CLCF1 signaling restrains thermogenesis and disrupts metabolic homeostasis by inhibiting mitochondrial biogenesis in brown adipocytes.

Great progress has been made in identifying positive regulators that activate adipocyte thermogenesis, but negative regulatory signaling of thermogenesis remains poorly understood. Here, we found that cardiotrophin-like cytokine factor 1 (CLCF1) signaling led to loss of brown fat identity, which impaired thermogenic capacity. CLCF1 levels decreased during thermogenic stimulation but were considerably increased in obesity. Adipocyte-specific CLCF1 transgenic (CLCF1-ATG) mice showed impaired energy expenditure and severe cold intolerance. Elevated CLCF1 triggered whitening of brown adipose tissue by suppressing mitochondrial biogenesis. Mechanistically, CLCF1 bound and activated ciliary neurotrophic factor receptor (CNTFR) and augmented signal transducer and activator of transcription 3 (STAT3) signaling. STAT3 transcriptionally inhibited both peroxisome proliferator-activated receptor-γ coactivator (PGC) 1α and 1ß, which thereafter restrained mitochondrial biogenesis in adipocytes. Inhibition of CNTFR or STAT3 could diminish the inhibitory effects of CLCF1 on mitochondrial biogenesis and thermogenesis. As a result, CLCF1-TG mice were predisposed to develop metabolic dysfunction even without external metabolic stress. Our findings revealed a brake signal on nonshivering thermogenesis and suggested that targeting this pathway could be used to restore brown fat activity and systemic metabolic homeostasis in obesity.

Clusterbody Enables Flow Sorting-Assisted Single-Cell Mass Spectrometry Analysis for Identifying Reversal Agent of Chemoresistance.

Identifying effective reversal agents overcoming multidrug resistance with causal mechanisms from an efflux pump protein is of vital importance for enhanced tumor chemotherapy in clinic. To achieve this end, we construct a metal cluster-based probe, named clusterbody, to develop flow sorting-assisted single-cell mass spectrometry analysis. This clusterbody synthesized by biomimetic mineralization possesses an antibody-like property to selectively recognize an efflux pump protein. The intrinsic red fluorescence emission of the clusterbody facilitates fluorescence-activated high-throughput cell sorting of subpopulations with different multidrug resistance levels. Furthermore, based on the accurate formula of the clusterbody, the corresponding protein abundance at the single-cell level is determined through detecting gold content via precise signal amplification by laser ablation inductively coupled plasma mass spectrometry. Therefore, the effect of reversal agent treatment overcoming multidrug resistance is evaluated in a quantitative manner. This work opens a new avenue to identify reversal agents, shedding light on developing combined or synergetic tumor therapy.

Synergistic Effect of Reactive Oxygen Species in Photothermocatalytic Removal of VOCs from Cooking Oil Fumes over Pt/CeO2/TiO2.

The volatile organic compounds (VOCs) from cooking oil fumes are very complex and do harm to humans and the environment. Herein, we develop the high-efficiency and energy-saving synergistic photothermocatalytic oxidation approach to eliminate the mixture of heptane and hexanal, the representative VOCs with high concentrations in cooking oil fumes. The Pt/CeO2/TiO2 catalyst with nanosized Pt particles was prepared by the simple hydrothermal and impregnation methods, and the physicochemical properties of the catalyst were measured using numerous techniques. The Pt/CeO2/TiO2 catalyst eliminated the VOC mixture at low light intensity (100 mW cm-2) and low temperature (200 °C). In addition, it showed 25 h of catalytic stability and water resistance (water concentration up to 20 vol %) at 140 or 190 °C. It is concluded that O2 picked up the electrons from Pt to generate the •O2- species, which were transformed to the O22- and O- species after the rise in temperature. In the presence of water, the •OH species induced by light irradiation on the catalyst surface and the •OOH species formed via the thermal reaction were both supplementary oxygen species for VOC oxidation. The synergistic interaction of photo- and thermocatalysis was generated by the reactive oxygen species.

Brain-targeted heptapeptide-loaded exosomes attenuated ischemia-reperfusion injury by promoting the transfer of healthy mitochondria from astrocytes to neurons.

BACKGROUND: The exchange of mitochondria reportedly plays an important role in cell-cell communication in the central nervous system (CNS). The transfer of fragmented and dysfunctional astrocytic mitochondria into neurons and subsequent mitochondrial fusion often cause serious neuronal damage and cerebral ischaemic injury. METHODS: In this study, we prepared macrophage-derived exosomes laden with heptapeptide (Hep) as a dynamin-related protein-1 (Drp1)-fission 1 (Fis1) peptide inhibitor P110 to alleviate cerebral ischemia-reperfusion injury by reducing mitochondrial Drp1/Fis1 interaction-mediated astrocytic mitochondrial disorder and promoting the transfer of astrocyte-derived healthy mitochondria into neurons. RESULTS: The results demonstrated that Hep-loaded macrophage-derived exosomes (EXO-Hep) reduced mitochondrial damage in astrocytes by inhibiting the Drp1/Fis1 interaction after ischemia-reperfusion, ensuring the release of heathy astrocytic mitochondria and their subsequent transmission to neurons, alleviating mitochondria-mediated neuronal damage. CONCLUSION: EXO-Hep significantly mitigated ischemic injury in a model of transient middle cerebral artery occlusion (tMCAO) by reducing the infarct area and improving neurological performance during the process of cerebral ischemia-reperfusion.

DoSGuard: Mitigating Denial-of-Service Attacks in Software-Defined Networks.

Software-defined networking (SDN) is a new networking paradigm that realizes the fast management and optimal configuration of network resources by decoupling control logic and forwarding functions. However, centralized network architecture brings new security problems, and denial-of-service (DoS) attacks are among the most critical threats. Due to the lack of an effective message-verification mechanism in SDN, attackers can easily launch a DoS attack by faking the source address information. This paper presents DoSGuard, an efficient and protocol-independent defense framework for SDN networks to detect and mitigate such attacks. DoSGuard is a lightweight extension module on SDN controllers that mainly consists of three key components: a monitor, a detector, and a mitigator. The monitor maintains the information between the switches and the hosts for anomaly detection. The detector utilizes OpenFlow message and flow features to detect the attack. The mitigator protects networks by filtering malicious packets. We implement a prototype of DoSGuard in the floodlight controller and evaluate its effectiveness in a simulation environment. Experimental results show the DoSGuard achieves 98.72% detecion precision, and the average CPU utilization of the controller is only around 8%. The results demonstrate that DoSGuard can effectively mitigate DoS attacks against SDN with limited overhead.

A thermoreversible antibacterial zeolite-based nanoparticles loaded hydrogel promotes diabetic wound healing via detrimental factor neutralization and ROS scavenging.

BACKGROUND: As recovery time of diabetic wound injury is prolonged by the production of detrimental factors, including reactive oxygen species (ROS) and inflammatory cytokines, attenuating the oxidative stress and inflammatory reactions in the microenvironment of the diabetic wound site would be significant. EXPERIMENTAL DESIGN: In our study, we prepared thermoreversible, antibacterial zeolite-based nanoparticles loaded hydrogel to promote diabetic wound healing via the neutralization of detrimental factors such as inflammatory cytokines and ROS. RESULTS: The cerium (Ce)-doped biotype Linde type A (LTA) zeolite nanoparticles synergistically eliminated mitochondrial ROS and neutralized free inflammatory factors, thus remodeling the anti-inflammatory microenvironment of the wound and enhancing angiogenesis. Moreover, the thermoreversible hydrogel composed of Pluronic F127 and chitosan demonstrated strong haemostatic and bactericidal behavior. CONCLUSIONS: In conclusion, the obtained thermoreversible, antibacterial, zeolite-based nanoparticles loaded hydrogels represent a multi-targeted combination therapy for diabetic wound healing.

Surface-modified engineered exosomes attenuated cerebral ischemia/reperfusion injury by targeting the delivery of quercetin towards impaired neurons.

BACKGROUND: The incidence of ischemic stroke in the context of vascular disease is high, and the expression of growth-associated protein-43 (GAP43) increases when neurons are damaged or stimulated, especially in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). EXPERIMENTAL: DESIGN: We bioengineered neuron-targeting exosomes (Exo) conjugated to a monoclonal antibody against GAP43 (mAb GAP43) to promote the targeted delivery of quercetin (Que) to ischemic neurons with high GAP43 expression and investigated the ability of Exo to treat cerebral ischemia by scavenging reactive oxygen species (ROS). RESULTS: Our results suggested that Que loaded mAb GAP43 conjugated exosomes (Que/mAb GAP43-Exo) can specifically target damaged neurons through the interaction between Exo-delivered mAb GAP43 and GAP43 expressed in damaged neurons and improve survival of neurons by inhibiting ROS production through the activation of the Nrf2/HO-1 pathway. The brain infarct volume is smaller, and neurological recovery is more markedly improved following Que/mAb GAP43-Exo treatment than following free Que or Que-carrying exosome (Que-Exo) treatment in a rat induced by MCAO/R. CONCLUSIONS: Que/mAb GAP43-Exo may serve a promising dual targeting and therapeutic drug delivery system for alleviating cerebral ischemia/reperfusion injury.

Brain Microvascular Endothelial Cell Derived Exosomes Potently Ameliorate Cognitive Dysfunction by Enhancing the Clearance of Aß Through Up-Regulation of P-gp in Mouse Model of AD.

Accumulation of amyloid-ß (Aß) peptides in the brain is regarded as a major contributor to the pathogenesis and progression of Alzheimer's disease (AD). P-glycoprotein (P-gp) as a member of ABC transporter family situated in blood brain barrier (BBB) plays a role on cleaning of Aß via its efflux transport effect in the treatment of AD. However, the expression of P-gp in pathological BBB was lower than that in normal BBB, thus impeding the clearance of Aß. Here, we used human brain microvascular endothelial cells (HBMVECs) derived exosomes (HBMVECs-Ex) inheriting P-gp as an extracorporeal Aß cleansing system to remove Aß peptides from the brain by specific capture between P-gp and Aß. The results showed that HBMVECs-Ex inheriting P-gp greatly facilitated the cerebral clearance of Aß by effectively transporting Aß out of brain and potently ameliorated cognitive dysfunction in AD mice. Taken together, HBMVECs-Ex provided a new strategy on the treatment of AD.

Edaravone-Loaded Macrophage-Derived Exosomes Enhance Neuroprotection in the Rat Permanent Middle Cerebral Artery Occlusion Model of Stroke.

Edaravone (Edv) can inhibit tissue damage, cause cerebral edema, and delay neuronal death caused by acute cerebral infarction. Exosomes are considered as cargo carriers for intercellular communication and serve as important regulators in many pathological processes. Here, we developed macrophage-derived exosomes (Exo) containing Edv (Exo + Edv) to improve the bioavailability of Edv and enhance the neuroprotective effects in a rat model of permanent middle cerebral artery occlusion (PMCAO). The results showed that Exo + Edv significantly improved the bioavailability of Edv and prolonged half-life (t1/2). At the same time, Exo + Edv made Edv more easily reach the ischemic side of rats with PMCAO and was localized with neuronal cells and microglia, thus reducing the death of neuronal cells and promoting the polarization of microglia from M1 to M2. Taken together, Exo + Edv may become a potential clinical treatment option for PMCAO.

Cache-Based Privacy Preserving Solution for Location and Content Protection in Location-Based Services.

Location-Based Services (LBSs) are playing an increasingly important role in people's daily activities nowadays. While enjoying the convenience provided by LBSs, users may lose privacy since they report their personal information to the untrusted LBS server. Although many approaches have been proposed to preserve users' privacy, most of them just focus on the user's location privacy, but do not consider the query privacy. Moreover, many existing approaches rely heavily on a trusted third-party (TTP) server, which may suffer from a single point of failure. To solve the problems above, in this paper we propose a Cache-Based Privacy-Preserving (CBPP) solution for users in LBSs. Different from the previous approaches, the proposed CBPP solution protects location privacy and query privacy simultaneously, while avoiding the problem of TTP server by having users collaborating with each other in a mobile peer-to-peer (P2P) environment. In the CBPP solution, each user keeps a buffer in his mobile device (e.g., smartphone) to record service data and acts as a micro TTP server. When a user needs LBSs, he sends a query to his neighbors first to seek for an answer. The user only contacts the LBS server when he cannot obtain the required service data from his neighbors. In this way, the user reduces the number of queries sent to the LBS server. We argue that the fewer queries are submitted to the LBS server, the less the user's privacy is exposed. To users who have to send live queries to the LBS server, we employ the l-diversity, a powerful privacy protection definition that can guarantee the user's privacy against attackers using background knowledge, to further protect their privacy. Evaluation results show that the proposed CBPP solution can effectively protect users' location and query privacy with a lower communication cost and better quality of service.

Exosomes derived from siRNA against GRP78 modified bone-marrow-derived mesenchymal stem cells suppress Sorafenib resistance in hepatocellular carcinoma.

BACKGROUND: Sorafenib is an effective clinical drug in therapy of hepatocellular carcinoma, having led to improved prognosis in hepatocellular carcinoma patients. However acquired resistance is still being encountered. So, it is urgently to develop alternative strategies to overcome drug resistance. Exosomes can be modified with a variety of molecules, thereby acting as a vehicle for the delivery of therapeutic agents. The GRP78 is overexpressed in Sorafenib resistant cancer cells compared to Sorafenib sensitive cancer cells and thus is able to act as a target for therapy of hepatocellular carcinoma. RESULTS: In this study, we modified BM-MSCs to express the exosomal siGRP78. And we show that siGRP78 modified exosomes combined with Sorafenib is able to target GRP78 in hepatocellular carcinoma cells and inhibit the growth and invasion of the cancer cells in vitro. Further, siGRP78 modified exosomes combined with Sorafenib also inhibit the growth and metastasis of the cancer cells in vivo. CONCLUSIONS: siGRP78 modified exosomes could sensitize Sorafenib resistant cancer cells to Sorafenib and reverse the drug resistance.

mAb MDR1-modified chitosan nanoparticles overcome acquired EGFR-TKI resistance through two potential therapeutic targets modulation of MDR1 and autophagy.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) that act against the epithelial growth factor receptor (EGFR) were once widely used in chemotherapy for many human cancers. However, acquired chemoresistance occurred in almost all patients, limiting the clinical application of EGFR-TKI. Thus far, no effective methods existing can resolve this problem. Designing a therapeutic treatment with a specific multi-target profile has been regarded as a possible strategy to overcome acquired EGFR-TKI resistance. METHODS: MDR1 antibody-modified chitosan nanoparticles loading gefitinib and autophagy inhibitor chloroquine were prepared by ionic crosslinking and electrostatic attracting method. MTT assay, flow cytometry analysis and western blot assay were all performed to confirm the effect of different formulations of gefitinib on the proliferation of SMMC-7721/gefitinib cells. The preparations demonstrated their multi-target potential to achieve both tumor-targeting selectivity and the desired antitumor effects by blocking cell-surface MDR1 and inhibiting autophagy. RESULTS: mAb MDR1-modified CS NPs, when combined with the co-delivery of gefitinib and chloroquine, showed targeting and therapeutic potential on enhancing the delivery of anticancer drugs and inducing significant cell apoptosis against acquired EGFR-TKI resistance through the modulation of autophagy and while blocking the activity of the MDR1 receptor. CONCLUSIONS: A new approach to design an excellent nanoparticle drug-delivery system can overcome acquired EGFR-TKI resistance against various multiple antitumor targets.

Hyaluronic acid-coated chitosan nanoparticles induce ROS-mediated tumor cell apoptosis and enhance antitumor efficiency by targeted drug delivery via CD44.

BACKGROUND: A targeted drug nanoparticle (NP) delivery system has shown potential as a possible cancer treatment. Given its merits, such as its selective distribution at tumor sites and its controllable drug release, drug-loaded NPs can be effectively delivered to selected organs and targeted cells, thus enhancing its antitumor efficiency and reducing its toxicity. METHODS: We reported that hyaluronic acid (HA)-coated chitosan NPs promoted the drug delivery of 5-fluorouracil (5-Fu) into tumor cells that highly expressed CD44. RESULTS: Our new findings suggested that HA-coated chitosan NPs enhanced drug accumulation by effectively transporting NPs into CD44-overexpressed tumor cells, and they also resulted in mitochondrial damage induced by the production of reactive oxygen species (ROS). Compared to free drug and uncoated NPs, HA-coated chitosan NPs exhibited stronger inhibition rates and induced obvious apoptosis in CD44-overexpressed A549 cells. CONCLUSIONS: Biocompatible and biodegradable HA-coated chitosan NPs were developed to encapsulate a chemotherapeutic drug (5-Fu) to enhance drug accumulation in tumor cells and to improve the agent's antitumor efficiency by offering targeted drug delivery via CD44.

Chitosan nanoparticle-mediated co-delivery of shAtg-5 and gefitinib synergistically promoted the efficacy of chemotherapeutics through the modulation of autophagy.

BACKGROUND: Autophagy reportedly plays vital and complex roles in many diseases. During times of starvation or energy deficiency, autophagy will occur at higher levels to provide cells with the nutrients or energy necessary to survive in stressful conditions. Some anti-cancer drugs induce protective autophagy and reduce cell apoptosis. Autophagy can adversely affect apoptosis, and blocking autophagy will increase the sensitivity of cells to apoptosis signals. METHODS: We designed chitosan nanoparticles (NPs) to promote the co-delivery of gefitinib (an anti-cancer drug) and shRNA-expressing plasmid DNA that targets the Atg-5 gene (shAtg-5) as an autophagy inhibitor to improve anti-cancer effects and autophagy mediation. RESULTS: The results showed that when compared to treatment with a single drug, chitosan NPs were able to facilitate the intracellular distribution of NPs, and they improved the transfection efficiency of gene in vitro. The co-delivery of gefitinib and shAtg-5 increased cytotoxicity, induced significant apoptosis through the prohibition of autophagy, and markedly inhibited tumor growth in vivo. CONCLUSIONS: The co-delivery of gefitinib/shAtg-5 in chitosan NPs produced superior anti-cancer efficacy via the internalization effect of NPs, while blocking autophagy with shAtg-5 enhanced the synergistic antitumor efficacy of gefitinib.

Co-delivery of Gefitinib and chloroquine by chitosan nanoparticles for overcoming the drug acquired resistance.

BACKGROUND: Acquired drug resistance is becoming common during cancer chemotherapy and leads to treatment failure in clinic. To conquer acquired drug resistance, nanotechnology has been employed to deliver drug. In this paper, we prepared chitosan nanoparticles (CS NPs) capable of entrapping Gefitinib and chloroquine (CQ) for multiple drugs combinational therapy. RESULTS: The results showed that Gefitinib/CQ-NPs were characterized of small particle size about 80.8 ± 9.7 nm and positive zeta potential about 21.3 ± 1.56 mV, and drug controlled to release slowly on a biphasic pattern. Compared with free Gefitinib and Gefitinib loaded NPs, Gefitinib and CQ co-delivery by CS nanoparticles showed the higher inhibition rates and enhanced cell apoptosis. Through western blot analysis, we found that Gefitinib could promote LC3 expression, which is the marker of autophagosomes. So, the acquired drug resistance may be associated with autophagy. CQ as an inhibitor of autophagolysosomes formation could overcome autophagy in the resistant cells. CONCLUSIONS: These findings demonstrated that chitosan nanoparticles entrapping Gefitinib and chloroquine have the potential to overcome acquired resistance and improve cancer treatment efficacy, especially towards resistant strains. Graphical abstract: Cellular distribution of NPs after incubating QGY (a) and QGY/Gefitinib cells (b) with rhodamine B-labeled NPs.

Gefitinib loaded folate decorated bovine serum albumin conjugated carboxymethyl-beta-cyclodextrin nanoparticles enhance drug delivery and attenuate autophagy in folate receptor-positive cancer cells.

BACKGROUND: Active targeting endocytosis mediated by the specific interaction between folic acid and its receptor has been a hotspot in biological therapy of many human cancers. Various studies have demonstrated that folate and its conjugates could facilitate the chemotherapeutic drug delivery into folate receptor (FR)-positive tumor cells in vitro and in vivo. In order to utilize FA-FR binding specificity to achieve targeted delivery of drugs into tumor cells, we prepared Gefitinib loaded folate decorated bovine serum albumin conjugated carboxymethyl-ß-cyclodextrin nanoparticles for enhancing drug delivery in cancer cells. On this context, the aim of our study was to develop a novel nano-delivery system for promoting tumor-targeting drug delivery in folate receptor-positive Hela cells. RESULTS: We prepared folic acid (FA)-decorated bovine serum albumin (BSA) conjugated carboxymethyl-ß-cyclodextrin (CM-ß-CD) nanoparticles (FA-BSA-CM-ß-CD NPs) capable of entrapping a hydrophobic Gefitinib. It was observed that nanoparticles are monodisperse and spherical nanospheres with an average diameter of 90.2 nm and negative surface charge of -18.6 mV. FA-BSA-CM-ß-CD NPs could greatly facilitate Gefitinib uptake and enhance the toxicity to folate receptor-positive Hela cells. Under the reaction between FA and FR, Gefitinib loaded FA-BSA-CM-ß-CD NPs induced apoptosis of Hela cells through elevating the expression of caspase-3 and inhibited autophagy through decreasing the expressing of LC3. It also confirmed that clathrin-mediated endocytosis and macropinocytosis exerted great influence on the internalization of both NPs. CONCLUSIONS: These results demonstrated that FA may be an effective targeting molecule and FA-BSA-CM-ß-CD NPs provided a new strategy for the treatment of human cancer cells which over-expressed folate receptors.

Modulation of microglial polarization by sequential targeting surface-engineered exosomes improves therapy for ischemic stroke.

Microglia are important cells that act on regulating neuroinflammation and neurofunction after the induction of ischemic stroke (IS). Consequently, the efficient accumulation of drugs within ischemic regions, particularly in microglia, serves as a valuable approach for achieving effective therapy by attenuating microglia-mediated cerebral ischemic injury. In this study, we designed mannose (man)-conjugated luteolin (lut)-loaded platelet-derived exosomes (lut/man-pEXO) as surface engineered multifunctional cascade-delivery drug carriers to target ischemic blood vessels and subsequent microglia to enhance drug accumulation and induce neuroprotection of neurovascular unit (NVU) against IS. The results revealed that as platelets naturally gathered in pathological ischemic cerebral vessels, lut/man-pEXO could bind to platelets and efficiently target ischemic injury sites. Moreover, owing to the selective binding affinity of mannose present in lut/man-pEXO towards the mannose receptor expressed on microglia, lut/man-pEXO exhibited superior microglia-targeting properties, inducing the increased uptake of lut by microglia. As a result, lut/man-pEXO regulated microglia by inhibiting the activation of detrimental M1 and promoting the transition towards the anti-inflammatory type (M2), thus attenuating ischemic damage of NVU by reducing the infarct area, rescuing the damage of blood-brain barrier (BBB) and preventing inflammatory transformation of astrocytes.

Advances in Synthesis and Applications of Single-Atom Catalysts for Metal Oxide-Based Gas Sensors.

As a stable, low-cost, environment-friendly, and gas-sensitive material, semiconductor metal oxides have been widely used for gas sensing. In the past few years, single-atom catalysts (SACs) have gained increasing attention in the field of gas sensing with the advantages of maximized atomic utilization and unique electronic and chemical properties and have successfully been applied to enhance the detection sensitivity and selectivity of metal oxide gas sensors. However, the application of SACs in gas sensors is still in its infancy. Herein, we critically review the recent advances and current status of single-atom catalysts in metal oxide gas sensors, providing some suggestions for the development of this field. The synthesis methods and characterization techniques of SAC-modified metal oxides are summarized. The interactions between SACs and metal oxides are crucial for the stable loading of single-atom catalysts and for improving gas-sensitive performance. Then, the current application progress of various SACs (Au, Pt, Cu, Ni, etc.) in metal oxide gas sensors is introduced. Finally, the challenges and perspectives of SACs in metal oxide gas sensors are presented.

NR2F6 is essential for brown adipocyte differentiation and systemic metabolic homeostasis.

OBJECTIVE: Brown adipose tissue (BAT) development and function are essential for maintaining energy balance. However, the key factors that specifically regulate brown adipogenesis require further identification. Here, we demonstrated that the nuclear receptor subfamily 2 group F member 6 (NR2F6) played a pivotal role in brown adipogenesis and energy homeostasis. METHODS: We examined the differentiation of immortalized brown adipocytes and primary brown adipocytes when NR2F6 were deleted, and explored the mechanism through which NR2F6 regulated adipogenesis using ChIP-qPCR in vitro. Male wild type (WT) and Pdgfra-Cre-mediated deletion of Nr2f6 in preadipocytes (NR2F6-PKO) mice were fed with high fat diet (HFD) for 12 weeks, and adiposity, glucose intolerance, insulin resistance and inflammation were assessed. RESULTS: NR2F6 exhibited abundant expression in BAT, while its expression was minimal in white adipose tissue (WAT). Within BAT, NR2F6 was highly expressed in preadipocytes, experienced a transient increase in the early stage of brown adipocyte differentiation, and significantly decreased in the mature adipocytes. Depletion of NR2F6 in preadipocytes inhibited brown adipogenesis, caused hypertrophy of brown adipocytes, and impaired thermogenic function of BAT, but without affecting WAT development. NR2F6 transcriptionally regulated PPARγ expression to promote adipogenic process in brown adipocytes. Loss of NR2F6 in preadipocytes led to increased susceptibility to diet-induced metabolic disorders. CONCLUSIONS: Our findings unveiled NR2F6 as a novel key regulator of brown adipogenesis, potentially opening up new avenues for maintaining metabolic homeostasis by targeting NR2F6.

Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction.

Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.