Synthesis of Double Trivalent Perovskite Quantum Dots Cs3BiSbX9 (X = Cl, Br, I) for Efficient CO2 Photoreduction Performance.

Non-toxic Bi halides have great potential in the field of CO2 photoreduction, but strong charge localization limits their charge separation and transfer. In this study, a series of Cs3BiSbX9 (X = Cl, Br, I) perovskite quantum dots (PQDs) are synthesized by antisolvent recrystallization at room temperature, in which Cs3BiSbBr9 PQDs has high selectivity (94.51%) and yield (15.32 µmol g-1 h-1) of CO2 to CO. In situ DRIFTS and theoretical calculations suggest that the surface charge can be tailored by halogen modulation, allowing for the customization of intermediate species. The Bi─Br─Sb symmetric charge distribution induced by the halogen Br promotes the formation of b─HCOO and reduces the reaction energy barrier of the rate-limiting step, while the weak electronegativity of Cl and the high electronegativity of I leads to m─HCOO and ─COOH production, which are detrimental to CO generation. This work provides new insights into the design of halide alloy perovskites for CO2 photoreduction.

Green Late-Stage Functionalization of Tryptamines.

An efficient and rapid protocol for the oxidative halogenation of tryptamines with 10% aqueous NaClO has been developed. This reaction is featured by its operational simplicity, metal-free conditions, no purification, and high yield. Notably, the resulting key intermediates are suitable for further functionalization with various nucleophiles, including amines, N-aromatic heterocycles, indoles and phenols. The overall transformation exhibits broad functional-group tolerance and is applicable to the late-stage functionalization of complex biorelevant molecules.

Counterion influence on near-infrared-II heptamethine cyanine salts for photothermal therapy.

Photothermal therapy (PTT) has attracted extensive attention in cancer treatment. Heptamethine cyanine dyes with near-infrared (NIR) absorption performance have been investigated for PTT. However, they are often accompanied by poor photostability, suboptimal photothermal conversion and limited therapeutic efficacy. The photophysical properties of fluorescent organic salts can be tuned through counterion pairing. However, whether the counterion can influence the photostability and photothermal properties of heptamethine cyanine salts has not been clarified. In this work, we investigated the effects of eleven counter anions on the physical and photothermal properties of NIR-II heptamethine cyanine salts with the same heptamethine cyanine cation. The anions have great impacts on the physiochemical properties of dyes in solution including aggregation, photostability and photothermal conversion efficiency. The physical tuning enables the control over the cytotoxicity and phototoxicity of the dyes. The selected salts have been demonstrated to significantly suppress 4T1 breast tumor growth with low toxicity. The findings that the counterion has great effects on the photothermal properties of cationic NIR-II heptamethine cyanine dyes will provide a reference for the preparation of improved photothermal agents through counterion pairing with possible translation to humans.

BODIPY-Based NO Probe for Macrophage-Targeted Immunotherapy Response Monitoring.

Precise and rapid detection of immune responses is critical for timely therapeutic regimen adjustment. Immunomodulation of tumor-associated macrophages (TAMs) from a protumorigenic phenotype (M2) to an antitumorigenic phenotype (M1) is crucial in macrophage-targeted immunotherapy. Herein, we developed a boron dipyrromethene (BODIPY)-based fluorescence probe BDP3 to detect the immune responses after immunotherapy by monitoring the nitric oxide (NO) released by M1 TAMs. With an aromatic primary monoamine structure and a p-methoxyanilin electron donor in the meso-position, BDP3 not only specifically activates stable and sensitive fluorescence by NO via a photoinduced electron transfer (PET) process but also achieves a long emission wavelength for efficient in vitro and in vivo imaging. Such NO-induced fluorescence signals of BDP3 are validated to correlate well with the phenotypes of TAMs detected in macrophage cell lines and tumor tissues. The distinct sensing effects toward two types of clinically used immunotherapeutic drugs further confirm the ability of BDP3 for specific monitoring of the M1/M2 switch in response to the macrophage-targeted immunotherapy. By virtue of good biocompatibility and appropriate tumor retention time, BDP3 could be a potential fluorescent probe for noninvasive evaluation of the immunotherapeutic efficacy of macrophage-targeted immunotherapy in living animals.

K2P1 leak cation channels contribute to ventricular ectopic beats and sudden death under hypokalemia.

Hypokalemia causes ectopic heartbeats, but the mechanisms underlying such cardiac arrhythmias are not understood. In reduced serum K+ concentrations that occur under hypokalemia, K2P1 two-pore domain K+ channels change ion selectivity and switch to conduct inward leak cation currents, which cause aberrant depolarization of resting potential and induce spontaneous action potential of human cardiomyocytes. K2P1 is expressed in the human heart but not in mouse hearts. We test the hypothesis that K2P1 leak cation channels contribute to ectopic heartbeats under hypokalemia, by analysis of transgenic mice, which conditionally express induced K2P1 specifically in hearts, mimicking K2P1 channels in the human heart. Conditional expression of induced K2P1 specifically in the heart of hypokalemic mice results in multiple types of ventricular ectopic beats including single and multiple ventricular premature beats as well as ventricular tachycardia and causes sudden death. In isolated mouse hearts that express induced K2P1, sustained ventricular fibrillation occurs rapidly after perfusion with low K+ concentration solutions that mimic hypokalemic conditions. These observed phenotypes occur rarely in control mice or in the hearts that lack K2P1 expression. K2P1-expressing mouse cardiomyocytes of transgenic mice much more frequently fire abnormal single and/or rhythmic spontaneous action potential in hypokalemic conditions, compared to wild type mouse cardiomyocytes without K2P1 expression. These findings confirm that K2P1 leak cation channels induce ventricular ectopic beats and sudden death of transgenic mice with hypokalemia and imply that K2P1 leak cation channels may play a critical role in human ectopic heartbeats under hypokalemia.

Oxygen-independent alkyl radical nanogenerator enhances breast cancer therapy.

The hypoxic microenvironment of breast cancer substantially reduces oxygen-dependent free radical generation. Overexpression of glutathione (GSH) in tumor cells mitigates the impact of free radical generation. In this study, we designed and developed an oxygen-independent alkyl radical nanogenerator (copper monosulfide/2,2'-azabis(2-imidazoline) dihydrochloride@bovine serum albumin; CuS/AIPH@BSA) with spatiotemporally controlled properties and GSH consumption to enhance breast cancer therapy. We encapsulated the alkyl radical initiator, AIPH, in hollow mesoporous CuS nanoparticles with photothermal conversion effect and enveloped them in BSA. AIPH was released and decomposed to generate alkyl radicals in hypoxic breast cancer with the photothermal conversion effect of CuS under near-infrared laser irradiation. CuS consumed high GSH levels in tumor cells because it could form complex with GSH and thereby enhanced free radical treatment. In vivo and in vitro assays demonstrated the anti-tumor efficacy of the rationally designed free-radical nanogenerator in hypoxic microenvironment of breast cancer without showing systemic toxicity.

Synthesis, structure-activity relationship, and biological evaluation of quinolines for development of anticancer agents.

Tetrahydro-ß-carbolines (THßCs) are a kind of natural alkaloids with multiple pharmaceutical activities. Herein, a focused compound library derived from THßCs was synthesized and their anticancer activities were studied in several cancer cell lines. Among them, three compounds showed considerable anticancer activities with low micromolar to submicromolar IC50 values. The abilities to induce apoptosis and alter mitochondrial membrane potential levels, which are comparable to those of the commercial anticancer drug adriamycin, were confirmed by one representative compound (21) on the B16/F10 cell line. Our preliminary structure-activity relationship studies indicated that alkylamines with suitable lengths are very important for potency improvement.

Chemical Modification of Chitosan for Developing Cancer Nanotheranostics.

Cancer is a worldwide public health issue that has not been conquered. Theranostics, the combination of a therapeutic drug and imaging agent in one formulation using nanomaterials, has been developed to better cure cancer in recent years. Although diverse biomaterials have been applied in cancer theranostics, chitosan (CS), a natural polysaccharide bearing easy modification sites with excellent biocompatibility and biodegradability, shows great potential for developing cancer nanotheranostics. In this review, we seek to describe the chemical functionalities of CS used in cancer theranostics and their synthesis methods. We also present recent discoveries and research progresses on how the CS functionalization could improve the delivery efficiency of CS-based nanotheranostics. Finally, we report several case studies about the application of CS-based nanotheranostics. This paper focuses on the strategies to construct CS-based theranostics systems via chemical routes and highlights their applications in cancer treatment, which can provide useful references for further studies.

Photostability investigation of a near-infrared-II heptamethine cyanine dye.

The development of small-molecule organic fluorophores in the second near-infrared region (NIR-II, 1000-1700 nm) has recently received immense attention due to deep tissue light penetration and reduced autofluorescence. Polymethine cyanine dyes as important building blocks are frequently used to design NIR-II light-activated fluorophores. However, applications of these fluorophores were restricted by their poor photostability. Herein, we synthesized a NIR-II heptamethine cyanine dye 4 as the model compound to investigate its photostability and identify its photoproducts. Compound 4 shows improved photostability compared to ICG, and remains relatively stable even under sunlight irradiation. The cyanine scaffold's good photostability promoted its stable photothermal properties. The effective photothermal activity of cyanine dye 4 and the low toxicity of its one major photoproduct demonstrated its potential for further photo-therapeutic applications. This work would pave the way for the development of NIR-II cyanines with photostability through delicate structure design.

Green Synthesis of Nano-Zero Valence Iron with Green Tea and It's Implication in Lead Removal.

The nano-zero valence iron (nZVI) via green synthesis for heavy metal remediation has attracted many attentions due to its low-cost, environmental-safety, relative reproductivity, and high stability. However, influence of synthesis conditions on the physiochemical properties of nZVI via green tea extracts and the responding suspensibility, which is required for high reactivity, has not been fully elucidated. In this study, we investigated the zeta potentials, sedimentation and lead (Pb2+) removal capacity of various nZVIs synthesized using green tea extracts. The results showed that the tea extracts extracted at 80oC presented an excellent activity, which contributed to the outstanding suspensibility and reaction activity of nZVI synthesized in a volume ratio of 1:1 (tea extraction versus Fe2+ solution). Thus, the optimized nZVI was successfully prepared with a Pb2+ removal capacity (377.3 mg/g), which was seven times stronger than 50.31 mg/g of traditional chemical synthesized nZVI.

Long noncoding RNA H19 act as a competing endogenous RNA of Let-7g to facilitate IEC-6 cell migration and proliferation via regulating EGF.

Intestinal mucosal injury is one of the most significant complications of burns. In our previous study, it was found that autophagy could alleviate burn-induced intestinal injury, but the underlying mechanisms are still unclear. Irregular expression of long noncoding RNAs (lncRNAs) is present in many diseases, including burns. However, the relationship between lncRNAs and intestinal mucosal injury requires further elucidation. In this study, we established a burn mice model and detected the expression level of autophagy-related proteins. Then, H19 content after autophagy intervention was tested in vitro and in vivo. The interaction of H19 with Let-7g and that of Let-7g with epidermal growth factor (EGF) were verified by dual-luciferase reporter assays. We found that the expression of the autophagy-associated proteins LC3-II and Beclin-1 was raised in the intestinal tract of the burn mice model. Similarly, the transfection of H19 raised autophagy levels. H19 was elevated after autophagy intervention in vitro and in vivo. H19 overexpression was able to promote IEC-6 cell migration and proliferation. Let-7g was suppressed by the overexpression of H19 and the combination of Let-7g mimic was able to abolish the physiological effect of H19. Moreover, the suppression of Let-7g increased the expression of EGF protein, which heightened IEC-6 cell migration and proliferation. Besides this, dual-luciferase assays revealed that Let-7g was a direct target of H19 as well as the EGF gene. Taken together, autophagy-mediated H19 increases in mouse intestinal tract after severe burn and functions as a sponge to Let-7g to regulate EGF, which suggests that H19 serves as a potential therapeutic target and biomarker for intestinal mucosal injury after burns.

Diverse Functionalization of Tetrahydro-ß-carbolines or Tetrahydro-γ-carbolines via Oxidative Coupling Rearrangement.

We report herein diverse functionalization of tetrahydro-ß-carbolines (THßCs) or tetrahydro-γ-carbolines (THγCs) via oxidative coupling rearrangement. The treatment of THßCs or THγCs with t-BuOOH (TBHP) afforded 3-peroxyindolenines, followed by HCl catalyzed indolation to form unexpected 2-indolyl-3-peroxyindolenines. Further rearrangement of these peroxides allows for rapid access to a skeletally diverse chemical library in good to excellent yields.

The prognostic value of MELD-XI in elderly patients with ST-segment elevation myocardial infarction: an observational study.

BACKGROUND: The model for end-stage liver disease excluding international normalized ratio (MELD-XI) is a simple score for risk assessment. However, the prognostic role of MELD-XI and its additional value to current risk assessment in elderly patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) is uncertain. METHODS: In all, 1029 elderly patients with STEMI undergoing PCI were consecutively included and classified into three groups according to the TIMI risk score: low-risk (≤ 3, n = 251); moderate-risk (4-6, n = 509); and high-risk (≥ 7, n = 269) groups. Multivariate analysis was performed to identify risk factors for adverse events. RESULTS: The overall in-hospital mortality was 5.3% and was significantly higher in the high-risk group (1.2% vs. 3.3% vs. 13.0%, p < 0.001). The optimal cut-off of the TIMI risk score and MELD-XI for in-hospital death was 7 and 13, respectively. MELD-XI was associated with in-hospital (adjusted odds ratio = 1.09, 95% CI = 1.04-1.14, p = 0.001) and one-year (adjusted hazard ratio = 1.05, 95% CI = 1.01-1.08, p = 0.005) mortality independently of the TIMI risk score. Combining TIMI risk score and MELD-XI exhibited better predictive power for in-hospital death than TIMI risk score (area under the curve [AUC] = 0.810 vs. 0.753, p = 0.008) or MELD-XI alone (AUC = 0.810 vs. 0.750, p = 0.018). Patients with TIMI risk score ≥ 7 and MELD-XI ≥ 13 had the worst prognosis. CONCLUSION: MELD-XI could be considered as a risk-stratified tool for elderly patients with STEMI undergoing PCI. It had an additive prognostic value to TIMI risk score.

Effect of early use of ivabradine on left ventricular remodeling after primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction: A pilot test.

OBJECTIVE: To investigate the effect of early use of ivabradine on left ventricular remodeling after primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 66 STEMI patients with sinus rhythm and the resting heart rate ≥80 bpm after successful emergency PCI were included. The patients in the test group were treated with ivabradine combined with metoprolol at 12 hr after PCI, while the control group was given only metoprolol orally. Their resting heart rate was controlled to <70 bpm at discharge and followed for 180 days. Heart rate and blood pressure were measured regularly. Echocardiogram was performed. N-terminal pro-B-type natriuretic peptide (NT-proBNP), high sensitivity troponin T, high sensitivity troponin I, and high sensitivity C-reactive protein were measured. The major adverse cardiovascular events during hospitalization and follow-up period were recorded. RESULTS: Compared with the control group, the heart rate of the test group decreased significantly (p < .05). Compared with the control group, the left ventricular end-diastolic volume and left ventricular end-systolic volume were significantly decreased while left ventricular ejection fraction was significantly increased in the test group at 90 days after operation. NT-proBNP of the test group was significantly lower than that of the control group at 7 days after operation (p < .05). CONCLUSION: For STEMI patients, early use of ivabradine combined with standard therapy such as ß-blocker after successful reperfusion can achieve effective heart rate control, with great safety and tolerance. But the effect of ivabradine on left ventricular remodeling is uncertain.

Increased risk of Ventriculostomy-Associated hemorrhage in patients treated with antiplatelet agents for stent-assisted coiling of ruptured intracranial aneurysms.

PURPOSE: The aim of this study is to evaluate the impact of antiplatelet agents for stent-assisted coiling, including intravenous (IV) tirofiban as an antiplatelet premedication, on rates of external ventricular drain (EVD)-related hemorrhage in acutely ruptured intracranial aneurysms. The impact of IV tirofiban in particular was also evaluated. METHODS: Rates of radiographically identified hemorrhage associated with EVD placement were compared between patients who received an antiplatelet agent for stent-assisted coil embolization (SACE), and patients who did not receive an antiplatelet agent between June 2013 and June 2019. RESULTS: 78 patients treated for a ruptured aneurysm which required an EVD were included. A total of 46 patients who underwent stent-assisted coiling and received IV tirofiban and oral asipirin and clopidogrel (DAPT) were included in the antiplatelet group, while 32 who underwent single coiling and received no antiplatelet therapy were included in the control group. Overall, EVD-related hemorrhage occurred in 13 patients (16.67%): 11 (23.91%) in the antiplatelet group and 2 (6.25%) in the control group (p = 0.040). Of 37 patients who underwent computed tomography after SACE, but before the use of DAPT, 8 (21.62%) exhibited EVD-related hemorrhage after IV tirofiban therapy (p = 0.070 vs. control group). EVD-related hemorrhage was not significantly different between patients with EVD placement after coil embolization versus before coil embolization (p = 0.124). In the subgroup analysis for the antiplatelet group, we did not observed increased EVD-related hemorrhage in patients receiving EVD placement after administration of antiplatelet agents (8/27 [29.63%]) versus before administration of antiplatelet agents (3/19 [15.79%]). CONCLUSION: Patients with ruptured aneurysm who receive an antiplatelet agent for stent-assisted coiling are at a higher risk for EVD-related hemorrhage. The order of EVD placement and EVT, as well as the order of EVD placement and antiplatelet initiation do not appear to be significantly different regarding the outcome of EVD-related hemorrhage.HighlightsPatients with ruptured aneurysm who receive an antiplatelet agent for stent-assisted coiling are at a higher risk for EVD-related hemorrhage.There was a trend towards higher EVD related haemorrhage when tirofiban was used but it did not reach statisitical significance.The order of EVD-whether before vs after endovascular treatment, or before vs after antiplatelet therapy did not influence the EVD-related hemorrhage rates.

Epidermal growth factor regulation by autophagy-mediated lncRNA H19 in murine intestinal tract after severe burn.

To investigate the regulation of epidermal growth factor (EGF) by autophagy-mediated long non-coding RNA (lncRNA) H19 in the intestinal tracts of severely burned mice. C57BL/6J mice received third-degree burns to 30% of the total body surface area. Rapamycin and 3-methyladenine (3-MA) were used to activate and inhibit autophagy, and the changes in LC3 and Beclin1 levels were assessed by Western blotting. The effect of autophagy on lncRNA H19 was detected by qRT-PCR. Adenovirus-mediated overexpression of lncRNA H19 in IEC-6 cells was used to assess the effects of lncRNA H19 on EGF and let-7g via bioinformatics analysis, Western blotting and qRT-PCR. let-7g mimic/inhibitor was used to overexpress/inhibit let-7g, and qRT-PCR and Western blotting were used to detect the effects of let-7g on EGF. The expression levels of LC3-II, Beclin1 and lncRNA H19 were increased in intestinal tissues and IEC-6 cells after rapamycin treatment but were reversed after 3-MA treatment. LC3-II, Beclin1 and lncRNA H19 levels increased in intestinal tissues after the burn, and these increases were more significant after rapamycin treatment but decreased after 3-MA treatment. The lncRNA H19 overexpression in IEC-6 cells resulted in increased and decreased expression levels of EGF and let-7g, respectively. Furthermore, overexpression and inhibition of let-7g resulted in decreased and increased expression of EGF, respectively. Taken together, intestinal autophagy is activated after a serious burn, which can increase the transcription level of lncRNA H19. lncRNA H19 may regulate the repair of EGF via let-7g following intestinal mucosa injury after a burn.

E35 ablates acute leukemia stem and progenitor cells in vitro and in vivo.

Leukemia stem cells (LSCs) have critical functions in acute leukemia (AL) pathogenesis, participating in its initiation and relapse. Thus, identifying new molecules to eradicate LSCs represents a high priority for AL management. This work identified E35, a novel Emodin derivative, which strongly inhibited growth and enhanced apoptosis of AL stem cell lines, and primary stem and progenitor cells from AL cases, while sparing normal hematopoietic cells. Furthermore, functional assays in cultured cells and animals suggested that E35 preferentially ablated primitive leukemia cell populations without impairing their normal counterparts. Moreover, molecular studies showed that E35 remarkably downregulated drug-resistant gene and dramatically inhibited the Akt/mammalian target of rapamycin signaling pathway. Notably, the in vivo anti-LSC activity of E35 was further confirmed in murine xenotransplantation models. Collectively, these findings indicate E35 constitutes a novel therapeutic candidate for AL, potentially targeting leukemia stem and progenitor cells.

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia.

Dysfunction of neural stem cells (NSCs) has been linked to fetal neuropathy, one of the most devastating complications of gestational diabetes. Several studies have demonstrated that melatonin (Mel) exerted neuroprotective actions in various stresses. However, the role of autophagy and the involvement of Mel in NSCs in hyperglycemia (HG) have not yet been fully established. Here, we found that HG increased autophagy and autophagic flux of NSCs as evidenced by increasing LC3B II/I ratio, Beclin-1 expression, and autophagosomes. Moreover, Mel enhanced NSCs proliferation and self-renewal in HG with decreasing autophagy and activated mTOR signaling. Consistently, inhibition of autophagy by 3-Methyladenine (3-Ma) could assist Mel effects above, and induction of autophagy by Rapamycin (Rapa) could diminish Mel effects. Remarkably, HG induced premature differentiation of NSCs into neurons (Map2 positive cells) and astrocytes (GFAP positive cells). Furthermore, Mel diminished HG-induced premature differentiation and assisted NSCs in HG differentiation as that in normal condition. Coincidentally, inhibiting of NSCs autophagy by 3-Ma assisted Mel to modulate differentiation. However, increasing NSCs autophagy by Rapa disturbed the Mel effects and retarded NSCs differentiation. These findings suggested that Mel supplementation could contribute to mimicking normal NSCs proliferation and differentiation in fetal central nervous system by inhibiting autophagy in the context of gestational diabetes. Stem Cells 2019;37:504-515.

Synthesis and structure-activity relationship studies of LLY-507 analogues as SMYD2 inhibitors.

SET and MYND domain-containing protein 2 (SMYD2), a lysine methyltransferase, is reported to catalyze the methylation of lysine residues on histone and non-histone proteins. As a potential target for cancer therapy, there are several SMYD2 inhibitors are reported, LLY-507 as a cell-active inhibitor exhibits submicromolar potency against SMYD2 in several cancer cell lines. To know which structural fragment of LLY-507 is suitable for chemical modification, three sites are chosen for structure-activity relationship studies (SARs). Among our focused library, compounds 43 and 44 with amide link on site C showed reasonably improved potency indicating that modification on this fragment is more flexible and introduction of electrophilic warheads in this position might provide lysine-targeting covalent inhibitors for SMYD2.

[Roles of multidisciplinary team in diagnosis and treatment of suspected cases of COVID-19].

OBJECTIVE: To analyze the roles of multidisciplinary team (MDT) in the diagnosis and treatment of suspected cases of coronavirus disease 2019 (COVID-19). METHODS: The clinical data of 48 patients with suspected COVID-19 admitted in Jinhua Municipal Central Hospital from January 21, 2020 to March 20, 2020 were retrospectively analyzed. RESULTS: In the 48 suspected cases, 18 were diagnosed with COVID-19, and 30 were excluded. Each of the confirmed cases were discussed among MDT for 2 to 12 times with an average of (4.7±3.2) times; while for non-COVID-19 patients were discussed for 2 to 4 times with an average of (2.3±0.6) times. With the guidance of MDT, one COVID-19 patient was transferred to designated provincial hospital after effective treatment; one patient complicated with acute cholecystitis underwent gallbladder puncture and drainage; and COVID-19 was excluded in a highly suspected patient after alveolar lavage fluid examination. Except one transferred patient, all 17 confirmed COVID-19 patients were cured and discharged. There was no cross-infection occurred in suspected patients during the hospitalization. There were no deaths and no medical staff infections. CONCLUSIONS: The efficiency of diagnosis and treatment for suspected COVID-19 patients can be improved with MDT, particularly for complicated cases.