Temperature-sensitive metal-enhanced fluorescence and plasmon resonance energy transfer.

Experimental decoupling of the effects of plasmon resonance energy transfer (PRET) and metal-enhanced fluorescence (MEF) within the same nanometal-fluorophore pair is fascinating but challenging. In this study, we presented a possible solution for this by coating plasmonic Au nanoparticles (AuNPs) with temperature-sensitive poly(N-isopropylacrylamide) (pNIPAM) shells and R6G hybrids, termed the Au@p-R nanoplatform, which could reversibly adjust the separation between dyes and the AuNP surface, enabling an ON/OFF switch between MEF and PRET. In our optimization process, we discovered that 20 kDa of pNIPAM causes an MEF effect owing to an appropriate shrinking distance of 6.86 ± 0.85 nm. This dual-model nanoplatform exhibits great potential for tracking temperature-dependent transitions.

The 50% effective dose of hydromorphone and morphine for epidural analgesia in the hemorrhoidectomy: a double-blind, sequential dose-finding study.

BACKGROUND: Although previous studies have showed that epidural morphine can be used as a complement to local anesthetics for analgesia after postcesarean delivery under spinal anesthesia, there is little known about the analgesic dosage of epidural morphine and hydromorphone for hemorrhoidectomy. Therefore, we conducted this study to examine the potency ratio of hydromorphone to epidural morphine as well as effective analgesic dose for 50% patients (ED50) undergoing elective hemorrhoidectomy. METHODS: 80 patients under elective hemorrhoidectomy with combined spinal and epidural anesthesia(CSEA) in department of anesthesia, Dongguan Tungwah hospital. To assess the ED50, patients were treated with epidural morphine or epidural hydromorphone randomly using a biased coin method-determined dose with a sequential allocation procedure. Following surgery, standardized multimodal analgesia was administered to all patients. A pain response score of ≤ 3 (on a scale of 0-10) was determined to be the effective dose after 24 h following CSEA. The ED50 in both groups were determined using the probit regression and isotonic regression method. We also measured pain intensity by patient interview using a 10 point verbal numeric rating scale prospectively at 6, 12 and 24 h after CSEA, and adverse effects were also noted. RESULTS: The ED50 was 0.350 mg (95% CI, 0.259-0.376 mg) in hydromorphone group and 1.129 mg (95% CI, 0.903-1.187 mg) in morphine group, respectively, estimated by isotonic regression method. Regression analysis with the probit, the ED50 of epidural hydromorphone was 0.366 mg (95% CI, 0.276-0.388 mg) and epidural morphine was 1.138 mg (95% CI, 0.910-1.201 mg). Exploratory findings showed that there was no difference between the most frequent dosages of epidural hydromorphone or epidural morphine in the occurrence of nausea, vomiting and pruritus. When administered with epidural opioids at ED50 doses or higher, 97.5% (39/40) of epidural morphine patients and 97.5% (39/40) epidural hydromorphone of patients were satisfied with their analgesia. CONCLUSION: Effective hemorrhoidectomy analgesia requires a 3:1 ratio of epidural morphine to epidural hydromorphone. Both drugs provide excellent patient satisfaction.

Research progress on post-stroke depression.

Stroke is a highly prevalent and widely detrimental cardiovascular disease, frequently resulting in impairments of both motor function and neural psychological capabilities, such as post-stroke depression (PSD). PSD is the most prevalent neuropsychological disorder among stroke patients, characterized by persistent emotional lowness and diminished interest as its primary features. This article summarizes the mechanism research, animal models and related treatments of PSD. Further improvements are needed in the screening of research subjects and the construction of animal models in the study of PSD. At the same time, in the study of the mechanism of PSD, we need to consider the interaction between multiple systems. The treatment of PSD requires more careful consideration. This can help us to find something new in the study of the mechanism of complex PSD, which provides a new direction for us to develop new treatment delivery.

Portable SERS sensing of volatile aldehydes in alcohols by aldol condensation reaction on liquid interfacial plasmonic arrays.

An aldol condensation reaction on oil-in-water (O/W) liquid interfacial plasmonic arrays was developed for sensing volatile aldehydes in alcohols by using an aromatic aldehyde as the probe for portable SERS assays. The detection limit was 10-8 M. The substrate exhibited an RSD value of 6.9%, and the probe showed good selectivity to four common interferences.

One-step hydrothermal method synthesized pH-dependent carbon dots for multistage anti-counterfeiting.

Work to combat counterfeiting has always been crucial to defending the interests of the public. The usual anti-counterfeiting marks are now fundamental and easy to imitate. Therefore, it is more beneficial to anti-counterfeiting work to develop an anti-counterfeiting mark with more variations to make forgery more difficult. Due to its exceptional stability and fluorescence variability, carbon dots (CDs), a newly developed fluorescent material, offer a wide range of potential applications in anti-counterfeiting. However, there currently needs to be more CD applications in multi-level anti-counterfeiting, and additional issues include high cost and environmental contamination. Therefore, considering the problems of green environmental protection and cost, CDs with excellent green (530 nm) and blue (475 nm, 486 nm) luminescence properties were prepared by a one-step reaction of m-phenylenediamine and glucose. The average fluorescence lifespan is longer than 5 ns, and the optimal quantum yield can reach 37%. Due to the large number of protonated amino groups and surface carboxyl functional groups, the prepared carbon dots exhibit green and blue fluorescence emission modes under acidic and alkaline conditions, respectively. Based on this situation, we produced CD ink and successfully used it for multi-level anti-counterfeiting.

Design and discovery of new selective and potent VEGF receptor 2 tyrosine kinase inhibitors.

A series of novel substituted 4-anilinoquinazolines and their related compounds were designed and prepared by 3D modeling as potential inhibitors of VEGFR-2. Evaluation of VEGFR inhibitory activities suggested that compound I10 was a more potent (IC50 = 0.11 nM) VEGFR-2 inhibitor than most of the listed drugs. Kinase panel assays demonstrated that compound I10 was the selective VEGFR-2 inhibitor. The prediction of 3D modeling unveiled a unique binding mode of this lead compound to VEGFR-2. Compound I10 exhibited remarkable anti-angiogenesis and anti-proliferation in HUVEC at low nanomolar concentrations. PK studies indicated that the lead compound possessed adequate oral bioavailability in various species. In vivo subcutaneous tumor model demonstrated that oral administration of I10 demonstrated potent efficacy in inhibiting tumor growth and angiogenesis. All these results suggested compound I10 is a potential drug candidate for cancer treatment.

Bimetallic core-shell nanoparticle arrays at liquid-liquid interface for the degradation and monitoring of dye pollutants in situ by surface-enhanced Raman spectroscopy.

In situ monitoring of chemical reactions has attracted great attention in many fields. Herein, we successfully in situ track the degradation reaction process of a dye pollutant, methylene blue (MB), on the liquid-liquid interface (LLI) of bimetallic gold core-silver shell nanoparticles (Au@AgNPs) by surface-enhanced Raman spectroscopy (SERS). The optimized LLI bimetallic array of Au50@Ag10NPs exhibits ultrahigh SERS enhancement and excellent catalytic activity. Results evidenced a detection limit of MB down to 1 ppb, and the degradation rate of Au@AgNPs was as high as 85.2% in 30 s, relying on the excellent self-healing properties of nanoarrays. Furthermore, as a practical SERS analyzer, the LLI bimetallic array was used to detect trace amounts of other harmful dyes, including Rhodamine 6G (R6G) and crystal violet (CV) in pure or complex media. Our LLI bimetallic array exhibits a new orientation for monitoring catalytic reactions involving highly toxic, hazardous, or costly targets in food security fields in the future.

Discovery of novel and bioavailable histone deacetylases and cyclin-dependent kinases dual inhibitor to impair the stemness of leukemia cells.

Acute myeloid leukemia (AML) has been confirmed as one of the most lethal heterogeneous clonal diseases. In addition to being essential for the development and progression of leukemia, leukemic stem cells (LSCs), a subpopulation of leukemia cells with stem cell characteristics, are also primarily responsible for the development of leukemia relapse and drug resistance. Elimination of stemness and induction of AML cell differentiation would become a promising and effective therapeutic strategy. In the present study, a novel class of HDACs/CDKs dual inhibitors was prepared and optimized. An active compound 33a has been identified, which exhibited potent and selective inhibition of CDK9, CDK12, CDK13, HDAC1, HDAC2 and HDAC3 at low nanomolar concentrations and significantly induced differentiation of leukemic stem-like cells and inhibited AML proliferation. Furthermore, the lead compound has relatively adequate oral bioavailability, suggesting that it might be used as a novel strategy to reduce the burden of LSCs and improve the prognosis for AML.

Structure optimization and discovery of novel compound for the treatment of insertion mutations within exon 20 of EGFR and HER2.

In previous decades, patients with the most active EGFR mutations in non-small cell lung cancer (NSCLC) have significantly benefited from EGFR tyrosine kinase inhibitors (TKIs). However, a minority with EGFR and HER2 exon 20 mutations are inherently resistant to treatment. Several molecular TKIs (such as TAK788 and Poziotinib) were recently discovered and demonstrated as effective inhibitors against the most prevalent HER2 or EGFR exon 20 mutations. However, low clinical efficiency and uncertain adverse reaction indicated that the development of effective therapies is still demanded. In the present work, we designed several hybrid compounds learning from 3D modeling of kinase structure. One lead compound (compound 56) was found to be the most potent compound with IC50 value of 0.027 nM against EGFR D770-N771 ins NPG and reduced binding affinity with hERG protein. In vitro and in vivo biological results suggested that compound 56 demonstrated good oral bioavailability, and it was significantly capable of inhibiting the growth of tumor cells with a variety of HER2 exon 20 mutations and EGFR mutants with negligible toxic effects. It was identified that compound 56 might be considered a potential drug candidate for NSCLC target therapy.

Correlation between persistent high-risk human papillomavirus infection and vaginal microecology and cervical lesions / 中国热带医学

@#Abstract: Objective To investigate the correlation between persistent and non-persistent HPV infection and vaginal microecology and cervical lesions, and to provide the basis for HPV prevention and treatment. Methods In this prospective study, 229 female patients with high-risk type (HR-HPV) were selected for cervical cytology and vaginal microecological examination in the gynecological outpatient department of Baise Maternal and Child Health Hospital from January 2018 to June 2021. The patients were followed up for 1 year to detect persistent HR-HPV infection. The relationship between HR-HPV persistent infection and vaginal microecology and cervical lesions was analyzed using the HPV-negative group as a control. Results Among 229 patients with HR-HPV, there were 109 patients with persistent HR-HPV infection and 120 patients with non-persistent HR-HPV infection in 1-year follow-up, and the incidence of persistent HR-HPV infection was 47.6%. In the HR-HPV persistent and non-persistent infection and HPV-negative groups, the bacterial vaginal incidence was 20.2%, 15.0% and 8.6%, respectively; vulvovaginal candidiasis was 19.3%, 13.3% and 7.9%, respectively; trichomoniasis vaginitis was 12.8%, 9.2% and 4.5%, respectively; mixed infection was 10.1%, 6.7% and 2.7%; H2O2 detection rate was 24.8%, 18.3% and 12.0%,the positive rate of pH value was 52.3%, 40.8% and 36.4%, and microecological normal detection rate was 22.9%, 32.7% and 40.2%, respectively. There were significant differences among the three groups (χ2=10.634, 10.522, 9.010, 9.374, 10.054, 8.268, P<0.01). In the HR-HPV persistent and non-persistent infection groups, the rates of atypical squamous cell detection were 12.8% and 10.0%, and 8.3% and 4.2% for low-grade squamous cell lesions, and 4.6% and 1.7% for high-grade squamous cell carcinoma, 2.8% and 0 for squamous cell carcinoma, respectively. There was no significant difference in the composition of atypical squamous cells between the two groups (χ2=4.358, P>0.05), there were significant differences in the composition of low-grade, high-grade and squamous cell carcinoma (χ2=11.472, 12.685, 11.378, P<0.01). Spearman rank correlation analysis showed that the presence or extent of HPV infection was positively correlated with bacterial vaginosis, vulvovaginal candidiasis, trichomonal vaginitis and mixed infection (P<0.05), positively correlated with H2O2, sialdase, leucocyte esterase,pH positive and positive for all four items (P<0.05), negatively correlated with microecology (P<0.01), positively correlated with low grade, high grade and squamous cell carcinoma (P<0.01), and not significantly correlated with atypical squamous cell carcinoma (P>0.05). Conclusion Persistent cervical HPV infection is an important factor of dysregulation in vaginal microecology and aggravates the degree of dysregulation in vaginal microecology, which is related to the development of cervical lesions.

5α-Epoxyalantolactone Inhibits Metastasis of Triple-Negative Breast Cancer Cells by Covalently Binding a Conserved Cysteine of Annexin A2.

Triple-negative breast cancer (TNBC) has been considered the most aggressive and mortal breast cancer. Thus far, it remains an important challenge to develop TNBC targeted therapy. As revealed from numerous recent studies, ANXA2 may be a potential target to treat TNBC. In the present study, a natural product 5α-epoxyalantolactone (5α-EAL) was discovered as an anti-breast cancer stem cells (BCSCs) lead compound. Furthermore, 5α-EAL was found to be able to notably suppress the function of ANXA2 by covalently targeting cysteine 9 (Cys9) of ANXA2. To the best of our knowledge, 5α-EAL was recognized as the first small molecule functional inhibitor of ANXA2. It could significantly inhibit the formation of the heterotetrameric complex of ANXA2 and S100A10, which is capable of transporting E-cadherin (E-Ca) to the membrane. The above findings may be used as a possible strategy to develop novel anti-TNBC therapies targeting ANXA2.

Discovery and Optimization of a Novel 2H-Pyrazolo[3,4-d]pyrimidine Derivative as a Potent Irreversible Pan-Fibroblast Growth Factor Receptor Inhibitor.

Fibroblast growth factor receptors (FGFRs) have become promising therapeutic targets in various types of cancers. In fact, several selective irreversible inhibitors capable of covalently reacting with the conserved cysteine of FGFRs are currently being evaluated in clinical trials. In this article, we optimized and discovered a novel lead compound 36 with remarkable inhibitory effects against FGFR (1-3), which is a derivative of 2H-pyrazolo[3,4-d]pyrimidine. The irreversible binding to FGFRs was characterized by LC-MS. This compound has been shown to exhibit significant anti-proliferation effects against NCI-H1581 and SNU-16 cancer cell lines both in vitro and in vivo. Compound 36 has also demonstrated a low toxicity profile and adequate pharmacokinetic properties and is currently under validation as a potential drug candidate.

First orally bioavailable prodrug of proteolysis targeting chimera (PROTAC) degrades cyclin-dependent kinases 2/4/6 in vivo.

A growing number of reports suggested that the inhibitor targeting cyclin-dependent kinases (CDK) 2/4/6 can act as a more feasible chemotherapy strategy. In the present paper, a novel PROTAC molecule was developed based on the structure of Ribociclib's derivative. In malignant melanoma cells, the degrader can not only degrade CDK 2/4/6 simultaneously and effectively, but also remarkably induce cell cycle arrest and apoptosis of melanoma cells. Moreover, PROTAC molecules with CRBN ligands always have poor oral bioavailability. We developed the orally bioavailable prodrug for the first time. It would provide general solution for oral administration of the PROTAC molecules, derived from CRBN ligands, for animal test conveniently.

Design and synthesis of novel Flavone-based histone deacetylase inhibitors antagonizing activation of STAT3 in breast cancer.

Histone deacetylases (HDACs) inhibitors have demonstrated a great clinical achievement in hematological malignancies. However, the efficacy of HDACs inhibitors in treating solid tumors remains limited due to the complicated tumor microenvironment. In this study, we designed and synthesized a class of novel HDACs inhibitors based on the structure of flavones and isoflavones, followed by biological evaluation. To be specific, a lead compound 15a was discovered with strong anti-proliferative effects on a variety of solid tumor cells, especially for breast cancer cells with resistance to SAHA. Studies demonstrated that 15a could significantly inhibit the activity of HDAC 1, 2, 3 (class I) and 6 (class IIB), leading to a dose-dependent accumulation of acetylated histones and α-Tubulin, cell cycle arrest (G1/S phase) and apoptosis in breast cancer cells. Furthermore, the lead compound 15a could also antagonize the activation of STAT3 induced by HDACs inhibition in some breast cancer cells, which further reduced the level of pro-survive proteins in tumor cells and enhanced anti-tumor activity regulated by STAT3 signaling in vivo. Overall, our findings demonstrated that the novel compound 15a might be a HDACs inhibitor candidate, which could be used as promising chemotherapeutic agent for breast cancer.

Design and synthesis of Leukotriene A4 hydrolase inhibitors to alleviate idiopathic pulmonary fibrosis and acute lung injury.

Idiopathic pulmonary fibrosis (IPF) and acute lung injury (ALI) are considered two severe public health issues, attributed to malfunctions of neutrophils. They can cause chronic inflammation and have association with subsequent tissue damages. There have been rare drugs applying to the efficient treatment in clinical practice. Existing research revealed that Leukotriene B4 (LTB4) is the critical endogenous molecule to induce neutrophil inflammatory response. LTB4 blocking biosynthesis is the potential strategy treating IPF and ALI. In the present study, 45 hydroxamic acid derivatives were produced, and compound 26 was screened out as a highly selective Lead compound of Leukotriene A4 Hydrolase (LTA4H), i.e., an enzyme critical to the biosynthesis of LTB4. This compound is capable of relieving neutrophilic inflammation in an IPF mouse model at early stage, as well as mitigating LPS-induced acute lung injury via a mechanism of LTB4 blocking biosynthesis in vivo. Whether this compound acts as the potential lead compound for the treatment of IPF and ALI requires further verification.

Synthesis and Discovery Novel Anti-Cancer Stem Cells Compounds Derived from the Natural Triterpenoic Acids.

Cancer stem cells (CSCs) have been reported to be involved in tumorigenesis, tumor recurrence, cancer invasion, metastasis, and drug-resistance. Therefore, the development of drug molecules targeting CSCs has become an attractive therapeutic approach. However, the molecules which can selectively ablate CSCs are extremely rare. To explore the leading compounds targeting CSCs, 52 analogues of triterpenoic acids were synthesized in this study, whose biological activities were evaluated. On the basis of the results of tumorsphere assay, two compounds 48 and 51, derived from oleanolic acid, exhibited suppressive effect on elimination of different type of CSCs. Meanwhile, compounds 48 and 51 could significantly inhibit the growth of several tumors both in vitro and in vivo. Furthermore, treatment of cancer cells with both of two compounds would dramatically increase the level of ROS, which might eliminate the CSCs. Collectively, the leading compounds 48 and 51 were promising anti-CSCs agents that merited further validation as a novel class of chemotherapeutics.

Synthesis and discovery of a drug candidate for treatment of idiopathic pulmonary fibrosis through inhibition of TGF-ß1 pathway.

In this study, anti-IPF lead compounds 42 and 44, derived from natural sesquiterpene lactones Isoalantolactone and alantolactone, were discovered by screening from a high-throughput TGF-ß1 reporter luciferase assay. Notably, they could reduce the myofibroblast activation and extracellular matrix deposition both in vitro and in vivo. Additionally, compounds 42 and 44 could significantly attenuate bleomycin-induced pulmonary fibrosis in mice. Further validation of pharmacokinetics study and toxicity evaluation indicated that compound 44 might be a promising anti-IPF drug candidate.