Design, synthesis and biological evaluation of aloperine derivatives as potential anticancer agents.

Modifications at different positions on the aloperine molecule were performed to improve its anticancer activity and develop anticancer drugs. The in vitro anticancer activities of 44 synthesized compounds were evaluated. The effect of modification positions on anticancer activity was discussed and a structure-activity relationship analysis was established. A novel series of compounds with modifications at the N12 position showed much higher cytotoxicity than aloperine. Among them, compound 22 displayed promising in vitro anticancer activity against PC9 cells with a median inhibitory concentration (IC50) of 1.43 µM. The mechanism studies indicated that compound 22 induced cell apoptosis and cell cycle arrest in PC9 cells. These results demonstrate the potential of aloperine thiourea derivatives in anticancer activity.

Hypoxia Inhibitor Combined with Chemotherapeutic Agents for Antitumor and Antimetastatic Efficacy against Osteosarcoma.

Chemotherapy is the main treatment method for osteosarcoma in the clinic. However, drug resistance and its poor antimetastatic effects greatly limit its clinical application. In this work, dual-drug nanoparticles (NPs) containing albendazole (ABZ) and doxorubicin (DOX), named AD@PLGA-PEG NPs, were prepared to solve the problems of chemotherapeutic drug resistance and poor antimetastasis effects. Compared with free DOX, ABZ combined with DOX can increase intracellular reactive oxygen species (ROS) and induce more tumor cell apoptosis; therefore, AD@PLGA-PEG NPs produced more mitochondria-mediated oxidative stress and better apoptosis efficiency. Importantly, ABZ can also effectively inhibit the expression of hypoxia inducible factor-1α (HIF-1α) and then reduce the expression of its downstream vascular endothelial growth factor (VEGF); thus, the AD@PLGA-PEG NPs effectively inhibited tumor metastasis in vivo. Collectively, the dual-drug AD@PLGA-PEG NPs delivery system provided prominent antitumor and antimetastatic efficacy and might be a promising treatment for osteosarcoma.

Diagnosis, treatment and genetic analysis of a child with infantile neuroaxonal dystrophy.

Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disease characterized by early hypotonia, and rapid progression to psychomotor development regression, pyramidal tract positivity, and spastic quadriplegia. In this report, we describe a Chinese patient with INAD who presented with hypotonia, delayed motor and language development, and subsequently improved with rehabilitation training. Genetic testing revealed that the patient had compound heterozygous PLA2G6 gene variants, with the heterozygous c.496dupG (p.Glu166fsTer32) variant inherited from her father and the heterozygous c.2189T>G (p.Met730Arg) variant inherited from her mother. The p.Met730Arg was a novel variant. The protein structure predicts that the structural stability of the mutant protein may change, and the in vivo experimental results show that the expression of the mutant protein decrease. This study enriches the PLA2G6 gene mutation spectrum, and improves the clinicians' diagnostic awareness of INAD.

Species divergence and phylogeography of Corylus heterophylla Fisch complex (Betulaceae): Inferred from molecular, climatic and morphological data.

Historical geo-climatic changes have shaped the geographical distributions and genetic diversity of numerous plant taxa in East Asia, which promote species divergence and ultimately speciation. Here, we integrated multiple approaches, including molecular phylogeography, ecological niche modeling, and morphological traits to examine the nucleotide diversity and interspecific divergence within Corylus heterophylla complex (C. heterophylla, C. kweichowensis, and C. yunnanensis). These three sibling taxa harbored similar high levels of nucleotide diversity at the species level. The molecular data (SCNG and cpDNA) unanimously supported the division of C. heterophylla complex into two major clades, with C. yunnanensis diverged earlier from the complex, whereas C. heterophylla and C. kweichowensis could hardly be separated. The split between the two clades (c. 12.89 Ma) coincided with the formation of Sichuan Basin in the middle Miocene, while the divergence among and within the five subclades (YUN1-YUN3, HK1-HK2) occurred from the late Miocene to the Pleistocene. C. heterophylla of northern China experienced glacial contraction and interglacial expansion during the Quaternary, whereas C. kweichowensis and C. yunnanensis of southern China presented population expansion even during the last glacial maximum. Despite of high levels of genetic admixture between C. heterophylla and C. kweichowensis, significant ecological and morphological discrepancy as well as incomplete geographic isolation indicated that adaptive evolution triggered by divergent selection may have played important roles in incipient ecological speciation.

In vitro genotoxicity study of silver nanoparticles and titanium dioxide nanoparticles.

Nanoparticles are widely used in cosmetic, pharmaceutical, and food industries, but their safety and genetic toxicity are still unclear. In this study, the genotoxicity of silver nanoparticles (AgNPs) and titanium dioxide nanoparticles (titanium dioxide nanoparticles) were evaluated by in vitro comet assay and PIG-A assay in TK6 cells. We exposed TK6 cells to two types of nanoparticles at the highest concentration of 200 µmol/L for 4 h and conducted the in vitro comet assay. We examined the mutation results of PIG-A gene in vitro after 4 h, 24 ho and 10 days of exposure, respectively. We also examined the endocytosis of nanoparticles in TK6 cells exposed to nanoparticles for 24 h. In the endocytosis assay, with the increase of nano-material concentration, the side scatter (SSC) of TK6 cells in flow cytometry showed a concentration-dependent and time-dependent increase, indicating that TK6 cells could uptake both types of nanoparticles. In the comet assay, AgNPs could induce a concentration-dependent increase in DNA tail intensity. However, titanium dioxide NPs could not induce the concentration-dependent increase of DNA fluorescence intensity of comet tail. In the PIG-A assay, both AgNPs and TiO2NPs did not induce PIG-A gene mutation frequency in TK6 cells. The results showed that AgNPs could induce DNA damage in TK6 cells, but could not induce increase of PIG-A gene mutation frequency. TiO2NPs neither induce DNA damage in TK6 cells nor increase PIG-A mutation frequency. Further tests are needed to determine whether TiO2NPs are genotoxic.

Divergent Coupling of Benzocyclobutenones with Indoles via C-H and C-C Activations.

Highly selective divergent coupling reactions of benzocyclobutenones and indoles, in which the chemoselectivity is controlled by catalysts, are reported herein. The substrates undergo C2(indole)-C8(benzocyclobutenone) coupling to produce benzylated indoles and benzo[b]carbazoles in the Ni- and Ru-catalyzed reactions. A completely different selectivity pattern C2(indole)-C2(benzocyclobutenone) coupling to form arylated indoles is observed in the Rh-catalyzed reaction. Preliminary mechanistic studies suggest C-H and C-C activations in the reaction pathway. Synthetic utility of this protocol is demonstrated by the selective synthesis of three different types of carbazoles from the representative products.

Directed Decarbonylation of Unstrained Aryl Ketones via Nickel-Catalyzed C-C Bond Cleavage.

The nickel-catalyzed decarbonylation of unstrained diaryl ketones has been developed. The reaction is catalyzed by a combination of Ni(cod)2 and an electron-rich N-heterocyclic carbene ligand. High functional group tolerance and excellent yields (up to 98%) are observed. This strategy provides an alternative and versatile approach to construct biaryls using an inexpensive nickel catalyst.

[Optimization of preparation procedures for nano-sponges of flavonoids fromGlycyrrhizae Radix et Rhizoma by Box-Behnken response surface methodology based on CRITIC weighted evaluation].

In this paper, nano-sponges of flavonoids from Glycyrrhizae Radix et Rhizoma (LF-NSP) were prepared by agitation-freeze drying method. Box-benhnken design and response surface method based on the single factor experiment was used to optimize the preparation process, with the stirring temperature as well as stirring time and speed as the independent variables, while with drug loading, particle size and the generalized "normalized value" as the response values. In addition, the nano-sponges were characterized by scanning electron microscope (SEM), infraredspectroscopy (FT-IR) and differential scanning calorimetry (DSC), and its release in vitro was also investigated. The results showed that the optimum preparation conditions for glycyrrhizin nano-sponges were as follows：The proportion of main drug and auxiliary drug was 1:2; the proportion of crosslinking agent DPC and ß-CD was 4:1; stirring temperature 45 °C for 4.8 h at 245 r·min⁻¹. The comprehensive score of LF-NSP prepared under these conditions was 94.78. FT-IR and DSC results indicated the formation of Glycyrrhiza flavonoids nano-sponges, and SEM showed that they were spherical particles in shape. In release experiment in vitro, the cumulative release of glycyrrhizin flavonoids nano-sponges for 240 min was 81.8%, while that of crude drug was only 31.5%. Nano-sponges can significantly improve the dissolution of flavonoids from Glycyrrhizae Radix et Rhizoma.

Small molecule targeted therapies for endometrial cancer: progress, challenges, and opportunities.

Endometrial cancer (EC) is a common malignancy among women worldwide, and its recurrence makes it a common cause of cancer-related death. Surgery and external radiation, chemotherapy, or a combination of strategies are the cornerstone of therapy for EC patients. However, adjuvant treatment strategies face certain drawbacks, such as resistance to chemotherapeutic drugs; therefore, it is imperative to explore innovative therapeutic strategies to improve the prognosis of EC. With the development of pathology and pathophysiology, several biological targets associated with EC have been identified, including PI3K/Akt/mTOR, PARP, GSK-3ß, STAT-3, and VEGF. In this review, we summarize the progress of small molecule targeted therapies in terms of both basic research and clinical trials and provide cases of small molecules combined with fluorescence properties in the clinical applications of integrated diagnosis and treatment. We hope that this review will facilitate the further understanding of the regulatory mechanism governing the dysregulation of oncogenic signaling in EC and provide insights into the possible future directions of targeted therapeutic regimens for EC treatment by developing new agents with fluorescence properties for the clinical applications of integrated diagnosis and treatment.

Clinical evolution of antisynthetase syndrome-associated interstitial lung disease after COVID-19 in a man with Klinefelter syndrome: A case report.

BACKGROUND: This study presents a case of rapidly developing respiratory failure due to antisynthetase syndrome (AS) following coronavirus disease 2019 (COVID-19) in a 33-year-old man diagnosed with Klinefelter syndrome (KS). CASE SUMMARY: A 33-year-old man with a diagnosis of KS was admitted to the Department of Pulmonary and Critical Care Medicine of a tertiary hospital in China for fever and shortness of breath 2 wk after the onset of COVID-19. Computed tomography of both lungs revealed diffuse multiple patchy heightened shadows in both lungs, accompanied by signs of partial bronchial inflation. Metagenomic next-generation sequencing of the bronchoalveolar lavage fluid suggested absence of pathogen. A biopsy specimen revealed organizing pneumonia with alveolar septal thickening. Additionally, extensive auto-antibody tests showed strong positivity for anti-SSA, anti-SSB, anti-Jo-1, and anti-Ro-52. Following multidisciplinary discussions, the patient received a final diagnosis of AS, leading to rapidly progressing respiratory failure. CONCLUSION: This study underscores the clinical progression of AS-associated interstitial lung disease subsequent to viral infections such as COVID-19 in patients diagnosed with KS.

Light-Promoted Nickel-Catalyzed C-O/C-N Coupling of Aryl Halides with Carboxylic Acids and Sulfonamides.

A general strategy for the construction of dual-functional carbon-heteroatom bonds has been developed via a light-promoted nickel catalytic system. Employing a simple NiBr2 as the catalyst without any exogeneous ligands and photosensitizers, a variety of esters and sulfonamide N-arylation derivatives, including celecoxib- and glimepiride-derived sulfonamides, were readily accessed with high functional group tolerance and high efficiency. Moreover, the UV-vis absorption spectrum and free radical trapping experiments aimed at revealing the mechanism of the reaction are also presented.

[Effect of polishing method and time on the fitness of CAD/CAM zirconia ceramic crown].

PURPOSE: To compare the effect of different polishing methods and time treatment on the fitness of CAD/CAM zirconia ceramic crowns. METHODS: Sixteen intact maxillary premolars were randomly divided into two groups, group A was treated with silicon carbide burs, while group B was treated with tungsten steel burs. At different polishing time points of the same tooth, digital impressions of each group were obtained, which were used to manufacture CAD/CAM zirconium ceramic crowns. After trial fitting, the gap impressions were obtained by using silicone rubber replication method, and the marginal and internal discrepancies were assessed. The data were statistically analyzed with SPSS 21.0 software package. RESULTS: The difference between the gap values of the marginal and internal markers of group A and group B was not statistically significant(P＞0.05). Compared with the no-polishing process, the differences of the marginal gap (39.67±8.35) µm and internal gap (45.18±7.16) µm of group A polished for 4 min, and the marginal gap (51.25±14.73) µm, and internal gap (48.56±6.45) µm of group B polished for 3 min, as well as the marginal gap (48.87±8.90) µm, and internal gap (45.99±7.12) µm of group B polished for 4 min, were all significant(P＜0.05). CONCLUSIONS: CAD/CAM zirconia ceramic crowns treated with silicon carbide bur for polishing 4 min and tungsten steel for 3 min has the best fitness.

Exploring the mechanism of the PTP1B inhibitors by molecular dynamics and experimental study.

Protein tyrosine phosphatase 1B (PTP1B) has proven to be an attractive target for the treatment of cancer, diabetes and other diseases. Although many PTP1B inhibitors with various scaffolds have been developed, there is still a lack of PTP1B inhibitor with high specificity and acceptable pharmacological properties. Therefore, it is urgent to develop more methods to explore complex action mode of PTP1B and ligands for designing ideal PTP1B modulators. In this work, we developed a potential molecular dynamics (MD) analytic mode to analyze the mechanism of active compounds 6a and 6e against PTP1B from different perspectives, including the stable ability, interactions and binding site of ligand and protein, the binding energy, relative movement between residues and changes in protein internal interactions. The simulated results demonstrated that compound 6a bound more stably to the active pocket of PTP1B than 6e due to its smaller molecular volume (326 Å3), matched electronegativity, and enhanced the positive correlation motion of residues, especially for WPD loop and P loop. Lastly, compound 6a as a competitive inhibitor for PTP1B was verified by enzyme kinetic assay. This work successfully studied the mechanism of compound 6a against PTP1B from various aspects, enriched the analysis of interaction mode between PTP1B and inhibitors. In summary, we hope that this work could provide more theoretical information for designing and developing more novel and ideal PTP1B inhibitors in the future.

Combined with UPLC-Triple-TOF/MS-based plasma lipidomics and molecular pharmacology reveals the mechanisms of schisandrin against Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD), a type of neurodegeneration disease, is characterized by Aß deposition and tangles of nerve fibers. Schisandrin is one of the main components of Fructus Schisandrae Chinensis. Researches showed that schisandrin can improve the cognitive impairment and memory of AD mice, but the specific mechanism has not been fully elucidated. PURPOSE: The purpose of this study is to investigate the possible mechanism of schisandrin in improving AD pathology. METHODS: The Morris water maze test was executed to detect spatial learning and memory. Ultra performance liquid chromatography-Triple time of flight mass spectrometry (UPLC-Triple-TOF/MS)-based plasma lipidomics was used to study the changes of plasma lipids. Moreover, we measured the levels of protein and mRNA expression of APOE and ABCA1 in the rat brains and in BV2 microglia. RESULTS: Our study found that schisandrin could improve learning and memory, and reduce Aß deposition in AD rats. Furthermore, we found that schisandrin can improve plasma lipid metabolism disorders. Therefore, we hypothesized schisandrin might act via LXR and the docking results showed that schisandrin interacts with LXRß. Further, we found schisandrin increased the protein and mRNA expression of LXR target genes APOE and ABCA1 in the brain of AD rats and in BV2 microglia. CONCLUSION: Our study reveals the neuroprotective effect and mechanism of schisandrin improves AD pathology by activating LXR to produce APOE and ABCA1.

[Development of therapeutic antibodies for gastric and colorectal cancers].

With the elucidation of structures and functions, antibodies are widely applied in the diagnosis and treatment of diseases. Today, therapeutic antibodies have played ever increasing roles in the treatment of cancers. In fact, there are over 20 monoclonal antibodies which have been approved by the U.S.Food and Drug Administration (FDA) for the therapeutic use in cancers. For the gastric and colorectal cancers, there are at least 9 antibodies have been approved for cancer therapy or for clinical trials. These antibody drugs target to tumor associate antigens and can destroy the cancer cells through several mechanisms such as antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity, blockage of blood nutrition and crucial signaling pathways. With the progress in gene engineering technology, the diverse structures of antibodies can be created. In addition, the antibody-conjugates with radioisotopes, toxins and cytotoxins, are also designed for targeted therapy of gastric and colorectal cancers. In this article, we review the trends in the clinical development and application of antibody drugs for future research and development of the rapidly expanding therapeutic modality in gastric and colorectal cancers.

Effect of phosphate salts on the shelf-life and quality characteristics of semi-dried noodles.

The effect of four types of phosphate salts (PS) on the shelf-life and quality characteristics of semi-dried noodles, as well as their underlying mechanism were investigated. Microbial analysis showed 0.2% or 0.4% sodium dihydrogen phosphate (MSP) extended the shelf-life of noodles from 3 days to 5 days. Nuclear magnetic resonance analysis revealed PS decreased the mobility of free water in noodles. Cooking and texture analysis showed sodium pyrophosphate (TSPP) increased the cooking loss of noodles, and MSP decreased the tensile force of noodles. Sodium hexametaphosphate (SHMP), TSPP, and MSP increased the hardness of noodles, while sodium tripolyphosphate (STPP) decreased the hardness. Thermal properties analysis indicated STPP and TSPP increased the gelatinization enthalpy (ΔH) of starch in noodles, while SHMP and MSP decreased the ΔH. Furthermore, confocal laser scanning microscopy and scanning electron microscopy showed SHMP, STPP, and MSP strengthened the gluten network formation, while TSPP weakened the network.

Photoredox/nickel dual catalyzed stereospecific synthesis of distal alkenyl ketones.

The selective C-C bond deconstruction/refunctionalization via a photoredox/nickel dual-catalyzed hydroalkylation of alkynes is developed under mild reaction conditions. In this protocol, a broad range of alkyl- and aryl-alkynes could react smoothly with cycloalkanols, affording the corresponding distal and site-specific vinyl-substituted ketones with high yields and excellent regioselectivities. Moreover, DFT calculations verified that the electron-rich behavior of aromatics and weak Brønsted bases have a common effect on the photocatalytic oxidant ring-opening of cyclobutanols.

Tubiechong：A review on ethnomedicinal uses, bioactive chemical constituents and pharmacological activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Tubiechong comprises mainly Eupolyphaga and Steleophaga is widely distributed in China. It has been used in the traditional medicine systems in Asian countries specially in China，Japan and Singapore for thousand years. AIM OF THE REVIEW: The aim of this work is to review the scientific work about Tubiechong regarding their ethnomedicinal uses, bioactive chemical constituents and pharmacological activities. MATERIALS AND METHODS: Relevant literature of Tubiechong was collected for its traditional uses, pharmacological activities, and bioactive compounds released from inception until May 2022. The online databases such as Web of Science, PubMed, Google Scholar, Science Direct, Scopus, SciFinder Scholar, Springer Link, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP database were used as electronic search engines for articles with the various specific keywords. Additionally, references from ancient texts and local information such as PhD and MSc theses, books, and Chinese journals were also included. RESULTS: The clinical researches have revealed that Tubiechong alone has been successfully used to treat bone disease, ache, sprain, herpes zoster, paronychia and so on. Tubichong's main clinical application is to form formulations with other herbs. The most widely used 34 kinds of Chinese patent medicine containing Tubiechong were included in Chinese Pharmacopoeia (2020 Edition) for the treatment of traumatic injury, low back pain, cardiovascular disease, tumors or mass and nodule, cervical spondylopathy, osteoarthritis and psoriasis. Its other derived formulas have been used in the clinical treatment of various diseases, such as blood stasis, hepatic cirrhosis, cyclomastopathy, chronic active hepatitis, nephropathy, gynaecopathia, cancer diseases. To date, the bioactive substances reported are limited to protein and peptides, fatty acids, polysaccharides and alkaloids from Eupolyphaga sinensis Walker. So far, the pharmacological activities of Tubiechong and its various extracts have been evaluated, including anticoagulant and antithrombotic, anticancer, bone repair, immunomodulation, analgesia, antioxidant, antihyperlipidemic, antimicrobial and protective and repair functions for damage to the liver, heart, brain and skin. As an edible insect, its safety has also been confirmed by acute toxicity tests and 30-day feeding trials. CONCLUSION: Tubiechong is an important insect medicine with the effect of promoting blood circulation and removing blood stasis, which has been used in traditional Chinese medicine for thousands of years for the treatment of trauma and abdominal lumps, and has now been clinically extended to the treatment of a variety of diseases. Its multiple pharmacological activities indicate that it has great potential for development and application. However, its chemical constituents with pharmacological activity require further excavation and detailed study. In addition, the in-depth molecular pharmacological mechanisms deserve further explanation.

Exosome-Mediated miR-21 Was Involved in the Promotion of Structural and Functional Recovery Effect Produced by Electroacupuncture in Sciatic Nerve Injury.

PURPOSE: Our study is aimed at investigating the mechanism by which electroacupuncture (EA) promoted nerve regeneration by regulating the release of exosomes and exosome-mediated miRNA-21 (miR-21) transmission. Furthermore, the effects of Schwann cells- (SC-) derived exosomes on the overexpression of miR-21 for the treatment of PNI were investigated. METHODS: A sciatic nerve injury model of rat was constructed, and the expression of miR-21 in serum exosomes and damaged local nerves was detected using RT-qPCR after EA treatment. The exosomes were identified under a transmission electron microscope and using western blotting analysis. Then, the exosome release inhibitor, GW4869, and the miR-21-5p-sponge used for the knockdown of miR-21 were used to clarify the effects of exosomal miR-21 on nerve regeneration promoted by EA. The nerve conduction velocity recovery rate, sciatic nerve function index, and wet weight ratio of gastrocnemius muscle were determined to evaluate sciatic nerve function recovery. SC proliferation and the level of neurotrophic factors were assessed using immunofluorescence staining, and the expression levels of SPRY2 and miR-21 were detected using RT-qPCR analysis. Subsequently, the transmission of exosomal miR-21 from SC to the axon was verified in vitro. Finally, the exosomes derived from the SC infected with the miR-21 overexpression lentivirus were collected and used to treat the rat SNI model to explore the therapeutic role of SC-derived exosomes overexpressing miR-21. RESULTS: We found that EA inhibited the release of serum exosomal miR-21 in a PNI model of rats during the early stage of PNI, while it promoted its release during later stages. EA enhanced the accumulation of miR-21 in the injured nerve and effectively promoted the recovery of nerve function after PNI. The treatment effect of EA was attenuated when the release of circulating exosomes was inhibited or when miR-21 was downregulated in local injury tissue via the miR-21-5p-sponge. Normal exosomes secreted by SC exhibited the ability to promote the recovery of nerve function, while the overexpression of miR-21 enhanced the effects of the exosomes. In addition, exosomal miR-21 secreted by SC could promote neurite outgrowth in vitro. CONCLUSION: Our results demonstrated the mechanism of EA on PNI from the perspective of exosome-mediated miR-21 transport and provided a theoretical basis for the use of exosomal miR-21 as a novel strategy for the treatment of PNI.

Schwann cells-derived exosomal miR-21 participates in high glucose regulation of neurite outgrowth.

As a common complication of diabetes, the pathogenesis of diabetic peripheral neuropathy (DPN) is closely related to high glucose but has not been clarified. Exosomes can mediate crosstalk between Schwann cells (SC) and neurons in the peripheral nerve. Herein, we found that miR-21 in serum exosomes from DPN rats was decreased. SC proliferation was inhibited, cell apoptosis was increased, and the expression of miR-21 in cells and exosomes was downregulated when cultured in high glucose. Increasing miR-21 expression reversed these changes, while knockdown of miR-21 led to the opposite results. When co-cultured with exosomes derived from SC exposed to high glucose, neurite outgrowth was inhibited. On the contrary, neurite outgrowth was accelerated when incubated with exosomes rich in miR-21. We further demonstrated that the SC-derived exosomal miR-21 participates in neurite outgrowth probably through the AKT signaling pathway. Thus, SC-derived exosomal miR-21 contributes to high glucose regulation of neurite outgrowth.