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Large mesopores of chiral silica nanoparticles applied as drug carrier are worth studying. In this study, chiral mesoporous silica nanoparticles (CMSN) and enlarged chiral mesoporous silica nanoparticles (E-CMSN) with a particle size from 200 to 300 nm were synthesized. Fourier transform infrared spectrometer (FTIR), circular dichroism spectrum, scanning electron microscopy (SEM), transmission electron microscope (TEM), and nitrogen adsorption/desorption measurement were adopted to explore their characteristics. The results showed that the surface area, pore volume, and pore diameter of E-CMSN were higher than those of CMSN due to enlarged mesopores. Poorly water-soluble drug nimesulide (NMS) was taken as the model drug and loaded into carriers using adsorption method. After NMS was loaded into CMSN and E-CMSN, most crystalline NMS converted to amorphous phase and E-CMSN was superior. The anti-inflammatory pharmacodynamics and in vivo pharmacokinetics results were consistent with the wetting property and in vitro drug dissolution results, verifying that NMS/E-CMSN exhibited superior NMS delivery system based on its higher oral relative bioavailability and anti-inflammatory effect because its enlarge mesopores contributed to load and release more amorphous NMS. The minor variations in the synthesis process contributed to optimize the chiral nano-silica drug delivery system.

Anti-PD1 therapies are primarily thought to rely on functional T cell responses; yet tumors with limited T cell infiltration can still benefit, suggesting alternative mechanisms contribute to therapeutic efficacy. Indeed, we found that myeloid-rich, T cell-poor tumor models respond to anti-Pd1, and this is dependent on a cancer cell-macrophage crosstalk mediated by cancer cell expression. Mechanistically, we found that cancer cells with decreased expression (C ), which occurs in ∼50% of all human cancers, reorganize zinc compartmentalization by upregulating the zinc importer Slc39a9 at the plasma membrane. Increased cancer cell plasma membrane Slc39a9 leads to intracellular zinc accumulation in cancer cells and depletion of zinc in the tumor microenvironment (TME), resulting in zinc-starved tumor-associated macrophages (TAMs) with reduced phagocytic activity. Restoring zinc availability in TAMs-via dietary supplementation or Slc39a9 knockdown in cancer cells-reprograms TAMs to a pro-phagocytic state and sensitizes tumors to anti-Pd1 therapy. Remarkably, Slc39a9 knockdown tumors respond to anti-Pd1 in Rag1 mice, and co-injection of zinc-replete macrophages is sufficient to drive an anti-Pd1 response in immunodeficient mice, demonstrating the T cell-independent nature of this response. Clinically, TAMs from cancer patients show reduced zinc and phagocytosis gene signatures. Moreover, patients with lower circulating zinc levels have significantly worse time-to-event outcomes than those with higher levels. Together, these findings uncover a previously unrecognized mechanism by which cancer cells outcompete TAMs for zinc, impairing their function and limiting anti-Pd1 efficacy. They also provide evidence that macrophages alone, without T cells, can enhance anti-PD1 response through zinc-mediated reprogramming of phagocytosis.

DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback mechanisms. Key mediators of the DNA damage response and cellular metabolic regulation include Ataxia Telangiectasia and Rad3-related protein (ATR) and the mechanistic Target of Rapamycin Complex 1 (mTORC1), respectively. Previous studies have established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms by which mTORC1 is activated in this context remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. Here, we demonstrate that ATR promotes mTORC1 activity across various cellular models under basal conditions. This effect is particularly enhanced in cells following the loss of p16, which we have previously associated with hyperactivation of mTORC1 signaling and here found have increased ATR activity. Mechanistically, we found that ATR promotes cholesterol synthesis and mTORC1 activation through the upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Furthermore, the attenuation of mTORC1 activity resulting from ATR inhibition was rescued by supplementation with lanosterol or cholesterol in multiple cellular contexts. This restoration corresponded with enhanced localization of mTOR to the lysosome. Collectively, our findings demonstrate a novel connection linking ATR and mTORC1 signaling through the modulation of cholesterol metabolism.

Cellular senescence, characterized by a stable cell cycle arrest, is a well-documented consequence of several widely used chemotherapeutics that has context-dependent roles in cancer. Although senescent cells are non-proliferative, they remain biologically active and secrete a complex and diverse array of factors collectively known as the senescence-associated secretome (SAS), which exerts pro-tumorigenic effects. Here, we aimed to mechanistically investigate how the SAS contributes to metastatic dissemination of high grade serous ovarian cancer (HGSOC) using standard-of-care cisplatin as a senescence inducer. Our findings demonstrate that the cisplatin-induced SAS enhances the dissemination of HGSOC without affecting cell proliferation or viability. We found that the SAS facilitates cell detachment, an effect that is mediated by a metabolic component. Using a metabolically focused CRISPR knockout screen, we identified complex I as the key driver of SAS-mediated cell detachment in bystander cells and validated that inhibition of complex I activity decreases HGSOC dissemination . Mechanistically, this effect was driven by SAS-mediated inhibition of an NAD -SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. Excitingly, we found that fructose is the key SAS component upstream of the NAD -SIRT-SREBP-cholesterol axis mediating increased detachment of bystander cells, and a high fructose diet increases HGSOC dissemination . These findings reveal that the cisplatin-induced SAS reprograms the metabolic microenvironment in HGSOC, driving cancer cell detachment and promoting metastatic dissemination in a paracrine fashion. They also point to a previously unrecognized pro-tumorigenic effect of the SAS that may contribute to the high recurrence rate of HGSOC patients.

Approximately 50% of cancers exhibit decreased CDKN2A expression ( CDKN2A Low ), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2A Low cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved tumor-associated macrophages (TAMs), leading to reduced phagocytic activity. Increasing zinc in TAMs through multiple approaches, including a dietary intervention that increases availability of TME zinc, re-educates these TAMs to a pro-phagocytic phenotype. Remarkably, both knockdown of Slc39a9 in cancer cells or providing a high zinc diet sensitizes Cdkn2a Low tumors to ICB. TAMs, not T cells, are indispensable for ICB response. Clinically, TAMs from CDKN2A Low cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2A Low cancer cells outcompete TAMs for zinc, directly disrupting their function and ICB efficacy.Approximately 50% of cancers exhibit decreased CDKN2A expression ( CDKN2A Low ), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2A Low cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved tumor-associated macrophages (TAMs), leading to reduced phagocytic activity. Increasing zinc in TAMs through multiple approaches, including a dietary intervention that increases availability of TME zinc, re-educates these TAMs to a pro-phagocytic phenotype. Remarkably, both knockdown of Slc39a9 in cancer cells or providing a high zinc diet sensitizes Cdkn2a Low tumors to ICB. TAMs, not T cells, are indispensable for ICB response. Clinically, TAMs from CDKN2A Low cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2A Low cancer cells outcompete TAMs for zinc, directly disrupting their function and ICB efficacy.

Approximately 50% of cancers exhibit decreased CDKN2A expression (CDKN2ALow), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2ALow cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved macrophages, leading to reduced phagocytic activity. Remarkably, restoring zinc levels in the TME through a dietary intervention re-educates macrophages to a pro-phagocytic phenotype, sensitizing CDKN2ALow tumors to ICB. Unexpectedly, T cells are not required for this response. Clinically, macrophages from CDKN2ALow cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2ALow cancer cells outcompete macro-phages for zinc, directly disrupting their function and ICB efficacy.Competing Interest StatementThe authors have declared no competing interest.

ObjectivesTo determine the clinical features and course of thyroid-associated ophthalmopathy (TAO) in a large sample of Chinese patients.Design and methodsWe retrospectively identified a cohort of consecutive patients diagnosed with TAO at the West China Hospital from October 1, 2009 to October 1, 2019. We analysed clinical data from 3620 patients, including demographic data, clinical manifestations, ophthalmology examinations, and prognosis.ResultsTAO most frequently occurred with hyperthyroidism, with most patients developing TAO after thyroid disease (TD). The TAO phenotype was asymmetric in 375 (50.7%) euthyroid patients, 25 (27.8%) hypothyroid patients, and 314 (12.1%) hyperthyroid patients (p < 0.0001). The most frequent symptom was lid lag and the most commonly involved extraocular muscle was the inferior rectus. Severity assessment (NOSPECS score) and clinical activity assessment (Clinical Activity Scores, CAS) differed significantly between male and female patients (P < 0.000). The majority (88.8%) of patients had clinically inactive TAO, and only 3.2% of cases were sight-threatening. Regarding the clinical process, 75.5% of patients had an active phase time less than 12 months and 2.1% showed complete remission.ConclusionsTAO most commonly develops in females and is closely related to hyperthyroidism. Euthyroid TAO often has an asymmetric clinical phenotype. CAS combined with magnetic resonance imaging can improve the detection of TAO. NOSPECS scores should be slightly refined regarding the criteria for corneal involvement. Clinical management of TAO should be individualized according to CAS or NOSPECS assessments and a multidisciplinary approach is paramount. A minority of patients showed complete remission.

Background Acetyl-CoA is an important metabolic intermediate and serves as an acetylation precursor for the biosynthesis of various value-added acetyl-chemicals. Acetyl-CoA can be produced from glucose, acetate, or fatty acids via metabolic pathways in Escherichia coli . Although glucose is an efficient carbon source for acetyl-CoA production, the pathway from acetate to acetyl-CoA is the shortest and fatty acids can produce acetyl-CoA through fatty acid oxidation along with abundant NADH and FADH 2 . In this study, metabolically engineered E. coli strains for efficiently supplying acetyl-CoA from glucose, acetate, and fatty acid were constructed and applied in one-step biosynthesis of N -acetylglutamate (NAG) from glutamate and acetyl-CoA. Results A metabolically engineered E. coli strain for NAG production was constructed by overexpressing N -acetylglutamate synthase from Kitasatospora setae in E. coli BW25113 with argB and argA knockout. The strain was further engineered to utilize glucose, acetate, and fatty acid to produce acetyl-CoA. When glucose was used as a carbon source, the combined mutants of ∆ ptsG::glk , ∆ galR::zglf , ∆ poxB::acs , ∆ ldhA , and ∆ pta were more efficient for supplying acetyl-CoA. The acetyl-CoA synthetase (ACS) pathway and acetate kinase-phosphate acetyltransferase (ACK-PTA) pathway from acetate to acetyl-CoA were investigated, and the ACK-PTA pathway showed to be more efficient for supplying acetyl-CoA. When fatty acid was used as a carbon source, acetyl-CoA supply was improved by deletion of fadR and constitutive expression of fadD under the strong promoter CPA1. Comparison of acetyl-CoA supply from glucose, acetate and palmitic acid revealed that a higher conversion rate of glutamate (98.2%) and productivity (an average of 6.25 mmol/L/h) were obtained when using glucose as a carbon source. The results also demonstrated the great potential of acetate and fatty acid to supply acetyl-CoA, as the molar conversion rate of glutamate was more than 80%. Conclusions Metabolically engineered E. coli strains were developed for NAG production. The metabolic pathways of acetyl-CoA from glucose, acetate, or fatty acid were optimized for efficient acetyl-CoA supply to enhance NAG production. The metabolic strategies for efficient acetyl-CoA supply used in this study can be exploited for other chemicals that use acetyl-CoA as a precursor or when acetylation is involved.

Super enhancers are a unique class of enhancers that possess a distinct structure and mechanism, which enable them to exhibit stronger gene transcription regulatory function than classical enhancers, thereby regulating cellular activities. In tumor samples, super enhancers have been identified as crucial players in the development and progression of tumor cells, opening up new avenues for cancer research and treatment. This review provides a concise overview of various models regarding super enhancer assembly and activation, examining the mechanisms through which tumor cells acquire or activate these enhancers and regulate carcinogenic transcription programs. Furthermore, we discuss the current landscape and challenges in developing cancer therapeutic drugs that target super enhancers.

Unnatural chiral α-tertiary amino acids containing two different carbon-based substituents at the α-carbon centre are widespread in biologically active molecules. This sterically rigid scaffold is becoming a growing research interest in drug discovery. However, a robust protocol for chiral α-tertiary amino acid synthesis remains scarce due to the challenge of stereoselectively constructing sterically encumbered tetrasubstituted stereogenic carbon centres. Herein we report a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides, including alkyl iodides, alkyl bromides and alkyl chlorides, enabling the formation of chiral α-tertiary amino esters with a high level of enantioselectivity and excellent functional group tolerance. Primary, secondary and tertiary organoelectrophiles are all tolerated in this asymmetric reductive addition protocol, which provides a complementary method for the well-exploited enantioselective nucleophilic addition with moisture- and air-sensitive organometallic reagents. Moreover, the three-component transformation of α-ketoester, amine and alkyl halide represents a formal asymmetric deoxygenative alkylamination of the carbonyl group. Robust protocols for the synthesis of chiral α-tertiary amino acids remain scarce due to the challenge of constructing congested tetrasubstituted stereocentres. Now a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides has been developed, forming diverse chiral α-tertiary amino esters with high enantioselectivity and excellent functional group tolerance.