Nanoscale Covalent Organic Framework with Staggered Stacking of Phthalocyanines for Mitochondria-Targeted Photodynamic Therapy.

Phthalocyanine photosensitizers (PSs) have shown promise in fluorescence imaging and photodynamic therapy (PDT) of malignant tumors, but their practical application is limited by the aggregation-induced quenching (AIQ) and inherent photobleaching of PSs. Herein, we report the synthesis of a two-dimensional nanoscale covalent organic framework (nCOF) with staggered (AB) stacking of zinc-phthalocyanines (ZnPc), ZnPc-PI, for fluorescence imaging and mitochondria-targeted PDT. ZnPc-PI isolates and confines ZnPc PSs in the rigid nCOF to reduce AIQ, improve photostability, enhance cellular uptake, and increase the level of reactive oxygen species (ROS) generation via mitochondrial targeting. ZnPc-PI shows efficient tumor accumulation, which allowed precise tumor imaging and nanoparticle tracking. With high cellular uptake and tumor accumulation, intrinsic mitochondrial targeting, and enhanced ROS generation, ZnPc-PI exhibits potent PDT efficacy with >95% tumor growth inhibition on two murine colon cancer models without causing side effects.

Vitamin D supplementation for cardiometabolic risk markers in pregnant women based on the gestational diabetes mellitus or obesity status : a randomized clinical trial.

PURPOSE: Women with gestational diabetes mellitus (GDM) or obesity are vulnerable to impaired gestational cardiovascular health (CVH) and cardiovascular disease (CVD) in the future. It is unclear if prenatal vitamin D supplementation improves gestational CVH, especially in women at high risk for developing CVD. Our goal was to find out if vitamin D supplementation could protect against gestational CVH, including the women with GDM or obesity. DESIGN: We randomly assigned women with a serum 25(OH)D concentration < 75 nmol/L to receive 1600 IU/d (intervention group) or 400 IU/d (control group) of vitamin D3 for two months at 24-28 weeks' gestation. The primary outcome was gestational CVH marks (lipids, inflammatory cytokines, endothelial function). RESULTS: There were 1537 participants divided into the intervention (N = 766) and control groups (N = 771). No baseline differences existed among study groups in CVH markers. At the two-month visit, the intervention group's HDL-C levels (2.01 ± 0.39 VS 1.96 ± 0.39 mmol/L) were significantly higher than those of the control group, while the hs-CRP levels were significantly lower (3.28 ± 2.02 VS 3.64 ± 2.42 mg/L). Subgroup analysis found that HDL-C, TC, hs-CRP, E-Selectin, and SBP were improved in the intervention group among women with GDM or overweight/obesity, and the improvement was not found in women without GDM or overweight/obesity. Vitamin D supplementation significantly decreased the mean triglyceride-glucose index at the two-month visit in women with GDM. CONCLUSIONS: Vitamin D supplementation at mid-gestation might optimize the gestational CVH status for pregnant women, particularly the women with GDM or obesity, which is advantageous for later-life primary prevention of CVD. CLINICAL TRIAL REGISTRATION: The Chinese Clinical Trial Registry (ChiCTR2100051914, 10/9/2021, Prospective registered, https://www.chictr.org.cn/showproj.aspx?proj=134700 ).

Nanoscale Metal-Organic Layer Reprograms Cellular Metabolism to Enhance Photodynamic Therapy and Antitumor Immunity.

Abnormal cancer metabolism causes hypoxic and immunosuppressive tumor microenvironment (TME), which limits the antitumor efficacy of photodynamic therapy (PDT). Herein, we report a photosensitizing nanoscale metal-organic layer (MOL) with anchored 3-bromopyruvate (BrP), BrP@MOL, as a metabolic reprogramming agent to enhance PDT and antitumor immunity. BrP@MOL inhibited mitochondrial respiration and glycolysis to oxygenate tumors and reduce lactate production. This metabolic reprogramming enhanced reactive oxygen species generation during PDT and reshaped the immunosuppressive TME to enhance antitumor immunity. BrP@MOL-mediated PDT inhibited tumor growth by >90 % with 40 % of mice being tumor-free, rejected tumor re-challenge, and prevented lung metastasis. Further combination with immune checkpoint blockade potently regressed the tumors with >98 % tumor inhibition and 80 % of mice being tumor-free.

Phosphate Coordination to Metal-Organic Layer Secondary Building Units Prolongs Drug Retention for Synergistic Chemoradiotherapy.

Chemoradiotherapy combines radiotherapy with concurrent chemotherapy to potentiate antitumor activity but exacerbates toxicities and causes debilitating side effects in cancer patients. Herein, we report the use of a nanoscale metal-organic layer (MOL) as a 2D nanoradiosensitizer and a reservoir for the slow release of chemotherapeutics to amplify the antitumor effects of radiotherapy. Coordination of phosphate-containing drugs to MOL secondary building units prolongs their intratumoral retention, allowing for continuous release of gemcitabine monophosphate (GMP) for effective localized chemotherapy. In the meantime, the MOL sensitizes cancer cells to X-ray irradiation and provides potent radiotherapeutic effects. GMP-loaded MOL (GMP/MOL) enhances cytotoxicity by 2-fold and improves radiotherapeutic effects over free GMP in vitro. In a colon cancer model, GMP/MOL retains GMP in tumors for more than four days and, when combined with low-dose radiotherapy, inhibits tumor growth by 98 %. The synergistic chemoradiotherapy enabled by GMP/MOL shows a cure rate of 50 %, improves survival, and ameliorates cancer-proliferation histological biomarkers.

Nanoscale Metal-Organic Framework with an X-ray Triggerable Prodrug for Synergistic Radiotherapy and Chemotherapy.

As heavy-metal-based nanoscale metal-organic frameworks (nMOFs) are excellent radiosensitizers for radiotherapy via enhanced energy deposition and reactive oxygen species (ROS) generation, we hypothesize that nMOFs with covalently conjugated and X-ray triggerable prodrugs can harness the ROS for on-demand release of chemotherapeutics for chemoradiotherapy. Herein, we report the design of a novel nMOF, Hf-TP-SN, with an X-ray-triggerable 7-ethyl-10-hydroxycamptothecin (SN38) prodrug for synergistic radiotherapy and chemotherapy. Upon X-ray irradiation, electron-dense Hf12 secondary building units serve as radiosensitizers to enhance hydroxyl radical generation for the triggered release of SN38 via hydroxylation of the 3,5-dimethoxylbenzyl carbonate followed by 1,4-elimination, leading to 5-fold higher release of SN38 from Hf-TP-SN than its molecular counterpart. As a result, Hf-TP-SN plus radiation induces significant cytotoxicity to cancer cells and efficiently inhibits tumor growth in colon and breast cancer mouse models.

Mechanoregulatory Cholesterol Oxidase-Functionalized Nanoscale Metal-Organic Framework Stimulates Pyroptosis and Reinvigorates T Cells.

Cancer cells alter mechanical tension in their cell membranes. New interventions to regulate cell membrane tension present a potential strategy for cancer therapy. Herein, the increase of cell membrane tension by cholesterol oxidase (COD) via cholesterol depletion in vitro and the design of a COD-functionalized nanoscale metal-organic framework, Hf-TBP/COD, for cholesterol depletion and mechanoregulation of tumors in vivo, are reported. COD is found to deplete cholesterol and disrupt the mechanical properties of lipid bilayers, leading to decreased cell proliferation, migration, and tolerance to oxidative stress. Hf-TBP/COD increases mechanical tension of plasma membranes and osmotic fragility of cancer cells, which induces influx of calcium ions, inhibits cell migration, increases rupturing propensity for effective caspase-1 mediated pyroptosis, and decreases tolerance to oxidative stress. In the tumor microenvironment, Hf-TBP/COD downregulates multiple immunosuppressive checkpoints to reinvigorate T cells and enhance T cell infiltration. Compared to Hf-TBP, Hf-TBP/COD improves anti-tumor immune response and tumor growth inhibition from 54.3% and 79.8% to 91.7% and 95% in a subcutaneous triple-negative breast cancer model and a colon cancer model, respectively.

Inhibition of PCSK9 Improves the Development of Pulmonary Arterial Hypertension Via Down-Regulating Notch3 Expression.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by continuous constriction and occlusion of small pulmonary arteries, leading to the development of right ventricular failure and death. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a kind of serine protease enzyme that increases low-density lipoprotein cholesterol (LDLC) levels through degrading low-density lipoprotein cholesterol receptors (LDLr). However, whether inhibition of PCSK9 can alleviate PAH has not been reported. METHODS AND RESULTS: We reported that PCSK9 expression was up-regulated in lung tissues of PAH patients. In addition, we used PCSK9 monoclonal antibody subcutaneously to inhibit PCSK9 expression in mice exposed to chronic hypoxia (10%) in combination with SU5416, a VEGF receptor inhibitor. Hypoxia plus SU5416-induced PAH was attenuated in PCSK9 monoclonal antibody-treated mice compared with wild-type mice. PCSK9 inhibited pulmonary vascular remodeling in mice. Moreover, PCSK9 knockdown significantly altered the proliferation and migration of hypoxia-induced PASMCs. We also found that PCSK9 monoclonal antibody inhibited Notch3 expression in vivo and in vitro. CONCLUSION: Our results suggest that the PCSK9-Notch3 signaling pathway is critical for the proliferation and migration of PASMCs and provides a potential drug target for the treatment of PAH.

Association between exposure to air pollution during preconception and risk of gestational diabetes mellitus: The role of anti-inflammatory diet.

BACKGROUND: Regarding the association between the sensitive time-windows of air pollution (AP) exposure and gestational diabetes mellitus (GDM), epidemiological findings are inconsistent. The dietary inflammatory potential has been implicated in the development of GDM, but it is unclear whether an anti-inflammatory diet during pregnancy reduces the association between AP and GDM. OBJECTIVE: We aimed to characterize the sensitive time-windows of AP to GDM risk. Further, to verify whether a maternal anti-inflammatory diet can reduce the risk of AP-induced GDM, by inhibiting inflammation. METHODS: A total of 8495 pregnant women were included between 2015 and 2021 in the Maternal & Infants Health in Hefei study. Weekly mean AP exposure to fine particles (PM2.5 and PM10), SO2, and NO2 was estimated from the data of Hefei City Ecology and Environment Bureau. High-sensitivity C-reactive protein (hs-CRP) concentrations were measured to evaluate systemic inflammation. The empirical dietary inflammatory pattern (EDIP) score based on a validated food frequency questionnaire was used to assess the dietary inflammatory potential of pregnant women. Logistic regression models with distributed lags were used to identify the sensitive time-window for the effect of AP on GDM. Mediation analysis estimated the mediated effect of hs-CRP, linking AP with GDM. Stratified analysis was used to investigate the potential effect of anti-inflammatory diet on GDM risk. RESULTS: The increased risks of GDM were found to be positively associated with exposure to PM2.5 (OR = 1.11, 95% CI:1.07-1.15), PM10 (OR = 1.12, 95% CI:1.09-1.16), and SO2 (OR = 1.42, 95% CI:1.25-1.60) by distributed lag models, and the critical exposure windows were 21st to 28th weeks of preconception. The proportion of association between PM2.5, PM10, and SO2 with GDM mediated by hs-CRP was 25.9%, 21.1%, and 19.4%, respectively, according to mediation analysis. In the stratified analyses by EDIP, the association between AP and GDM was not statistically significant among women those with anti-inflammatory diets. CONCLUSIONS: Exposure to AP, especially in 21st to 28th week of preconception, is associated with risk of GDM, which is partly mediated by hs-CRP. Adherence to the anti-inflammatory dietary pattern may reduce the risk of AP-induced GDM.

Establishment of a canine model of pulmonary arterial hypertension induced by dehydromonocrotaline and ultrasonographic study of right ventricular remodeling.

OBJECTIVE: Pulmonary arterial hypertension (PAH) means high blood pressure in the lungs. We aimed to observe the right ventricular size, wall thickness and characteristic functional changes and their associations with PAH in an established model of beagle dogs, and to explore convenient, reliable and sensitive ultrasound indicators for assessing right ventricular remodeling. METHODS: Twenty healthy beagle dogs (8-10 kg) were randomly divided into control group (N-dimethylformamide, n = 10) and dehydromonocrotaline (DHMCT) group (DHMCT, n = 10). N-dimethylformamide or DHMCT was injected through a catheter into the right atrium, and then right heart catheterization, routine echocardiography and two-dimensional speckle tracking imaging (2D-STI) were performed before modeling (0 weeks) and 8, 14 weeks after modeling. Hemodynamic parameters and right ventricular function-related ultrasound data were acquired. At the end of the experiment, the animals were killed and the lung tissues were taken for HE staining. Left and right ventricular walls were separated and weighed respectively, and right ventricular hypertrophy index (RVHI) was measured. The associations of the routine ultrasound data and 2D-STI data at each time point with hemodynamic parameters and RVHI were analyzed. RESULTS: At 0, 8 and 14 weeks, gradual decreases in the right ventricular global longitudinal strain (RVLS) were found in DHMCT group. RVH occurred in DHMCT group, and DHMCT group had a significantly higher RVHI than that of control group (49.83 ± 4.83% vs. 39.80 ± 1.40%, P < .001) and larger pulmonary artery media thickness. RVLS had significant positive correlations with RVSP (r = 0.74, P < .001), mRVP (r = 0.72, P < .001), PASP (r = 0.75, P < .001), mPAP (r = 0.72, P < .001) and PVR (r = 0.68, P < .001). There was a significant positive correlation between RVLS and RVHI (r = 0.74, P < .001). CONCLUSION: The right ventricular function in PAH can be effectively assessed by echocardiography, and RVLS measured by 2D-STI sensitively reflects right ventricular remodeling following PAH.

Triptonodiol, a Diterpenoid Extracted from Tripterygium wilfordii, Inhibits the Migration and Invasion of Non-Small-Cell Lung Cancer.

Lung cancer is the most prevalent oncological disease worldwide, with non-small-cell lung cancer accounting for approximately 85% of lung cancer cases. Tripterygium wilfordii is a traditional Chinese herb that is widely used to treat rheumatism, pain, inflammation, tumors, and other diseases. In this study, we found that Triptonodiol extracted from Tripterygium wilfordii inhibited the migration and invasion of non-small-cell lung cancer and inhibited cytoskeletal remodeling, which has not been previously reported. Triptonodiol significantly inhibited the motility activity of NSCLC at low toxic concentrations and suppressed the migration and invasion of NSCLC. These results can be confirmed by wound healing, cell trajectory tracking, and Transwell assays. We found that cytoskeletal remodeling was inhibited in Triptonodiol-treated NSCLC, as evidenced by the reduced aggregation of actin and altered pseudopod morphology. Additionally, this study found that Triptonodiol induced an increase in complete autophagic flux in NSCLC. This study suggests that Triptonodiol reduces the aggressive phenotype of NSCLC by inhibiting cytoskeletal remodeling and is a promising anti-tumor compound.

Metal-Organic Layer Delivers 5-Aminolevulinic Acid and Porphyrin for Dual-Organelle-Targeted Photodynamic Therapy.

The efficacy of photodynamic therapy (PDT) depends on the subcellular localization of photosensitizers. Herein, we report a dual-organelle-targeted nanoparticle platform for enhanced PDT of cancer. By grafting 5-aminolevulinic acid (ALA) to a Hf12 -based nanoscale metal-organic layer (Hf-MOL) via carboxylate coordination, ALA/Hf-MOL enhanced ALA delivery and protoporphyrin IX (PpIX) synthesis in mitochondria, and trapped the Hf-MOL comprising 5,15-di-p-benzoatoporphyrin (DBP) photosensitizers in lysosomes. Light irradiation at 630 nm simultaneously excited PpIX and DBP to generate singlet oxygen and rapidly damage both mitochondria and lysosomes, leading to synergistic enhancement of the PDT efficacy. The dual-organelle-targeted ALA/Hf-MOL outperformed Hf-MOL in preclinical PDT studies, with a 2.7-fold lower half maximal inhibitory concentration in cytotoxicity assays in vitro and a 3-fold higher cure rate in a colon cancer model in vivo.

Ultrathin and Porous 2D PtPdCu Nanoalloys as High-Performance Multifunctional Electrocatalysts for Various Alcohol Oxidation Reactions.

We precisely synthesized two-dimensional (2D) PtPdCu nanostructures with the morphology varying from porous circular nanodisks (CNDs) and triangular nanoplates (TNPs) to triangular nanoboomerangs (TNBs) by tuning the molar ratios of metal precursors. The PtPdCu trimetallic nanoalloys exhibit superior electrocatalytic performances to alcohol oxidation reactions due to their unique structural features and the synergistic effect. Impressively, PtPdCu TNBs exhibit a high mass activity of 3.42 mgPt+Pd-1 and 1.06 A·mgPt-1 for ethanol and methanol oxidation compared to PtPd, PtCu, and pure Pt, which is 3.93 and 4.07 times that of commercial Pt/C catalysts, respectively. Moreover, 2D PtPdCu TNPs and PtPdCu CNDs also show a highly improved electrocatalytic activity. Furthermore, as all-in-one electrocatalysts, PtPdCu nanoalloys display excellent electrocatalytic activity and stability toward the oxidation of other alcohol molecules, such as isopropyl alcohol, glycerol, and ethylene glycol. The enhanced mechanism was well proposed to be the abundant active sites and upshifted d-band center based on density functional theory calculations.

Mitoferrin 2 deficiency prevents mitochondrial iron overload-induced endothelial injury and alleviates atherosclerosis.

Endothelial dysfunction is an early step in the development of atherosclerotic cardiovascular disease. Iron overload can lead to excessive mitochondrial reactive oxygen species (mtROS) production, resulting in mitochondrial dysfunction and vascular endothelial cell (EC) damage. Mitoferrin 2 (Mfrn2) is an iron transporter in the inner mitochondrial membrane. This study aimed to assess whether Mfrn2 and mitochondrial iron overload were involved in atherosclerosis progression and to explore the potential mechanism. We observed significant upregulation of Mfrn2 in the arteries of high-fat diet (HFD)-fed Apolipoprotein E-/- (ApoE-/-) mice and in TNF-α-induced mouse aortic endothelial cells (MAECs). Mfrn2 gene silencing inhibited mitochondrial iron overload, stabilized mitochondrial membrane potential and improved mitochondrial function in TNF-α-induced MAECs. Vascular EC-specific knockdown of Mfrn2 in ApoE-/- mice markedly decreased atherosclerotic lesion formation and the levels of ICAM-1 in aortas and reduced monocyte infiltration into the vascular wall. Furthermore, TNF-α increased the binding of 14-3-3 epsilon (ε) and Mfrn2, preventing Mfrn2 degradation and leading to mitochondrial iron overload in ECs, while 14-3-3ε overexpression increased Mfrn2 stability by inhibiting its ubiquitination. Together, our results reveal that Mfrn2 deficiency attenuates endothelial dysfunction by decreasing iron levels within the mitochondria and mitochondrial dysfunction. These findings may provide new insights into preventive and therapeutic strategies against vascular endothelial dysfunction in atherosclerotic disease.

Association of maternal prenatal depression and anxiety with toddler sleep: the China-Anhui Birth Cohort study.

Maternal prenatal depression is associated with child sleep. We investigated whether maternal depression comorbid with anxiety worsens toddler's sleep problems in a prospective cohort study. A total of 1583 mother-infant pairs from the China-Anhui Birth Cohort study were examined. The participants completed the Center for Epidemiologic Studies Depression Scale (CES-D) and Self-Rating Anxiety Scale (SAS) at 30-34 weeks of gestation, and the Edinburgh Postnatal Depression Scale (EPDS) at 3-month postpartum. Toddler's sleep was assessed by the Brief Infant Sleep Questionnaire (BISQ) at 30 months old. Logistic regression models were used to investigate the associations between prenatal depression and anxiety and toddler's sleep, while adjusting for maternal gestational age, education, family income, alcohol use, premature birth, fetal growth restriction, mode of delivery, postnatal depression, and 3-month breastfeeding. In total, 9.0% of participants reported prenatal depression comorbid with anxiety symptoms, and the prevalence of depression, anxiety was 6.7% and 7.3%, respectively. Compared with mothers without depression and anxiety, maternal depression combined with anxiety were significantly associated with shorter total sleep duration (11.16 ± 1.06 h), longer settling time (29.25 ± 23.57 min), and higher risk of toddlers' sleep problems assessed by BISQ (OR = 2.09, 95% CI: 1.22-3.57) or parental report (OR = 1.84, 95% CI: 1.22-2.77). However, there was no significant association between maternal postnatal depression and toddler sleep behaviors. Maternal prenatal depression comorbid with anxiety significantly associated with poorer toddler's sleep. Strategies to regulate prenatal mood status should be considered during prenatal health care to improve children's sleep development.

Perceived uncertainty stress and its predictors among residents in China during the COVID-19 pandemic.

The prevalence of and risk factors for uncertainty stress among residents during the COVID-19 pandemic remain unclear. An online cross-sectional survey was conducted to explore and identify the risk factors for high perceived uncertainty stress among the general public in China during the COVID-19 outbreak. Information about the respondents' socioeconomic characteristics, knowledge of and attitudes towards COVID-19, perceived uncertainty stress, social capital, anxiety, and depressive symptoms was collected and analysed. Among the 1205 respondents, 45.3% (546) reported a high level of uncertainty stress. Multiple linear regression analysis indicated that anxiety (ß=3.871,P<0.001) and depression symptoms (ß=2.458, P<0.001), family residence (in towns or rural areas) (ß=0.947, P<0.001), lack of support for local epidemic control strategies (ß=1.253, P<0.001), worry about the pandemic (ß=1.191, P<0.001), and symptoms of weakness among family members (ß=1.525, P=0.002) were positively associated with perceived uncertainty stress. Cognitive social capital (ß=-0.883, P<0.001) and social networks (ß=-0.726, P<0.001) were negatively, but social participation (ß=0.714, P<0.001) was positively associated with perceived uncertainty stress. Our findings identify factors associated with a higher level of uncertainty stress and should be helpful in the consideration of effective policies and interventions for uncertainty stress during the initial phases of public health emergencies.

Nanoscale Metal-Organic Framework Confines Zinc-Phthalocyanine Photosensitizers for Enhanced Photodynamic Therapy.

The performance of photodynamic therapy (PDT) depends on the solubility, pharmacokinetic behaviors, and photophysical properties of photosensitizers (PSs). However, highly conjugated PSs with strong reactive oxygen species (ROS) generation efficiency tend to have poor solubility and aggregate in aqueous environments, leading to suboptimal PDT performance. Here, we report a new strategy to load highly conjugated but poorly soluble zinc-phthalocyanine (ZnP) PSs in the pores of a Hf12-QC (QC = 2″,3'-dinitro-[1,1':4',1";4″,1'"-quaterphenyl]-4,4'"-dicarboxylate) nanoscale metal-organic framework to afford ZnP@Hf-QC with spatially confined ZnP PSs. ZnP@Hf-QC avoids aggregation-induced quenching of ZnP excited states to significantly enhance ROS generation upon light irradiation. With higher cellular uptake, enhanced ROS generation, and better biocompatibility, ZnP@Hf-QC mediated PDT exhibited an IC50 of 0.14 µM and achieved exceptional antitumor efficacy with >99% tumor growth inhibition and 80% cure rates on two murine colon cancer models.

Bifunctional Metal-Organic Layer with Organic Dyes and Iron Centers for Synergistic Photoredox Catalysis.

Here we report the design of a bifunctional metal-organic layer (MOL), Hf-EY-Fe, by bridging eosin Y (EY)-capped Hf6 secondary building units (SBUs) with Fe-TPY (TPY = 4'-(4-carboxyphenyl)[2,2':6',2''-terpyridine]-5,5''-dicarboxylate) ligands. With the organic dye EY as an efficient photosensitizer and TPY-Fe(OTf)2 as the catalytic center, Hf-EY-Fe efficiently catalyzes aminotrifluoromethylation, hydroxytrifluoromethylation, and chlorotrifluoromethylation of alkenes. Hf-EY-Fe also catalyzes the synthesis of CF3-substituted derivatives of large bioactive molecules such as rotenone, estrone, and adapalene with sizes of up to 2.2 nm. The proximity between EY and iron centers and their site isolation in Hf-EY-Fe enhance catalytic activity while inhibiting their mutual deactivation, leading to high turnover numbers of up to 1840 and good recyclability of the MOL catalyst.

Bifunctional Metal-Organic Layers for Tandem Catalytic Transformations Using Molecular Oxygen and Carbon Dioxide.

Tandem catalytic reactions improve atom- and step-economy over traditional synthesis but are limited by the incompatibility of the required catalysts. Herein, we report the design of bifunctional metal-organic layers (MOLs), HfOTf-Fe and HfOTf-Mn, consisting of triflate (OTf)-capped Hf6 secondary building units (SBUs) as strong Lewis acidic centers and metalated TPY ligands as metal active sites for tandem catalytic transformations using O2 and CO2 as coreactants. HfOTf-Fe effectively transforms hydrocarbons into cyanohydrins via tandem oxidation with O2 and silylcyanation whereas HfOTf-Mn converts styrenes into styrene carbonates via tandem epoxidation and CO2 insertion. Density functional theory calculations revealed the involvement of a high-spin FeIV (S = 2) center in the challenging oxidation of the sp3 C-H bond. This work highlights the potential of MOLs as a tunable platform to incorporate multiple catalysts for tandem transformations.

Nanoscale Coordination Polymers for Combined Chemotherapy and Photodynamic Therapy of Metastatic Cancer.

Combination therapy enhances anticancer efficacy through synergistic effects of different drugs/modalities and can potentially address the challenges in the treatment of metastatic diseases. Here we report the design of carb/pyro nanoscale coordination polymer nanoparticles that carry carboplatin (carb) in the core and the photosensitizer pyrolipid (pyro) on the shell for the treatment of metastatic triple negative breast cancer. Upon light irradiation, carb/pyro generated reactive oxygen species to cause severe cell apoptosis and early calreticulin exposure. Upon intravenous injection and local light irradiation, carb/pyro significantly regressed tumor growth in the 4T1 murine metastatic breast cancer model. When combined with an anti-CD47 antibody, carb/pyro with light irradiation completely eradicated primary and metastatic 4T1 tumors in 50% mice. The anticancer efficacy of carb/pyro was also demonstrated in the CT26 murine colorectal cancer model.

Bioactive Compounds From Coptidis Rhizoma Alleviate Pulmonary Arterial Hypertension by Inhibiting Pulmonary Artery Smooth Muscle Cells' Proliferation and Migration.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by excessive proliferation and vasoconstriction of small pulmonary artery vascular smooth muscle cells (PASMCs). Coptidis rhizoma (CR) because of the complexity of the components, the underlying pharmacological role and mechanism of it on PAH remains unknown. In this article, the network pharmacological analysis was used to screen the main active constituents of CR and the molecular targets that these constituents act on. Then, we evaluated the importance of berberine and quercetin (biologically active components of CR) on the proliferation and migration of PASMCs and vascular remodeling in experimental models of PAH. Our results showed that berberine and quercetin effectively inhibited the proliferation and migration of hypoxia-induced PASMCs in a manner likely to be mediated by the suppression of MAPK1, NADPH oxidase 4 (NOX4), and cytochrome P450 1B1 (CYP1B1) expression. Furthermore, berberine and quercetin treatment attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension in rat models. In conclusion, this research demonstrates CR might be a promising treatment option for PAH, and the network pharmacology approach can be an effective tool to reveal the potential mechanisms of Chinese herbal medicine.