Herein, we found that kurarinone, a unique natural product from Sophora flavescens, alleviated the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits and dopaminergic neurotoxicity, including the losses of neurotransmitters and tyrosine hydroxylase (TH)-positive cells (SN and striatum [STR]). Furthermore, kurarinone attenuated the MPTP-mediated neuroinflammation via suppressing the activation of microglia involved in the nuclear factor kappa B signaling pathway. The proteomics result of the solvent-induced protein precipitation and thermal proteome profiling suggest that the soluble epoxide hydrolase (sEH) enzyme, which is associated with the neuroinflammation of PD, is a promising target of kurarinone. This is supported by the increase of plasma epoxyeicosatrienoic acids (sEH substrates) and the decrease of dihydroxyeicosatrienoic acids (sEH products), and the results of in vitro inhibition kinetics, surface plasmon resonance, and cocrystallization of kurarinone with sEH revealed that this natural compound is an uncompetitive inhibitor. In addition, sEH knockout (KO) attenuated the progression of PD, and sEH KO plus kurarinone did not further reduce the protection of PD in MPTP-induced PD mice. These findings suggest that kurarinone could be a potential natural candidate for the treatment of PD, possibly through sEH inhibition.

Risk factors for surgical site infection after cesarean delivery in a rural area in China: A case-controlled study.

BACKGROUND: We aimed to determine the prevalence and risk factors of surgical site infection (SSI) after cesarean delivery (CD) in a rural area in China. METHODS: We identified 155 patients with incisional and organ/space SSIs by International Classification of Disease codes and matched them with 465 patients (controls) in a time-matched retrospective quality assurance analysis. Multiple logistic regression analyses were performed to examine the risk factors for SSI: the work-years of providers, the number of antenatal care (ANC) visits, CD after labor, positive discharge culture, postoperative C-reactive protein (CRP) levels and fever. RESULTS: and discussion: During the study, 155 women with SSI were identified among the 8640 patients who delivered by CD. The incidence of SSIs was 179 per 10 000patients (95%CI: 151-207 per 10 000 patients). The total duration of hospitalization in patients with SSI was 14.49 ± 8.68 days compared with 7.96 ± 2.35 days in patients with no SSI (P < 0.01). Multiple logistic regression analysis showed that the work-years of providers (odds ratio [OR] = 3.729, 95% confidence interval [CI]: 1.463-9.501, p = 0.006), irregular ANC visits (OR = 3.245, 95% CI: 1.264-8.329, p = 0.028), CD after labor (OR = 2.545, 95% CI: 0.935-6.926, p = 0.020), postoperative CRP level (OR = 2.545, 95% CI: 0.935-6.926, p = 0.016) and a positive discharge culture (OR = 2.954, 95% CI: 0.305-28.643, p = 0.019) were positively associated with SSI. However, the rates of maternal request (OR = 0.186, 95% CI: 0.065-0.535, p = 0.002) and postoperative fever (OR = 0.208, 95% CI: 0.087-0.494, p = 0.001) were negatively related to SSI. CONCLUSIONS: Special attentions should be paid to CD patients who had irregular ANC visits, attempted labor, a positive discharge culture, higher CRP levels and fever after surgery, who had a greater risk of SSI.

Inhibition of sEH via stabilizing the level of EETs alleviated Alzheimer's disease through GSK3ß signaling pathway.

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by dementia. Inhibition of soluble epoxide hydrolase (sEH) regulates inflammation involving in central nervous system (CNS) diseases. However, the exactly mechanism of sEH in AD is still unclear. In this study, we evaluated the vital role of sEH in amyloid beta (Aß)-induced AD mice, and revealed a possible molecular mechanism for inhibition of sEH in the treatment of AD. The results showed that the sEH expression and activity were remarkably increased in the hippocampus of Aß-induced AD mice. Chemical inhibition of sEH by TPPU, a selective sEH inhibitor, alleviated spatial learning and memory deficits, and elevated levels of neurotransmitters in Aß-induced AD mice. Furthermore, inhibition of sEH could ameliorate neuroinflammation, neuronal death, and oxidative stress via stabilizing the in vivo level of epoxyeicosatrienoic acids (EETs), especially 8,9-EET and 14,15-EET, further resulting in the anti-AD effect through the regulation of GSK3ß-mediated NF-κB, p53, and Nrf2 signaling pathways. These findings revealed the underlying mechanism of sEH as a potential therapeutic target in treatment of AD.

Peroxiredoxin 3 Inhibits Acetaminophen-Induced Liver Pyroptosis Through the Regulation of Mitochondrial ROS.

Pyroptosis is a newly discovered form of cell death. Peroxiredoxin 3 (PRX3) plays a crucial role in scavenging reactive oxygen species (ROS), but its hepatoprotective capacity in acetaminophen (APAP)-induced liver disease remains unclear. The aim of this study was to assess the role of PRX3 in the regulation of pyroptosis during APAP-mediated hepatotoxicity. We demonstrated that pyroptosis occurs in APAP-induced liver injury accompanied by intense oxidative stress and inflammation, and liver specific PRX3 silencing aggravated the initiation of pyroptosis and liver injury after APAP intervention. Notably, excessive mitochondrial ROS (mtROS) was observed to trigger pyroptosis by activating the NLRP3 inflammasome, which was ameliorated by Mito-TEMPO treatment, indicating that the anti-pyroptotic role of PRX3 relies on its powerful ability to regulate mtROS. Overall, PRX3 regulates NLRP3-dependent pyroptosis in APAP-induced liver injury by targeting mitochondrial oxidative stress.

Uncaria rhynchophylla ameliorates unpredictable chronic mild stress-induced depression in mice via activating 5-HT1A receptor: Insights from transcriptomics.

BACKGROUND: Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain. PURPOSE: The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE). STUDY DESIGN AND METHODS: A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT1A receptor was assayed by dual-luciferase reporter system. RESULTS: URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT1A signaling pathway 5-HT1A, CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT1A receptor with an EC50 value of 17.42 µg/ml. CONCLUSION: U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT1A receptor.

circ-CBFB upregulates p66Shc to perturb mitochondrial dynamics in APAP-induced liver injury.

p66Shc, a master regulator of mitochondrial reactive oxygen species (mtROS), is a crucial mediator of hepatocyte oxidative stress. However, its functional contribution to acetaminophen (APAP)-induced liver injury and the mechanism by which it is modulated remain unknown. Here, we aimed to assess the effect of p66Shc on APAP-induced liver injury and to evaluate if circular RNA (circRNA) functions as a competitive endogenous RNA (ceRNA) to mediate p66Shc in APAP-induced liver injury. p66Shc-, miR-185-5p-, and circ-CBFB-silenced mice were injected with APAP. AML12 cells were transfected with p66Shc, miR-185-5p, and circ-CBFB silencing or overexpression plasmids or siRNAs prior to APAP stimulation. p66Shc was upregulated in liver tissues in response to APAP, and p66Shc silencing in vivo protected mice from APAP-induced mitochondrial dynamics perturbation and liver injury. p66Shc knockdown in vitro attenuated mitochondrial dynamics and APAP-induced hepatocyte injury. Mechanically, p66Shc perturbs mitochondrial dynamics partially by inhibiting OMA1 ubiquitination. miR-185-5p, which directly suppressed p66Shc translation, was identified by microarray and bioinformatics analyses, and its overexpression attenuated mitochondrial dynamics and hepatocyte injury in vitro. Furthermore, luciferase, pull-down and RNA immunoprecipitation assays demonstrated that circ-CBFB acts as a miRNA sponge of miR-185-5p to mediate p66Shc in APAP-induced liver injury. circ-CBFB knockdown also alleviated APAP-induced mitochondrial dynamics perturbation and hepatocyte injury. More importantly, we found that the protective effects of circ-CBFB knockdown on p66Shc, mitochondrial dynamics and liver injury were abolished by miR-185-5p inhibition both in vivo and in vitro. In conclusion, p66Shc is a key regulator of APAP-induced liver injury that acts by triggering mitochondrial dynamics perturbation. circ-CBFB functions as a ceRNA to regulate p66Shc during APAP-induced liver injury, which may provide a potential therapeutic target.

miR-103a-3p regulates mitophagy in Parkinson's disease through Parkin/Ambra1 signaling.

Parkin is a crucial protein that promotes the clearance of damaged mitochondria via mitophagy in neuron, and parkin mutations result in autosomal-recessive Parkinson's disease (AR-PD). However, the exact mechanisms underlying the regulation of Parkin-mediated mitophagy in PD remain unclear. In this study, PD models were generated through incubation of SH-SY5Y cells with 1-methyl-4-phenylpyridinium ion (MPP+, 1.5 mM for 24 h) and intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg for five consecutive days) in mice. A Bioinformatics database was used to identify Parkin-targeting microRNAs (miRNAs). Then, miR-103a-3p agomir, miR-103a-3p antagomir and Parkin siRNA were used to assess the effects of miR-103a-3p/Parkin/Ambra1 signaling-mediated mitophagy in PD in vitro and in vivo. The protein and mRNA levels of Parkin and Ambra1 were significantly decreased, while miR-103a-3p, which is a highly expressed miRNA in the human brain, was obviously increased in PD mouse and SH-SY5Y cell models. Moreover, miR-103a-3p suppressed Parkin expression by targeting a conserved binding site in the 3'-untranslated region (UTR) of Parkin mRNA. Importantly, miR-103a-3p inhibition resulted in neuroprotective effects and improved mitophagy in vitro and in vivo, whereas Parkin siRNA strongly abolished these effects. These findings suggested that miR-103a-3p inhibition has neuroprotective effects in PD, which may be involved in regulating mitophagy through the Parkin/Ambra1 pathway. Modulating miR-103a-3p levels may be an applicable therapeutic strategy for PD.

Inhibition of p66Shc Oxidative Signaling via CA-Induced Upregulation of miR-203a-3p Alleviates Liver Fibrosis Progression.

We previously found that inhibition of p66Shc confers protection against hepatic stellate cell (HSC) activation during liver fibrosis. However, the effect of p66Shc on HSC proliferation, as well as the mechanism by which p66Shc is modulated, remains unknown. Here, we elucidated the effect of p66Shc on HSC proliferation and evaluated microRNA (miRNA)-p66Shc-mediated reactive oxidative species (ROS) generation in liver fibrosis. An in vivo model of carbon tetrachloride (CCl4)-induced liver fibrosis in rats and an LX-2 cell model were developed. p66Shc expression was significantly upregulated in rats with CCl4-induced liver fibrosis and in human fibrotic livers. Additionally, p66Shc knockdown in vitro attenuated mitochondrial ROS generation and HSC proliferation. Interestingly, p66Shc promoted HSC proliferation via ß-catenin dephosphorylation in vitro. MicroRNA (miR)-203a-3p, which was identified by microarray and bioinformatics analyses, directly inhibited p66Shc translation and attenuated HSC proliferation in vitro. Importantly, p66Shc was found to play an indispensable role in the protective effect of miR-203a-3p. Furthermore, carnosic acid (CA), the major antioxidant compound extracted from rosemary leaves, protected against CCl4-induced liver fibrosis through the miR-203a-3p/p66Shc axis. Collectively, these results suggest that p66Shc, which is directly suppressed by miR-203a-3p, is a key regulator of liver fibrosis. This finding may lead to the development of therapeutic targets for liver fibrosis.