Sulfur(VI) fluoride exchange (SuFEx) is a second-generation click chemistry reaction that relies on the unique reactivities of SVI–F bonds. The development of efficient methods for incorporating a ...S(VI)–F motif into molecules is of great significance. Sulfamoyl fluorides (R1R2NSO2F), serving as versatile SuFExable hubs, are typically synthesized by using “+SO2F” reagents to establish N-SO2F bonds. In this study, we report the development of N-fluorosulfamoyl pyridium salts (NFSAPs) as radical fluorosulfonamidation reagents that are readily accessible and bench-stable. By employing NFSAPs as essential fluorosulfamoyl radical (•NSO2F) precursors, the direct installation of the NSO2F group onto (hetero)arenes and alkenes is achieved through distinct C–N bond formation reactions. This platform facilitates the collective synthesis of highly functionalized N-aryl, N-alkyl, and N-alkenyl sulfamoyl fluorides (R1R2NSO2F) under mild photocatalytic conditions and has been applied in the late-stage functionalization of pharmaceuticals and peptides.
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IJS, KILJ, NUK, PNG, UL, UM
Because of rapid change in lifestyle risk factors, cardiovascular disease has become the leading cause of death in China. We sought to estimate the national levels of serum lipids and lipoproteins ...among the Chinese adult population.
We conducted a cross-sectional study in a nationally representative sample of 46 239 adults aged ≥20 years. Fasting serum total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglycerides were measured by standard methods. The age-standardized estimates of total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglycerides were 4.72 (95% confidence interval, 4.70-4.73), 1.30 (1.29-1.30), 2.68 (2.67-2.70), and 1.57 (1.55-1.58) mmol/L, respectively, in the Chinese adult population. In addition, 22.5% (21.8-23.3%) or 220.4 million (212.1-228.8) Chinese adults had borderline high total cholesterol (5.18-6.21 mmol/L), and 9.0% (8.5-9.5%) or 88.1 million (83.4-92.8) had high total cholesterol (≥6.22 mmol/L). The population estimates for borderline high (3.37-4.13 mmol/L), high (4.14-4.91 mmol/L), and very high (≥4.92 mmol/L) low-density lipoprotein cholesterol were 13.9% (13.3-14.5%) or 133.5 million (127.0-140.1), 3.5% (3.3-3.8%) or 33.8 million (31.2-36.5), and 3.0% (2.8-3.3%) or 29.0 million (26.3-31.8) persons, respectively. In addition, 22.3% (21.6-23.1%) or 214.9 million (207.0-222.8) persons had low high-density lipoprotein cholesterol (<1.04 mmol/L). The awareness, treatment, and control of borderline high or high total cholesterol were 11.0%, 5.1%, and 2.8%, respectively, in the Chinese adult population.
Serum total and low-density lipoprotein cholesterol levels were high and increasing in the Chinese population. Without effective intervention, atherosclerotic cardiovascular diseases may soar in the near future in China.
Paclitaxel and anthracycline-based chemotherapy is one of the standard treatment options for breast cancer. However, only about 6–30% of breast cancer patients achieved a pathological complete ...response (pCR), and the mechanism responsible for the difference is still unclear. In this study, random forest algorithm was used to screen feature genes, and artificial neural network (ANN) algorithm was used to construct an ANN model for predicting the efficacy of neoadjuvant chemotherapy for breast cancer. Furthermore, digital pathology, cytology, and molecular biology experiments were used to verify the relationship between the efficacy of neoadjuvant chemotherapy and immune ecology. It was found that paclitaxel and doxorubicin, an anthracycline, could induce typical pyroptosis and bubbling in breast cancer cells, accompanied by gasdermin E (GSDME) cleavage. Paclitaxel with LDH release and Annexin V/PI doubule positive cell populations, and accompanied by the increased release of damage-associated molecular patterns, HMGB1 and ATP. Cell coculture experiments also demonstrated enhanced phagocytosis of macrophages and increased the levels of IFN-γ and IL-2 secretion after paclitaxel treatment. Mechanistically, GSDME may mediate paclitaxel and doxorubicin-induced pyroptosis in breast cancer cells through the caspase-9/caspase-3 pathway, activate anti-tumor immunity, and promote the efficacy of paclitaxel and anthracycline-based neoadjuvant chemotherapy. This study has practical guiding significance for the precision treatment of breast cancer, and can also provide ideas for understanding molecular mechanisms related to the chemotherapy sensitivity.
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EMUNI, NUK, SBMB, SBNM, UL, UM, UPUK
Currently, acquired resistance to cisplatin (DDP) is a substantial obstacle to reducing the morbidity and mortality due to ovarian malignant tumors. Nevertheless, cisplatin plays a vital role in ...killing the tumor cells while it may also be a 'primer' involved in chemotherapy resistance. We found that the cisplatin-induced chemokine (C-C motif) ligand 5 (CCL5) secretion derived from cancer-associated fibroblasts (CAFs) promoted ovarian cancer cell resistance to cisplatin. Via a cytokine chip assay, we identified a spectrum of secreted proteins that were derived from the CAFs through cisplatin-induced treatment. Among these, CCL5 significantly attenuated the cytotoxic effect of cisplatin chemotherapy in vitro and in vivo. Additionally, CCL5 expression was also detected in 62 serous ovarian cancer patient tissue specimens using IHC, and the results demonstrated that chemotherapy resistant patients displayed higher expression of CCL5 than the chemo-sensitive patients (P<0.05). Mechanistically, we found that CCL5 notably increased STAT3 and Akt phosphorylation levels in ovarian cancer cells. These results indicated that cisplatin- induced CCL5 secretion derived from the CAFs may promote cisplatin resistance, which was mediated by regulation of the STAT3 and PI3K/Akt signal pathways.
Aristolactams (ALs) have been recognized as one kind of metabolites of aristolochic acids (AAs), the nephrotoxic components of Aristolochiaceae plants, and are more widely distributed than AAs in ...herbal medicines. This study evaluated the oral subacute nephrotoxicity of aristolactam I (AL I), a representative compound of ALs. AL I was intragastrically administered to rats at 20 mg·kg−1·d−1 for 10 or 20 days, with aristolochic acid I (AA I) used as positive control at the same dose. After 10-day treatment, AL I led to a significant increase in early renal injury-related indices in urine and obvious histopathological lesions in kidneys, including degeneration of tubular epithelial cells, inflammatory cell infiltration and fibrosis. The lesions induced by AL I were significantly aggravated after 20-day exposure. However, AL I induced less histopathological damage in kidneys than AA I in both 10- and 20-day groups. Our results indicated that oral AL I caused nephrotoxicity by inducing oxidative stress, inflammation, and overactivation of the complement system as AA I did. Three detected apoptosis-associated indicators were not affected by AL I but remarkably increased by AA I. In summary, oral AL I induced evident renal damage in rats after only 10 days of treatment, and the damage was aggravated after 20 days. However, AL I was obviously less nephrotoxic than AA I via oral gavage.
•Oral aristolactam Ⅰ caused renal damage after only 10-day administration.•Nephrotoxicity of aristolactam Ⅰ correlated with oxidative stress and inflammation.•Aristolactam Ⅰ might not affect apoptosis in kidney as aristolochic acid Ⅰ did.•Aristolactam Ⅰ was less nephrotoxic than aristolochic acid I after taken orally.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tumor metastasis is a leading cause of breast cancer-related death. Taxane-loaded polymeric formulations, such as Genexol PM and Nanoxel M using poly(ethylene glycol)-poly(d,l-lactide) (PEG-PLA) ...micelles as drug carriers, have been approved for the treatment of metastatic breast cancer. Unfortunately, the physical instability of PEG-PLA micelles, leading to poor drug loading, premature drug leakage, and consequently limited drug delivery to tumors, largely hinders their therapeutic outcome. Inspired by the enantiomeric nature of PLA, this work developed stereocomplex PEG-PLA micelles through stereoselective interactions of enantiomeric PLA, which are further incorporated with a hypoxia-responsive moiety used as a hypoxia-cleavable linker of PEG and PLA, to maximize therapeutic outcomes. The results showed that the obtained micelles had high structural stability, showing improved drug loading for effective drug delivery to tumors as well as other tissues. Especially, they were capable of sensitively responding to the hypoxic tumor environment for drug release, reversing hypoxia-induced drug resistance and hypoxia-promoted cell migration for enhanced bioavailability under hypoxia. In vivo results further showed that the micelles, especially at a high dose, inhibited the growth of the primary tumor and improved tumor pathological conditions, consequently remarkably inhibiting its metastasis to the lungs and liver, while not causing any systemic toxicity. Hypoxia-responsive stereocomplex micelles thus emerge as a reliable drug delivery system to treat breast cancer metastasis.
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IJS, KILJ, NUK, PNG, UL, UM
This study explored and compared the effects of depression and antidepressants on sexual dysfunction in men with diabetes mellitus (DM).
Patients older than 18 years who had been newly diagnosed with ...DM (International Classification of Diseases, Ninth Revision, Clinical Modification ICD-9-CM code 250) between 1999 and 2010 were identified from Taiwan's National Health Insurance Research Database and were followed up until 2013. Patients with preexisting depression or sexual dysfunction were excluded. A total of 636,210 patients with DM were enrolled. These patients were divided into two groups: DM with comorbid depression and a matched cohort without depression. The groups were followed up until the end of 2010 for the first diagnosis of sexual dysfunction (ICD-9-CM codes 302.70, 302.71, 302.72, 302.74, 302.75, 302.76, 302.79, 607.84, and V417). A Cox proportional hazard model and a Cox regression model with time-dependent covariates were applied.
Patients with DM and depression had a higher risk of sexual dysfunction than those with DM without depression (hazard ratio HR = 1.44; 95% confidence interval CI, 1.33-1.55). The risk of sexual dysfunction was lower in the subgroup who used antidepressants (per 28 cumulative defined daily doses cDDDs), HR = 0.96; 95% CI, 0.94-0.97). A significantly lower incidence of sexual dysfunction was also associated with the use of selective serotonin reuptake inhibitors (SSRIs, per 28 cDDD). The adjusted HR was 0.95 (95% CI, 0.93-0.97). Subgroup analysis indicated that SSRI use was significantly associated with an amelioration of erectile dysfunction (per 28 cDDD), with an HR of 0.95 (95% CI, 0.92-0.97).
Male patients with DM and depression are at increased risk of sexual dysfunction. Antidepressant use had a small inverse association with the risk of sexual dysfunction in men with DM and depression. Antidepressants, in particular SSRIs, did not increase the risk of sexual dysfunction in this population.
Conventional LiPF
6
/carbonate electrolytes with poor oxidative stability and reactive decomposition products (HF, PF
5
, POF
3
,
etc.
) dictate less-stable electrode/electrolyte interphases, which ...thereby promote the dissolution of transition metal ions, accelerate the constant decomposition of electrolyte solvent, and result in the degradation of LIBs. Herein, we demonstrate a new type of electrolyte,
id est
, 1.6 M lithium bis(fluorosulfonyl)imide (LiFSI) in (2-cyanoethyl)triethoxysilane (TEOSCN) with a self-purifying feature. TEOSCN molecules in the electrolyte can effectively eliminate the reactive pernicious species, while the anions of FSI
−
dominate the interphase components with low-resistance on both graphite and Ni-rich NMC cathode although at an essentially low concentration. This self-purifying electrolyte system enables long-term cycling of MCMB|NMC811 full-cells for 1000 cycles with an ultra-high capacity retention of 91% at 25 °C and for 500 cycles with a retention of 81% at 60 °C. Even in extreme cases,
i.e.
, exposed in the air for 1 h, this electrolyte still allows the stable charge-discharge cycling of MCMB|NMC811 full-cells without degradation, which can largely simplify the manufacturing processes of LIBs. The 'self-purifying-plus-passivation' strategy opens a promising frontier for electrolyte engineering towards next-generation high-energy LIBs.
Self-purifying electrolyte effectively eliminates the reactive pernicious species and endows high energy Li ion batteries with stable long-term cycling.
Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a ...therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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