1,5-Hydrogen atom transfer of α-iminyl radical cations: a new platform for relay annulation for pyridine derivatives and axially chiral heterobiaryls.

The exploitation of new reactive species and novel transformation modes for their synthetic applications have significantly promoted the development of synthetic organic methodology, drug discovery, and advanced functional materials. α-Iminyl radical cations, a class of distonic ions, exhibit great synthetic potential for the synthesis of valuable molecules. For their generation, radical conjugate addition to α,ß-unsaturated iminium ions represents a concise yet highly challenging route, because the in situ generated species are short-lived and highly reactive and they have a high tendency to cause radical elimination (ß-scission) to regenerate the more stable iminium ions. Herein, we report a new transformation mode of the α-iminyl radical cation, that is to say, 1,5-hydrogen atom transfer (1,5-HAT). Such a strategy can generate a species bearing multiple reactive sites, which serves as a platform to realize (asymmetric) relay annulations. The present iron/secondary amine synergistic catalysis causes a modular assembly of a broad spectrum of new structurally fused pyridines including axially chiral heterobiaryls, and exhibits good functional group tolerance. A series of mechanistic experiments support the α-iminyl radical cation-induced 1,5-HAT, and the formation of several radical species in the relay annulations. Various synthetic transformations of the reaction products demonstrate the usefulness of this relay annulation protocol for the synthesis of significant molecules.

Correction: Zhao et al. Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN). Cells 2020, 9, 559.

In the original publication [...].

Investigative biological therapies for primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease characterized by dryness of the eyes and mouth. The histological feature is mononuclear cell infiltration in exocrine glands, primarily salivary and lachrymal glands. As the disease progresses, some other tissues and organs may be involved and extraglandular manifestations ensue. The major current treatments are palliative and empirical, and in most cases the outcomes are not satisfactory. Emerging data indicate a critical role of lymphocytes in its development and progression. While pioneering work targeting B cells has demonstrated some encouraging results, more trials are warranted to validate the safety and efficacy. In addition, modulation of T cell function with abatacept ameliorates the severity of pSS. Furthermore, clinical trials to inhibit important cytokines involved in its formation have been carried out. In this article, we summarize and compare current biological therapies in order to find new and effective treatments for pSS.

Unexpected thermal transport properties of MgSiO3monolayer at extreme conditions.

The thermal transport properties of mantle minerals are of paramount importance to understand the thermal evolution processes of the Earth. Here, we perform extensively structural searches of two-dimensional MgSiO3monolayer by CALYPSO method and first-principles calculations. A stable MgSiO3monolayer withPmm2 symmetry is uncovered, which possesses a wide indirect band gap of 4.39 eV. The calculations indicate the lattice thermal conductivities of MgSiO3monolayer are 49.86 W (mK)-1and 9.09 W (mK)-1inxandydirections at room temperature. Our findings suggest that MgSiO3monolayer is an excellent low-dimensional thermoelectric material with highZTvalue of 4.58 from n-type doping in theydirection at 2000 K. The unexpected anisotropic thermal transport of MgSiO3monolayer is due to the puckered crystal structure and the asymmetric phonon dispersion as well as the distinct electron states around the Fermi level. These results offer a detailed description of structural and thermal transport properties of MgSiO3monolayer at extreme conditions.

Interplay of IL-17A/IL-17RA signaling with microbial homeostasis in systemic anti-tumoral responses.

Enteric IL-17RA deficiency leads to gut dysbiosis, consequently initiating the proliferation of tumors at remote locations. The deficiency or blockade of enteric IL-17RA induces the secretion of IL-17A by B cells and Th17 cells in response to microbial signals, resulting in a systemic elevation of IL-17A and fostering the growth of remote tumors. This figure was created with BioRender.com.

Intranasal Delivery of Curcumin Nanoparticles Improves Neuroinflammation and Neurological Deficits in Mice with Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) represents one of the most severe subtypes of stroke. Due to the complexity of the brain injury mechanisms following ICH, there are currently no effective treatments to significantly improve patient functional outcomes. Curcumin, as a potential therapeutic agent for ICH, is limited by its poor water solubility and oral bioavailability. In this study, mPEG-PCL is used to encapsulate curcumin, forming curcumin nanoparticles, and utilized the intranasal administration route to directly deliver curcumin nanoparticles from the nasal cavity to the brain. By inhibiting pro-inflammatory neuroinflammation of microglia following ICH in mice, reprogramming pro-inflammatory microglia toward an anti-inflammatory function, and consequently reducing neuronal inflammatory death and hematoma volume, this approach improved blood-brain barrier damage in ICH mice and promoted the recovery of neurological function post-stroke. This study offers a promising therapeutic strategy for ICH to mediate neuroinflammatory microenvironments.

Evaluation of canine adipose-derived mesenchymal stem cells for neurological functional recovery in a rat model of traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a common condition in veterinary medicine that is difficult to manage.Veterinary regenerative therapy based on adipose mesenchymal stem cells seem to be an effective strategy for the treatment of traumatic brain injury. In this study, we evaluated therapeutic efficacy of canine Adipose-derived mesenchymal stem cells (AD-MSCs)in a rat TBI model, in terms of improved nerve function and anti-neuroinflammation. RESULTS: Canine AD-MSCs promoted neural functional recovery, reduced neuronal apoptosis, and inhibited the activation of microglia and astrocytes in TBI rats. According to the results in vivo, we further investigated the regulatory mechanism of AD-MSCs on activated microglia by co-culture in vitro. Finally, we found that canine AD-MSCs promoted their polarization to the M2 phenotype, and inhibited their polarization to the M1 phenotype. What's more, AD-MSCs could reduce the migration, proliferation and Inflammatory cytokines of activated microglia, which is able to inhibit inflammation in the central system. CONCLUSIONS: Collectively, the present study demonstrates that transplantation of canine AD-MSCs can promote functional recovery in TBI rats via inhibition of neuronal apoptosis, glial cell activation and central system inflammation, thus providing a theoretical basis for canine AD-MSCs therapy for TBI in veterinary clinic.

A Targeted and Responsive Nanoprodrug Delivery System for Synergistic Glioma Chemotherapy.

Doxorubicin (DOX) is widely used as a chemotherapeutic agent for both hematologic and solid tumors and is a reasonable candidate for glioma treatment. However, its effectiveness is hindered by significant toxicity and drug resistance. Moreover, the presence of the blood-brain barrier (BBB) brings a crucial challenge to glioma therapy. In response, a GSH-responsive and actively targeted nanoprodrug delivery system (cRGD/PSDOX-Cur@NPs) are developed. In this system, a disulfide bond-bridged DOX prodrug (PEG-SS-DOX) is designed to release specifically in the high glutathione (GSH) tumor environment, markedly reducing the cardiotoxicity associated with DOX. To further address DOX resistance, curcumin, serving as a P-glycoprotein (P-gp) inhibitor, effectively increased cellular DOX concentration. Consequently, cRGD/PSDOX-Cur@NPs exhibited synergistic anti-tumor effects in vitro. Furthermore, in vivo experiments validated the superior BBB penetration and brain-targeting abilities of cRGD/PSDOX-Cur@NPs, showcasing the remarkable potential for treating both subcutaneous and orthotopic gliomas. This research underscores that this nanoprodrug delivery system presents a novel approach to inhibiting glioma while addressing resistance and systemic toxicity.

Sesquiterpenoids and Cytochalasins with Immunosuppressive Activity from Sonchus wightianus.

The plant species, Sonchus wightianus DC., was historically used in China for both medicinal and dietary uses. In present study, seven new guaiane sesquiterpenoids (1-7) and one cytochalasin (8), along with five known guaianes (9-13) and two known cytochalasins (14 and 15), were isolated from the whole plants of S. wightianus. These guaianes showed structural variations in the substituents at C-8 and/or C-15, and compounds 6 and 7 are two sesquiterpenoid glycoside derivatives. Their structures were determined by extensive analysis of spectroscopic, electronic circular dichroism, and X-ray diffraction data, and chemical method. Biological tests revealed that compounds 5 and 8 are potent and selective immunosuppressive reagents.

Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy.

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor (iPDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of pIL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation, macrophage polarization and DC maturation. The F-DPC/pIL-12/iPDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/pIL-12/iPDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

Molecular network analysis of 308 newly diagnosed HIV infection and 210 ART failure patients from rural counties in Sichuan.

BACKGROUND: Few studies on molecular epidemiology have studied people with newly diagnosed HIV infection and ART Failure Patients at the same time in rural China. With more serious HIV epidemic than in other provinces in China, Sichuan is an area suitable for this study. OBJECTIVE: To analyze the characteristics of HIV-1 molecular networks and factors related to network entry among newly diagnosed HIV infection and ART Failure Patients in three county-level cities (A, B, C) in Sichuan Province, to provide scientific basis for accurate prevention and control. METHODS: Nested PCR amplification method was used to amplify HIV-1 pol gene region of 530 blood samples, Sequencer 4.9 was used to edit, clean and splice the gene sequence, Bioedit correction, Fastree 2.1.8 and Figtree 1.4.2 to construct evolutionary tree and determine genotype. HyPhy2.2.4 and Cytoscape 3.6.1 software were used to construct molecular network. Logistic regression analysis was applied. RESULTS: 523(98.68%) pol sequences were obtained, and a total of 518 valid sequences with basic information came into the final analyses. A total of 6 genotypes were detected, namely CRF01_AE (320,61.78%), CRF07_BC (149,28.76%), B (30,5.79%), CRF08_BC (11, 2.12%), CRF55_01B (6, 1.16%) and C (2, 0.39%). 186 of 518(35.91%) sequences entered the network at a genetic distance of 0.8%, forming 42 propagation clusters. "High-risk transmitters"(connected with two and more) accounted for 21.62%. Logistic regression showed that≥50 years old (OR = 2.474) were more risky than 18-49 years old, CRF07_BC sub-type (OR = 0.174) were less risky than CRF01_AE sub-type, B sub-type (OR = 6.698) is higher risky than CRF01_AE sub-type, and District B (OR = 0.077) less risky than that of A city. CONCLUSION: The sources of HIV infection in rural Sichuan are diversified and complicated. The prevention and control of HIV infection in Sichuan Province should focus on strengthening the long-term dynamic detection of elderly population, B strain sub-type, and in City A.

Transcription factor ATMIN facilitates chemoresistance in nasopharyngeal carcinoma.

Despite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients' survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC.

Modular Assembly of 2-Aminoaniline Derivatives by Merging Hydroxylamine-Passerini and Hetero-Cope Rearrangement.

A metal-free three-component protocol that combines a hydroxylamine-Passerini reaction and hetero-Cope rearrangement was realized, which enables the modular assembly of a wide range of structurally new and interesting 2-aminoanilines bearing an α-hydroxyamide substructure.

The E3 ligase NEURL3 suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma by promoting vimentin degradation.

BACKGROUND: Metastasis has emerged as the major reason of treatment failure and mortality in patients with nasopharyngeal carcinoma (NPC). Growing evidence links abnormal DNA methylation to the initiation and progression of NPC. However, the precise regulatory mechanism behind these processes remains poorly understood. METHODS: Bisulfite pyrosequencing, RT-qPCR, western blot, and immunohistochemistry were used to test the methylation and expression level of NEURL3 and its clinical significance. The biological function of NEURL3 was examined both in vitro and in vivo. Mass spectrometry, co-immunohistochemistry, immunofluorescence staining, and ubiquitin assays were performed to explore the regulatory mechanism of NEURL3. RESULTS: The promoter region of NEURL3, encoding an E3 ubiquitin ligase, was obviously hypermethylated, leading to its downregulated expression in NPC. Clinically, NPC patients with a low NEURL3 expression indicated an unfavorable prognosis and were prone to develop distant metastasis. Overexpression of NEURL3 could suppress the epithelial mesenchymal transition and metastasis of NPC cells in vitro and in vivo. Mechanistically, NEURL3 promoted Vimentin degradation by increasing its K48-linked polyubiquitination at lysine 97. Specifically, the restoration of Vimentin expression could fully reverse the tumor suppressive effect of NEURL3 overexpression in NPC cells. CONCLUSIONS: Collectively, our study uncovers a novel mechanism by which NEURL3 inhibits NPC metastasis, thereby providing a promising therapeutic target for NPC treatment.

Tumor-Microenvironment-Activatable Nanoparticle Mediating Immunogene Therapy and M2 Macrophage-Targeted Inhibitor for Synergistic Cancer Immunotherapy.

Immunotherapy has achieved prominent clinical efficacy in combating cancer and has recently become a mainstream treatment strategy. However, achieving broad efficacy with a single modality is challenging, and the heterogeneity of the tumor microenvironment (TME) restricts the accuracy and effectiveness of immunotherapy strategies for tumors. Herein, a TME-responsive targeted nanoparticle to enhance antitumor immunity and reverse immune escape by codelivering interleukin-12 (IL-12) expressing gene and colony-stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (PLX) is presented. The introduction of disulfide bonds and cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGD) peptides conferred reduction reactivity and tumor targeting to the nanoparticles, respectively. It is hypothesized that activating host immunity by the local expression of IL-12, while modulating the tumor-associated macrophages (TAM) function through blocking CSF-1/CSF-1R signaling, could constitute a feasible approach for cancer immunotherapy. The fabricated functional nanoparticle successfully ameliorated the TME by stimulating the proliferation and activation of T lymphocytes, promoting the repolarization of TAMs, reducing myeloid-derived suppressor cells (MDSCs), and promoting the maturation of dendritic cells (DC) as well as the secretion of antitumor cytokines, which efficiently suppressed tumor growth and metastasis. Finally, substantial changes in the TME were deciphered by single-cell analysis including infiltration of different cells, transcriptional states, secretory signaling and cell-cell communications. These findings provide a promising combinatorial immunotherapy strategy through immunomodulatory nanoparticles.

Reversible SAHH inhibitor ameliorates MIA-induced osteoarthritis of rats through suppressing MEK/ERK pathway.

Osteoarthritis (OA) is characterized by gradual articular cartilage degradation, accompanied by persistent low-grade joint inflammation, correlating with radiographic and pain-related progression. The latent therapeutic potential of DZ2002, a reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH), holds promise for OA intervention. This study endeavored to examine the therapeutic efficacy of DZ2002 within the milieu of OA. The cytotoxicity of DZ2002 was evaluated using the MTT assay on bone marrow-derived macrophages. The inhibitory impact of DZ2002 during the process of osteoclastogenesis was assessed using TRAP staining, analysis of bone resorption pits, and F-actin ring formation. Mechanistic insights were derived from qPCR and Western blot analyses. Through the intra-articular injection of monosodium iodoacetate (MIA), an experimental rat model of OA was successfully instituted. This was subsequently accompanied by a series of assessments including Von Frey filament testing, analysis of weight-bearing behaviors, and micro-CT imaging, all aimed at assessing the effectiveness of DZ2002. The findings emphasized the effectiveness of DZ2002 in mitigating osteoclastogenesis induced by M-CSF/RANKL, evident through a reduction in TRAP-positive OCs and bone resorption. Moreover, DZ2002 modulated bone resorption-associated gene and protein expression (CTSK, CTR, Integrin ß3) via the MEK/ERK pathway. Encouragingly, DZ2002 also alleviates MIA-induced pain, cartilage degradation, and bone loss. In conclusion, DZ2002 emerges as a potential therapeutic contender for OA, as evidenced by its capacity to hinder in vitro M-CSF/RANKL-induced osteoclastogenesis and mitigate in vivo osteoarthritis progression. This newfound perspective provides substantial support for considering DZ2002 as a compelling agent for osteoarthritis intervention.

Nanodelivery Systems as a Novel Strategy to Overcome Treatment Failure of Cancer.

Despite the tremendous progress in cancer treatment in recent decades, cancers often become resistant due to multiple mechanisms, such as intrinsic or acquired multidrug resistance, which leads to unsatisfactory treatment effects or accompanying metastasis and recurrence, ultimately to treatment failure. With a deeper understanding of the molecular mechanisms of tumors, researchers have realized that treatment designs targeting tumor resistance mechanisms would be a promising strategy to break the therapeutic deadlock. Nanodelivery systems have excellent physicochemical properties, including highly efficient tissue-specific delivery, substantial specific surface area, and controllable surface chemistry, which endow nanodelivery systems with capabilities such as precise targeting, deep penetration, responsive drug release, multidrug codelivery, and multimodal synergy, which are currently widely used in biomedical researches and bring a new dawn for overcoming cancer resistance. Based on the mechanisms of tumor therapeutic resistance, this review summarizes the research progress of nanodelivery systems for overcoming tumor resistance to improve therapeutic efficacy in recent years and offers prospects and challenges of the application of nanodelivery systems for overcoming cancer resistance.

DZ2002 alleviates corneal angiogenesis and inflammation in rodent models of dry eye disease via regulating STAT3-PI3K-Akt-NF-κB pathway.

Dry eye disease (DED) is a prevalent ocular disorder with a multifactorial etiology. The pre-angiogenic and pre-inflammatory milieu of the ocular surface plays a critical role in its pathogenesis. DZ2002 is a reversible type III S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, which has shown excellent anti-inflammatory and immunosuppressive activities in vivo and in vitro. In this study, we evaluated the therapeutic potential of DZ2002 in rodent models of DED. SCOP-induced dry eye models were established in female rats and mice, while BAC-induced dry eye model was established in female rats. DZ2002 was administered as eye drops (0.25%, 1%) four times daily (20 µL per eye) for 7 or 14 consecutive days. We showed that topical application of DZ2002 concentration-dependently reduced corneal neovascularization and corneal opacity, as well as alleviated conjunctival irritation in both DED models. Furthermore, we observed that DZ2002 treatment decreased the expression of genes associated with angiogenesis and the levels of inflammation in the cornea and conjunctiva. Moreover, DZ2002 treatment in the BAC-induced DED model abolished the activation of the STAT3-PI3K-Akt-NF-κB pathways in corneal tissues. We also found that DZ2002 significantly inhibited the proliferation, migration, and tube formation of human umbilical endothelial cells (HUVECs) while downregulating the activation of the STAT3-PI3K-Akt-NF-κB pathway. These results suggest that DZ2002 exerts a therapeutic effect on corneal angiogenesis in DED, potentially by preventing the upregulation of the STAT3-PI3K-Akt-NF-κB pathways. Collectively, DZ2002 is a promising candidate for ophthalmic therapy, particularly in treating DED.

Limonoids and alkaloids from Tetradium austrosinense (Hand.-Mazz.) T.G.Hartley.

A pair of new enantiomeric indolopyridoquinazoline-type alkaloids, (+)-1,7S,8R- and (-)-1,7R,8S-trihydroxyrutaecarpine (3a and 3b), and a new limonoid-tyrosamine hybrid, austrosinin (8), along with six known alkaloids and limonoids, were isolated from the stems with leaves of Tetradium austrosinense. Their structures were elucidated on the basis of analysis of MS, NMR, ECD and time-dependent density functional theory-based electronic circular dichroism (TDDFT-ECD) calculations, as well as proposed biosynthetic pathway. An anti-inflammatory bioassay in vitro showed 8 had significant immunosuppressive effect against the production of pro-inflammatory cytokine TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells.

High-grade transformation of head and neck adenoid cystic carcinoma demonstrates distinctive clinicopathological features and an unfavorable prognosis: a matched case-control study of the largest series in China.

PURPOSE: Amidst the rarity of High-grade transformation (HGT) in adenoid cystic carcinoma (ACC), this study offers unprecedented insights into its aggressive nature and clinical implications. METHODS: A 1:1 match comparison between 23 HGT patients and non-HGT counterparts was extracted from 412 ACC cases, focusing on dissecting distinctive clinicopathological features and prognostic outcomes. RESULTS: The predominant sites of HGT were the sinonasal and lacrimal glands (30.4% each). Notably, the solid subtype was the most prevalent pattern within HGT, accounting for 69.6% of cases. Compared to non-HGT, the HGT cohort exhibited significantly higher rates of lymph node metastasis (39.1% vs. 8.7%; P < 0.05), perineural invasion (60.9% vs. 26.1%; P < 0.05), and increased Ki-67 proliferation index (35.0% vs. 10.0%; P < 0.05). Moreover, HGT regions typically showed reduced or absent p63 expression, along with high-grade pathomorphology. HGT was associated with increased recurrence (55.0%) and distant metastasis (78.3%), leading to an average survival of 35.9 months and a 3-years mortality rate of 35.0%. Overall and progression-free survival rates were significantly decreased in the HGT group. CONCLUSION: This study represents the largest single-center cohort of HGT cases to our knowledge, highlighting its frequent occurrence in the sinonasal and lacrimal glands and association with poorer outcomes. The findings support classifying HGT in ACC as Grade 4, reflecting its severity.