Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors.

Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8+ T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8+ T cells, MFN2 enhances mitochondria-endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca2+-ATPase SERCA2, facilitating the mitochondrial Ca2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca2+ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8+ T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8+ T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function.

Constructing spin crossover-fluorescence bifunctional iron(II) complexes based on tetraphenyl ethylene-decorated AIEgens.

Investigating spin crossover (SCO)-fluorescence bifunctional materials and establishing their structure-function relationships are attractive topics in chemistry and materials science. However, it remains challenging to preserve the fluorescence and SCO properties simultaneously in aggregated solid states. Herein, we design an (E)-2,6-bis(1H-pyrazol-1-yl)-4-(4-(1,2,2-triphenylvinyl)styryl)pyridine (tpe-bpp) ligand, which contains coordinated SCO and fluorescence units of an aggregation-induced emission luminogen (AIEgen). The coordination of the tpe-bpp ligand with different FeII salts generated three mononuclear complexes: [Fe(tpe-bpp)2](ClO4)2·5.75CH2Cl2 (1), [Fe(tpe-bpp)2](ClO4)2·CH2Cl2·3CH3OH (2) and [Fe(tpe-bpp)2](BF4)2·CH2Cl2·3CH3OH (3). Single-crystal X-ray diffraction studies showed that they shared a similar [Fe(tpe-bpp)2]2+ complex cation. Their counterions and co-crystallized solvents were different. Magnetic measurements revealed that 1, 2, and 3 exhibited a complete SCO behavior with the transition temperatures T1/2 of 375, 260, and 248 K, respectively. Fluorescence measurements confirmed the existence of the AIE property for both the tpe-bpp ligand and Fe(II) complexes. A monotonic decrease of the photoluminescence (PL) intensity upon increasing the temperature was behavior observed for all three complexes.

A Water-Soluble Hydrogen Sulfide Donor Suppresses the Growth of Hepatocellular Carcinoma via Inhibiting the AKT/GSK-3ß/ß-Catenin and TGF-ß/Smad2/3 Signaling Pathways.

Hepatocellular carcinoma (HCC) is a disease with high morbidity, high mortality, and low cure rate. Hyaluronic acid (HA) is widely adopted in tissue engineering and drug delivery. 5-(4-Hydroxyphenyl)-3H-1, 2-dithiol-3-thione (ADT-OH) is one of commonly used H2S donors. In our previous study, HA-ADT was designed and synthesized via coupling of HA and ADT-OH. In this study, compared with sodium hydrosulfide (NaHS, a fast H2S-releasing donor) and morpholin-4-ium (4-methoxyphenyl)-morpholin-4-ylsulfanylidenesulfido-λ5-phosphane (GYY4137, a slow H2S-releasing donor), HA-ADT showed stronger inhibitory effect on the proliferation, migration, invasion, and cell cycle of human HCC cells. HA-ADT promoted apoptosis by suppressing the expressions of phospho (p)-protein kinase B (PKB/AKT), p-glycogen synthase kinase-3ß (GSK-3ß), p-ß-catenin, and also inhibited autophagy via the downregulation of the protein levels of p-Smad2, p-Smad3, and transforming growth factor-ß (TGF-ß) in human HCC cells. Moreover, HA-ADT inhibited HCC xenograft tumor growth more effectively than both NaHS and GYY4137. Therefore, HA-ADT can suppress the growth of HCC cells by blocking the AKT/GSK-3ß/ß-catenin and TGF-ß/Smad2/3 signaling pathways. HA-ADT and its derivatives may be developed as promising antitumor drugs.

HA-ADT suppresses esophageal squamous cell carcinoma progression via apoptosis promotion and autophagy inhibition.

Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer-related deaths. We have previously connected a non-sulfated glycosaminoglycan, hyaluronic acid (HA), with a common hydrogen sulfide (H2S) donor, 5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-thione (ADT-OH), to reconstruct a novel conjugate, HA-ADT. In this study, we determined the effect of HA-ADT on the growth of ESCC. Our data suggested that HA-ADT exerted more potent effects than sodium hydrosulfide (NaHS, a fast H2S-releasing donor) and morpholin-4-ium (4-methoxyphenyl)-morpholin-4-ylsulfanylidenesulfido-λ5-phosphane (GYY4137, a slow H2S-releasing donor) on inhibiting the viability, proliferation, migration, and invasion of human ESCC cells. HA-ADT increased apoptosis by suppressing the protein expressions of phospho (p)-Ser473-protein kinase B (PKB/AKT), p-Tyr199/Tyr458-phosphatidylinositol 3-kinase (PI3K), and p-Ser2448-mammalian target of rapamycin (mTOR), but suppressed autophagy through the inhibition of the protein levels of p-Ser552-ß-catenin, p-Ser9-glycogen synthase kinase-3ß (GSK-3ß), and Wnt3a in human ESCC cells. In addition, HA-ADT was more effective in terms of the growth inhibition of human ESCC xenograft tumor than NaHS and GYY4137. In conclusion, HA-ADT can suppress ESCC progression via apoptosis promotion and autophagy inhibition. HA-ADT might be efficacious for the treatment of cancer.

Spin-Crossover Tuned Rotation of Pyrazolyl Rings in a 2D Iron(II) Complex towards Synergetic Magnetic and Dielectric Transitions.

Materials showing synergy of magnetic and dielectric transitions are promising candidates for future molecular devices. The challenge is how to realize synergy between spin and dielectric transitions with responses to external stimuli. Herein, we design a 2D spin crossover (SCO) complex, [FeII (dpa)][(pzTp)FeIII (CN)3 ]2 (1) (dpa=1,2-bis(4-pyridyl)ethyne and pzTp=tetrakis(pyrazolyl)borate). The local structural changes about the FeII ion were propagated to the whole crystal through the rigid bridging ligands (dpa), leading to elastic interactions to realize the abrupt SCO and rotational movements of polar apical pyrazolyl rings in the [(pzTp)FeIII (CN)3 ]- units. Dielectric measurements confirmed a substantial dielectric change (Δϵ'=2.3) upon the spin transition. This work provides a rational strategy to couple the spin transition and rotation of polar components, which is crucial for the synergetic switch of magnetism and dielectricity.

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C.

BACKGROUND: Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of aberrant plasma cells within the bone marrow. The high frequent mutation of family with sequence similarity 46, member C (FAM46C) is closely related with the occurrence and progression of MM. Recently, FAM46C has been identified as a non-canonical poly(A) polymerase (PAP) that functions as a tumor suppressor in MM. This study aimed to elucidate the structural features of this novel non-canonical PAP and how MM-related mutations affect the structural and biochemical properties of FAM46C, eventually advancing our understandings towards FAM46C mutation-related MM occurrence. METHODS: We purified and crystallized a mammalian FAM46C construct, and solved its structure. Next, we characterized the property of FAM46C as a PAP through a combination of structural analysis, site-directed mutagenesis and biochemical assays, and by comparison with its homolog FAM46B. Finally, we structurally analyzed MM-related FAM46C mutations and tested the enzymatic activity of corresponding mutants. RESULTS: We determined the crystal structure of a mammalian FAM46C protein at 2.35 Å, and confirmed that FAM46C preferentially consumed adenosine triphosphate (ATP) and extended A-rich RNA substrates. FAM46C showed a weaker PAP activity than its homolog FAM46B, and this difference was largely dependent on the residue variance at particular sites. Of them, residues at positions 77, 290, and 298 of mouse FAM46C were most important for the divergence in enzymatic activity. Among the MM-associated FAM46C mutants, those residing at the catalytic site (D90G and D90H) or putative RNA-binding site (I155L, S156F, D182Y, F184L, Y247V, and M270V) showed abolished or compromised PAP activity of FAM46C, while N72A and S248A did not severely affect the PAP activity. FAM46C mutants D90G, D90H, I155L, S156F, F184L, Y247V, and M270V had significantly lower inhibitory effect on apoptosis of RPMI-8226 cells as compared to wild-type FAM46C. CONCLUSIONS: FAM46C is a prokaryotic-like PAP with preference for A-rich RNA substrates, and showed distinct enzymatic efficiency with its homolog FAM46B. The MM-related missense mutations of FAM46C lead to various structural and biochemical outcomes to the protein.

A novel hydrogen sulfide-releasing donor, HA-ADT, suppresses the growth of human breast cancer cells through inhibiting the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways.

Breast cancer is one of the most frequent cancers among women worldwide. Hyaluronic acid (HA) is one of the best biopolymers in terms of safety issues and has been widely used in drug delivery and tissue engineering. 5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-thione (ADT-OH) is a commonly used H2S donor. In this study, we designed and synthesized a conjugate, HA-ADT, by connecting HA with ADT-OH through chemical reactions. Our results indicated that HA-ADT could produce more H2S than NaHS and GYY4137. HA-ADT exerted more potent inhibitory effects than NaHS and GYY4137 in the proliferation, viability, migration, and invasion of human breast cancer cells. Similar trends were observed in the apoptosis and the protein levels of phospho (p)-PI3K, p-AKT, p-mTOR, H-RAS, p-RAF, p-MEK, and p-ERK in human breast cancer cells. Furthermore, HA-ADT exhibited more powerful inhibitory effects on the growth of human breast cancer xenograft tumors in nude mice. In conclusion, HA-ADT could suppress the growth of human breast cancer cells through the inhibition of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK signaling pathways. HA-ADT and its derivatives might be of great potential in the treatment of different types of cancer.

Stable Indium-Pyridylcarboxylate Framework: Selective Gas Capture and Sensing of Fe3+ Ion in Water.

By employing a pyridyl-decorated dicarboxylic acid ligand, 3-(2',5'-dicarboxylphenyl)pyridine acid (H2dcpy), a three-dimensional In3+-based metal-organic framework, H3O[In3(dcpy)4(OH)2]·3DMF·4H2O (1), with a good chemical stability toward acid and base has been synthesized. The compound 1 shows an uncommon (3,8)-connected tfz-d; UO3 topological net based on linear In3(COO)4(OH)2 clusters and also contains one-dimensional open channels. Particularly, 1 contains two types of dcpy2- linkers, in which the pyridyl group in one participates in coordination with the In3+ ion, whereas that in the other is uncoordinated but hangs in the inner sides of the channels as functionalized sites. Gas adsorption experiments demonstrate that 1 is able to selectively adsorb C2H2, C2H4, and CO2 over CH4. Simultaneously, 1 shows a highly selective and sensitive fluorescence detection toward Fe3+ ion in water with good recyclability.

[Association between serum nitric oxide and hypertension among 1453 women in Suzhou].

OBJECTIVE: To investigate the association between serum nitric oxide (NO) and hypertension among women in Suzhou. METHODS: Blood pressure, height, weight and waist circumference (WC) were measured and factors including smoking, alcohol intake, family history of hypertension were investigated and blood glucose, blood lipid, serum NO were tested among 1453 women aged ≥ 30 years who lived in Jinchang district of Suzhou. Association between serum NO and hypertension was analyzed by univariate and multivariate methods. RESULTS: The mean levels of serum NO in hypertensive and normotensive persons were 28.17 (17.42 - 45.30) µmol/L and 27.56 (17.19 - 44.42) µmol/L, respectively, with no significant difference between the two groups (P > 0.05). RESULTS: from multivariable logistic regression analysis showed that low serum NO was not associated with hypertension, after adjustment for confounders (OR = 0.979, 95%CI: 0.747 - 1.283). The mean levels of systolic blood pressure/diastolic blood pressure were 130.1/83.3, 128.5/82.7, 129.8/83.2 and 129.1/83.3 mm Hg for whose serum NO level were in the first, second, third and fourth quartile, respectively. The risk of hypertension did not change along with the elevated serum NO levels. Compared to the first quartile of serum NO, the risks of hypertension in the second, third and fourth quartile did not change after adjustment for confounders and OR were 0.988 (0.709 - 1.377), 1.001 (0.720 - 1.390) and 1.077 (0.774 - 1.499), respectively. CONCLUSION: The serum NO level was not associated with hypertension in women in Suzhou.