A mechanism linking ferroptosis and ferritinophagy in melatonin-related improvement of diabetic brain injury.

Ferroptosis and ferritinophagy play critical roles in various disease contexts. Herein, we observed that ferroptosis and ferritinophagy were induced both in the brains of mice with diabetes mellitus (DM) and neuronal cells after high glucose (HG) treatment, as evidenced by decreases in GPX4, SLC7A11, and ferritin levels, but increases in NCOA4 levels. Interestingly, melatonin administration ameliorated neuronal damage by inhibiting ferroptosis and ferritinophagy both in vivo and in vitro. At the molecular level, we found that not only the ferroptosis inducer p53 but also the ferritinophagy mediator NCOA4 was the potential target of miR-214-3p, which was downregulated by DM status or HG insult, but was increased after melatonin treatment. However, the inhibitory effects of melatonin on ferroptosis and ferritinophagy were blocked by miR-214-3p downregulation. These findings suggest that melatonin is a potential drug for improving diabetic brain damage by inhibiting p53-mediated ferroptosis and NCOA4-mediated ferritinophagy through regulating miR-214-3p in neurons.

Towards high performance wood composites through interface customization with cellulose-based adhesive.

How to efficiently produce high performance plywood is of particular interest, while its sensitivity to moisture is overcome. This paper presents a simple and scalable strategy for the preparation of high-performance plywood based on the chemical bonding theory; a wood interfacial functionalized platform (WIFP) based on (3-aminopropyl) triethoxysilane (APTES) was established. Interestingly, the APTES-enhanced dialdehyde cellulose-based adhesive (DAC-APTES) was able to effectively establish chemically active adhesive interfaces; the dry/wet shear strength of WIFP/DAC-APTES adhesive was 3.15/1.31 MPa, which was much higher than 0.7 MPa (GB/T 9846-2015). The prepared plywood showed excellent wood-polymer interface adhesion, which exceeded the force that the wood itself could withstand. In addition, the DAC-APTES adhesive exhibits moisture evaporation-induced curing behavior at room temperature and can easily support the weight of an adult weighing 65.7 Kg. This research provides a novel approach for functionalized interface design of wood products, an effective means to prepare high-performance plywood.

TGF-ß1 induces PD-1 expression in macrophages through SMAD3/STAT3 cooperative signaling in chronic inflammation.

Programmed cell death protein 1 (PD-1), a coinhibitory T cell checkpoint, is also expressed on macrophages in pathogen- or tumor-driven chronic inflammation. Increasing evidence underscores the importance of PD-1 on macrophages for dampening immune responses. However, the mechanism governing PD-1 expression in macrophages in chronic inflammation remains largely unknown. TGF-ß1 is abundant within chronic inflammatory microenvironments. Here, based on public databases, significantly positive correlations between PDCD1 and TGFB1 gene expression were observed in most human tumors. Of note, among immune infiltrates, macrophages as the predominant infiltrate expressed higher PDCD1 and TGFBR1/TGFBR2 genes. MC38 colon cancer and Schistosoma japonicum infection were used as experimental models for chronic inflammation. PD-1hi macrophages from chronic inflammatory tissues displayed an immunoregulatory pattern and expressed a higher level of TGF-ß receptors. Either TGF-ß1-neutralizing antibody administration or macrophage-specific Tgfbr1 knockdown largely reduced PD-1 expression on macrophages in animal models. We further demonstrated that TGF-ß1 directly induced PD-1 expression on macrophages. Mechanistically, TGF-ß1-induced PD-1 expression on macrophages was dependent on SMAD3 and STAT3, which formed a complex at the Pdcd1 promoter. Collectively, our study shows that macrophages adapt to chronic inflammation through TGF-ß1-triggered cooperative SMAD3/STAT3 signaling that induces PD-1 expression and modulates macrophage function.

Discovery of macrocyclic CDK2/4/6 inhibitors with improved potency and DMPK properties through a highly efficient macrocyclic drug design platform.

Cyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that enabled the highly efficient discovery of a novel, macrocyclic CDK2/4/6 inhibitor from an acyclic precursor (NUV422). Using dihedral angle scan and structure-based, computer-aided drug design to select an optimal ring-closing site and linker length for the macrocycle, we identified compound 8 as a potent new CDK2/4/6 inhibitor with optimized cellular potency and safety profile compared to NUV422. Our platform leverages both experimentally-solved as well as generative chemistry-derived macrocyclic structures and can be deployed to streamline the design of macrocyclic new drugs from acyclic starting compounds, yielding macrocyclic compounds with enhanced potency and improved drug-like properties.

CD1d protects against hepatocyte apoptosis in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Hepatocyte apoptosis, a well-defined form of cell death in non-alcoholic steatohepatitis (NASH), is considered the primary cause of liver inflammation and fibrosis. However, the mechanisms underlying the regulation of hepatocyte apoptosis in NASH remain largely unclear. We explored the anti-apoptotic effect of hepatocyte CD1d in NASH. METHODS: Hepatocyte CD1d expression was analyzed in patients with NASH and mouse models. Hepatocyte-specific gene overexpression or knockdown and anti-CD1d crosslinking were used to investigate the anti-apoptotic effect of hepatocyte CD1d on lipotoxicity-, Fas-, and concanavalin (ConA)-mediated liver injuries. A high-fat diet, a methionine-choline-deficient diet, a Fas agonist, and ConA were used to induce lipotoxic and/or apoptotic liver injuries. Palmitic acid was used to mimic lipotoxicity-induced apoptosis in vitro. RESULTS: We identified a dramatic decrease in CD1d expression in hepatocytes of patients with NASH and mouse models. Hepatocyte-specific CD1d overexpression and knockdown experiments collectively demonstrated that hepatocyte CD1d protected against hepatocyte apoptosis and alleviated hepatic inflammation and injuries in NASH mice. Furthermore, decreased JAK2-STAT3 signaling was observed in NASH patient livers. Mechanistically, anti-CD1d crosslinking on hepatocytes induced tyrosine phosphorylation of the CD1d cytoplasmic tail, leading to the recruitment and phosphorylation of JAK2. Phosphorylated JAK2 activated STAT3 and subsequently reduced apoptosis in hepatocytes, which was associated with an increase in anti-apoptotic effectors (Bcl-xL and Mcl-1) and a decrease in pro-apoptotic effectors (cleaved-caspase 3/7). Moreover, anti-CD1d crosslinking effectively protected against Fas- or ConA-mediated hepatocyte apoptosis and liver injury in mice. CONCLUSIONS: Our study uncovered a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 axis in hepatocytes that conferred hepatoprotection and highlighted the potential of hepatocyte CD1d-directed therapy for liver injury and fibrosis in NASH, as well as in other liver diseases associated with hepatocyte apoptosis. IMPACT AND IMPLICATIONS: Excessive and/or sustained hepatocyte apoptosis is critical in driving liver inflammation and injury. The mechanisms underlying the regulation of hepatocyte apoptosis in non-alcoholic steatohepatitis (NASH) remain largely unclear. Here, we found that CD1d expression in hepatocytes substantially decreases and negatively correlates with the severity of liver injury in patients with NASH. We further revealed a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 signaling axis in hepatocytes, which confers significant protection against liver injury in NASH and acute liver diseases. Thus, hepatocyte CD1d-targeted therapy could be a promising strategy to manipulate liver injury in both NASH and other hepatocyte apoptosis-related liver diseases.

Lobster-Inspired Chitosan-Derived Adhesives with a Biomimetic Design.

Polysaccharide-based adhesives, especially chitosan (CS)-derived adhesives, serve as promising sustainable alternatives to traditional adhesives. However, most demonstrate a poor adhesive strength. Inspired by the inherent layered structure of marine arthropods (lobsters), a core-shell structure (SiO2-NH2@OPG) with amine-functionalized silica (SiO2-NH2) as the core and oxidized pyrogallol (OPG) as the shell is prepared in this study. The compound is blended with CS to produce a structural biomimetic wood adhesive (SiO2-NH2@OPG/CS) with excellent performance. In addition to thermocompressive curing, this adhesive exhibits a water-evaporation-induced curing behavior at room temperature. With reference to the design mechanism of the lobster cuticle, this microphase-separated structure consists of clustered nanofibers with varying amounts of SiO2-NH2@OPG particles between the fibers. This intriguing microphase structure and its mechanical effects could offer a powerful solution for improving the functional modification of wood composites.

One-Minute Preparation of Iron Foam-Drug Implant for Ultralow-Power Magnetic Hyperthermia-Based Combination Therapy of Tumors in Vivo.

The magnetic hyperthermia-based combination therapy (MHCT) is a powerful tumor treatment approach due to its unlimited tissue penetration depth and synergistic therapeutic effect. However, strong magnetic hyperthermia and facile drug loading are incompatible with current MHCT platforms. Herein, an iron foam (IF)-drug implant is established in an ultra-facile and universal way for ultralow-power MHCT of tumors in vivo for the first time. The IF-drug implant is fabricated by simply immersing IF in a drug solution at an adjustable concentration for 1 min. Continuous metal structure of IF enables ultra-high efficient magnetic hyperthermia based on eddy current thermal effect, and its porous feature provides great space for loading various hydrophilic and hydrophobic drugs via "capillary action". In addition, the IF has the merits of low cost, customizable size and shape, and good biocompatibility and biodegradability, benefiting reproducible and large-scale preparation of IF-drug implants for biological application. As a proof of concept, IF-doxorubicin (IF-DOX) is used for combined tumor treatment in vivo and achieves excellent therapeutic efficacy at a magnetic field intensity an order of magnitude lower than the threshold for biosafety application. The proposed IF-drug implant provides a handy and universal method for the fabrication of MHCT platforms for ultralow-power combination therapy.

Targeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia.

Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting immune niches may ameliorate disease progression and tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive B-ALL (Ph+ B-ALL). Here, we show that T helper type 17 (Th17) cells and IL-17A expression are distinctively elevated in Ph+ B-ALL patients. IL-17A promotes the progression of Ph+ B-ALL. Mechanistically, IL-17A activates BCR-ABL, IL6/JAK/STAT3, and NF-kB signalling pathways in Ph+ B-ALL cells, resulting in robust cell proliferation and survival. In addition, IL-17A-activated Ph+ B-ALL cells secrete the chemokine CXCL16, which in turn promotes Th17 differentiation, attracts Th17 cells and forms a positive feedback loop supporting leukemia progression. These data demonstrate an involvement of Th17 cells in Ph+ B-ALL progression and suggest potential therapeutic options for Ph+ B-ALL with Th17-enriched niches.

Complete Mitochondrial Genome and Phylogenetic Analysis of Tarsiger indicus (Aves: Passeriformes: Muscicapidae).

Tarsiger indicus (Vieillot, 1817), the White-browed Bush Robin, is a small passerine bird widely distributed in Asian countries. Here, we successfully sequenced its mitogenome using the Illumina Novaseq 6000 platform (Illumina, San Diego, CA, USA) for PE 2 × 150 bp sequencing. Combined with other published mitogenomes, we conducted the first comprehensive comparative mitogenome analysis of Muscicapidae birds and reconstructed the phylogenetic relationships between Muscicapidae and related groups. The T. indicus mitogenome was 16,723 bp in size, and it possessed the typical avian mitogenome structure and organization. Most PCGs of T. indicus were initiated strictly with the typical start codon ATG, while COX1 and ND2 were started with GTG. RSCU statistics showed that CUA, CGA, and GCC were relatively high frequency in the T. indicus mitogenome. T. cyanurus and T. indicus shared very similar mitogenomic features. All 13 PCGs of Muscicapidae mitogenomes had experienced purifying selection. Specifically, ATP8 had the highest rate of evolution (0.13296), whereas COX1 had the lowest (0.01373). The monophylies of Muscicapidae, Turdidae, and Paradoxornithidae were strongly supported. The clade of ((Muscicapidae + Turdidae) + Sturnidae) in Passeriformes was supported by both Bayesian Inference and Maximum likelihood analyses. The latest taxonomic status of many passerine birds with complex taxonomic histories were also supported. For example, Monticola gularis, T. indicus, and T. cyanurus were allocated to Turdidae in other literature; our phylogenetic topologies clearly supported their membership in Muscicapidae; Paradoxornis heudei, Suthora webbiana, S. nipalensis, and S. fulvifrons were formerly classified into Muscicapidae; we supported their membership in Paradoxornithidae; Culicicapa ceylonensis was originally classified as a member of Muscicapidae; our results are consistent with a position in Stenostiridae. Our study enriches the genetic data of T. indicus and provides new insights into the molecular phylogeny and evolution of passerine birds.

Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway.

Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1WT) as a potential diagnostic and prognostic biomarker for non-small cell lung cancer (NSCLC), but how IDH1WT modulates NSCLC progression remains elusive. Here, we report that IDH1WT activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1WT interacts with and stabilizes PHGDH and fragile X-related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports PSAT1 mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1WT-PHGDH and IDH1WT-FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine-depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1WT in serine metabolism, highlighting IDH1WT as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC.

Photoaffinity labeling coupled with proteomics identify PDI-ADAM17 module is targeted by (-)-vinigrol to induce TNFR1 shedding and ameliorate rheumatoid arthritis in mice.

Various biological agents have been developed to target tumor necrosis factor alpha (TNF-α) and its receptor TNFR1 for the rheumatoid arthritis (RA) treatment, whereas small molecules modulating such cytokine receptors are rarely reported in comparison to the biologicals. Here, by revealing the mechanism of action of vinigrol, a diterpenoid natural product, we show that inhibition of the protein disulfide isomerase (PDI, PDIA1) by small molecules activates A disintegrin and metalloprotease 17 (ADAM17) and then leads to the TNFR1 shedding on mouse and human cell membranes. This small-molecule-induced receptor shedding not only effectively blocks the inflammatory response caused by TNF-α in cells, but also reduces the arthritic score and joint damage in the collagen-induced arthritis mouse model. Our study indicates that targeting the PDI-ADAM17 signaling module to regulate the shedding of cytokine receptors by the chemical approach constitutes a promising strategy for alleviating RA.

Efficacy and safety of Huachansu combined with adjuvant chemotherapy in resected colorectal cancer patients: a prospective, open-label, randomized phase II study.

Although some studies in China have suggested Huachansu (HCS) combined with chemotherapy is effective in the treatment of various cancers, there are few studies on colorectal cancer (CRC), especially in postoperative adjuvant chemotherapy. The aim of this study was to test the hypothesis that HCS combined with adjuvant chemotherapy would improve survival probability in resected CRC patients. This was a prospective, open-label, randomized phase II study. Patients with stage III or high-risk stage II resected CRC were randomly assigned to the chemotherapy and HCS + chemotherapy groups. The Chemotherapy group was treated with the FOLFOX regimen for ≥ 6 cycles or the CAPEOX regimen for ≥ 4 cycles. The HCS + chemotherapy group was treated with HCS on the basis of the chemotherapy group. The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints were 3-year overall survival (OS) and toxicity. A total of 250 patients were included in this study (126 chemotherapy, 124 HCS + chemotherapy). There were significant differences in 3-year DFS between the two groups (median 28.7 vs. 31.6 months, respectively; P = 0.027), but no significant differences in 3-year OS between the two groups (median 32.7 vs. 34 months, respectively; P = 0.146). No patients experienced grade four adverse events, and the rates of leukopenia, neutropenia, and diarrhea in the HCS + chemotherapy group were lower than that those in the chemotherapy group. HCS combined with adjuvant chemotherapy after radical resection for patients with stage III or high-risk stage II CRC was demonstrated to be an effective and feasible treatment.

ID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer.

Elimination of cancer stem cells (CSCs) and reinvigoration of antitumor immunity remain unmet challenges for cancer therapy. Tumor-associated macrophages (TAMs) constitute the prominant population of immune cells in tumor tissues, contributing to the formation of CSC niches and a suppressive immune microenvironment. Here, we report that high expression of inhibitor of differentiation 1 (ID1) in TAMs correlates with poor outcome in patients with colorectal cancer (CRC). ID1 expressing macrophages maintain cancer stemness and impede CD8+ T cell infiltration. Mechanistically, ID1 interacts with STAT1 to induce its cytoplasmic distribution and inhibits STAT1-mediated SerpinB2 and CCL4 transcription, two secretory factors responsible for cancer stemness inhibition and CD8+ T cell recruitment. Reducing ID1 expression ameliorates CRC progression and enhances tumor sensitivity to immunotherapy and chemotherapy. Collectively, our study highlights the pivotal role of ID1 in controlling the protumor phenotype of TAMs and paves the way for therapeutic targeting of ID1 in CRC.

Changes in the structure and hydration properties of high-temperature peanut protein induced by cold plasma oxidation.

To improve the hydration properties of high-temperature pressed peanut protein isolate (HPPI), we investigated the effect of cold plasma (CP) oxidation on functional and structural properties. Compared to HPPI, the hydrated molecules number and the surface contact angle were significantly decreased at 70 W, from 77.2 × 109 to 17.7 × 109 and from 85.74° to 57.81°, respectively. The reduction of the sulfhydryl content and the increase of the disulfide bond and di-tyrosine content indicated that the structural transformation was affected by the oxidation effect. In terms of structural changes, a stretched tertiary structure, ordered secondary structure, and rough apparent structure were observed after CP treatment. Additionally, the enhancement of surface free energy and group content such as -COOH, -CO and -OH on the surface of HPPI contributed to the formation of hydrated crystal structures. In general, the oxidation effect of CP effectively improved the hydration properties of HPPI and broaden its application field.

Bioremediation of environmental organic pollutants by Pseudomonas aeruginosa: Mechanisms, methods and challenges.

The development of the chemical industry has led to a boom in daily consumption and convenience, but has also led to the release of large amounts of organic pollutants, such as petroleum hydrocarbons, plastics, pesticides, and dyes. These pollutants are often recalcitrant to degradation in the environment, whereby the most problematic compounds may even lead to carcinogenesis, teratogenesis and mutagenesis in animals and humans after accumulation in the food chain. Microbial degradation of organic pollutants is efficient and environmentally friendly, which is why it is considered an ideal method. Numerous studies have shown that Pseudomonas aeruginosa is a powerful platform for the remediation of environmental pollution with organic chemicals due to its diverse metabolic networks and its ability to secrete biosurfactants to make hydrophobic substrates more bioavailable, thereby facilitating degradation. In this paper, the mechanisms and methods of the bioremediation of environmental organic pollutants (EOPs) by P. aeruginosa are reviewed. The challenges of current studies are highlighted, and new strategies for future research are prospected. Metabolic pathways and critical enzymes must be further deciphered, which is significant for the construction of a bioremediation platform based on this powerful organism.

Strontium Attenuates Hippocampal Damage via Suppressing Neuroinflammation in High-Fat Diet-Induced NAFLD Mice.

Non-alcoholic fatty liver disease (NAFLD) leads to hippocampal damage and causes a variety of physiopathological responses, including the induction of endoplasmic reticulum stress (ERS), neuroinflammation, and alterations in synaptic plasticity. As an important trace element, strontium (Sr) has been reported to have antioxidant effects, to have anti-inflammatory effects, and to cause the inhibition of adipogenesis. The present study was undertaken to investigate the protective effects of Sr on hippocampal damage in NAFLD mice in order to elucidate the underlying mechanism of Sr in NAFLD. The mouse model of NAFLD was established by feeding mice a high-fat diet (HFD), and the mice were treated with Sr. In the NAFLD mice, we found that treatment with Sr significantly increased the density of c-Fos+ cells in the hippocampus and inhibited the expression of caspase-3 by suppressing ERS. Surprisingly, the induction of neuroinflammation and the increased expression of inflammatory cytokines in the hippocampus following an HFD were attenuated by Sr treatment. Sr significantly attenuated the activation of microglia and astrocytes induced by an HFD. The expression of phospho-p38, ERK, and NF-κB was consistently significantly increased in the HFD group, and treatment with Sr decreased their expression. Moreover, Sr prevented HFD-induced damage to the ultra-structural synaptic architecture. This study implies that Sr has beneficial effects on repairing the damage to the hippocampus induced by an HFD, revealing that Sr could be a potential candidate for protection from neural damage caused by NAFLD.

TRIB3 promotes pulmonary fibrosis through inhibiting SLUG degradation by physically interacting with MDM2.

Pulmonary fibrosis (PF) is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration (LAR). Here, we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells (AEC2s). The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells (AEC1s). We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s, which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK, two critical kinases supporting LAR, leading to LAR failure. TRIB3, a stress sensor, interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination. Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF. Our study reveals a mechanism of the TRIB3-MDM2-SLUG-SLC34A2 axis causing the LAR failure in PF, which confers a potential strategy for treating patients with fibroproliferative lung diseases.

Clinical features and surgical outcomes of Rathke cleft cysts with suprasellar components: a single-center experience of 157 cases.

BACKGROUND: Both intrasuprasellar and suprasellar Rathke cleft cysts (RCCs) have suprasellar components, and we aimed to explore their clinical features and surgical outcomes. METHOD: Patients with surgically treated intrasuprasellar or suprasellar RCCs were retrospectively analyzed. All patients with intrasuprasellar RCCs were treated with the standard endoscopic endonasal approach (EEA, group I); the patients with suprasellar RCCs received the extended EEA (group II) or supraorbital keyhole approach (SKA, group III) according to the relevant indications. A surgical strategy of maximal safe resection aiming to protect neuroendocrine function was adopted. In addition, patients (distinguished from the above 3 groups) who had aggressive resection of suprasellar RCC were also enrolled for comparison of different surgical strategies. RESULTS: A total of 157 patients were eligible, including 121 patients with intrasuprasellar RCCs in group I, 19 patients with suprasellar RCCs in group II, and 17 patients with suprasellar RCCs in group III. Preoperatively, the patients with suprasellar RCC (groups II and III) more commonly presented with visual dysfunction, diabetes insipidus (DI), and hyperprolactinemia than the patients with intrasuprasellar RCCs (all p<0.05). A higher incidence of hypopituitarism and a larger diameter were observed for intrasuprasellar RCCs (both p<0.05). Postoperatively, group II had a higher rate of new-onset DI, hyponatremia, and recurrence than group I (all p<0.025) and similar outcomes to group III. For suprasellar RCCs, comparison of the maximal safe resection vs. aggressive resection (supplementary patients: 14 with extended EEA, 12 with SKA) showed similar improvement and recurrence, with higher rates of DI and hyponatremia with the latter strategy (all p<0.05). CONCLUSIONS: Suprasellar RCC is associated with more complicated preoperative presentations, intricate postoperative complications, and frequent recurrence compared with intrasuprasellar RCC. Under rational indications, both extended EEA and SKA achieve satisfactory outcomes. The strategy of maximal safe resection is recommended for greatest functional preservation.

Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy.

Aberrant mitophagy has been identified as a driver for energy metabolism disorder in most cardiac pathological processes. However, finding effective targeted agents and uncovering their precise modulatory mechanisms remain unconquered. Fuzi, the lateral roots of Aconitum carmichaelii, shows unique efficacy in reviving Yang for resuscitation, which has been widely used in clinics. As a main cardiotonic component of Fuzi, mesaconine has been proven effective in various cardiomyopathy models. Here, we aimed to define a previously unrevealed cardioprotective mechanism of mesaconine-mediated restoration of obstructive mitophagy. The functional implications of mesaconine were evaluated in doxorubicin (DOX)-induced heart failure models. DOX-treated mice showed characteristic cardiac dysfunction, ectopic myocardial energy disorder, and impaired mitophagy in cardiomyocytes, which could be remarkably reversed by mesaconine. The cardioprotective effect of mesaconine was primarily attributed to its ability to promote the restoration of mitophagy in cardiomyocytes, as evidenced by elevated expression of PINK1, a key mediator of mitophagy induction. Silencing PINK1 or deactivating mitophagy could completely abolish the protective effects of mesaconine. Together, our findings suggest that the cardioprotective effects of mesaconine appear to be dependent on the activation of PINK1-induced mitophagy and that mesaconine may constitute a promising therapeutic agent for the treatment of heart failure.

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Inhibitors of CDK8 for the Treatment of Cancer.

Cyclin-dependent kinase 8 (CDK8), as a kinase subunit of the Mediator complex, is involved in the regulation of RNA polymerase II-mediated transcription, thereby modulating multiple signaling pathways and multiple transcription factors involved in oncogenic control. CDK8 deregulation has been implicated in human diseases, particularly in acute myeloid leukemia (AML) and advanced solid tumors, where it has been reported as a putative oncogene. Here, we report the successful optimization of an azaindole series of CDK8 inhibitors that were identified and further progressed through a structure-based generative chemistry approach. In several optimization cycles, we improved in vitro microsomal stability, kinase selectivity, and in vivo pharmacokinetic profile cross-species, leading to the discovery of compound 23, which demonstrated robust tumor growth inhibition in multiple in vivo efficacy models after oral administration.