Oral sericin ameliorates type 2 diabetes through passive intestinal and bypass transport into the systemic circulation.

ETHNOPHARMACOLOGICAL RELEVANCE: Boiled silkworm cocoons have been used to treat 'Xiaoke disease' (diabetes mellitus) recorded in Chinese medicine for over 800 years. In recent years, it has been found that the active substance silk sericin (SS) has therapeutic benefits in treating type 2 diabetes mellitus (T2DM). SS promotes pancreatic islet signalling, the proliferation of pancreatic islet cells, and insulin secretion. It is inferred that SS enters the bloodstream after oral administration and plays a role in the body's circulation. As a natural protein, SS needs to resist digestion by proteases in the gastrointestinal tract and cross the gastrointestinal barrier after oral administration. It is currently unclear how SS crosses the gastrointestinal barrier and whether it exerts therapeutic effects on T2DM by entering the circulation. AIM OF THE STUDY: To study how SS crosses the gastrointestinal barrier and whether it enters the body circulation to exert a therapeutic effect on T2DM. MATERIALS AND METHODS: SS was extracted from silkworm cocoons using an alkaline method with sodium carbonate. The antidigestive capacity of SS was detected using SDS-PAGE gel electrophoresis experiments. The mode of uptake and translocation of orally consumed SS in vivo was analysed using the AP-side to BL-side and BL-side-AP-side translocations, apparent Permeability coefficient (Papp), and Exocytosis rates (ER). The study compared the differences between the adSS group and the adSS + EDTA group by using Ethylenediaminetetraacetic acid (EDTA) to separate the tight junctions between Caco-2 cells. The aim was to analyze whether the transport mode of oral filaggrin proteins in vivo could be absorbed by bypass transport. By administering SS through oral and intraperitoneal injection to type 2 diabetic mice, we measured its concentration in the blood, as well as blood glucose and insulin levels, to determine its effectiveness in treating diabetes and its ability to enter the body's circulation for treatment. RESULTS: The molecular weight of SS decreased from 10k∼25 kDa to 10k∼15 kDa after in vitro simulated gastrointestinal fluid digestion, indicating its good antidigestive properties. The apparent Papp was greater than 1 × 10-6 cm·s-1, and the ER was between 0.5 and 1.5, indicating that adSS was well-absorbed and mainly passively transported. The Caco-2 cell model showed that the addition of EDTA promoted the transport of adSS, resulting in significantly larger Papp and ER values, indicating that adSS was absorbed by bypass transport. After oral administration of SS, the concentration of SS in the blood was lower than after intraperitoneal injection, which is 60% of intraperitoneal administration. Mice with a T2DM model who were administered SS for 5 weeks showed significant improvement in insulin resistance and glucose tolerance. Additionally, the pancreatic tissue appeared more regular. In the treatment of T2DM, injections of SS have been shown to be more effective than oral administration. Both oral and intraperitoneal injections have been partially involved in the circulation. CONCLUSIONS: SS is enzymatically cleaved by proteolytic enzymes in the gastrointestinal tract. The smaller molecules are partially absorbed into the body's circulation through passive and paracrine transport, exerting a therapeutic effect on T2DM.

Regulatory effects of stress release from decellularized periosteum on proliferation, migration, and osteogenic differentiation of periosteum-derived cells.

Bone injury is often associated with tears in the periosteum and changes in the internal stress microenvironment of the periosteum. In this study, we investigated the biological effects of periosteal prestress release on periosteum-derived cells (PDCs) and the potential mechanisms of endogenous stem cell recruitment. Decellularized periosteum with natural extracellular matrix (ECM) components was obtained by a combination of physical, chemical, and enzymatic decellularization. The decellularized periosteum removed immunogenicity while retaining the natural network structure and composition of the ECM. The Young's modulus has no significant difference between the periosteum before and after decellularization. The extracted PDCs were further composited with the decellularized periosteum and subjected to 20% stress release. It was found that the proliferative capacity of PDCs seeded on decellularized periosteum was significantly enhanced 6 h after stress release of the periosteum. The cell culture supernatant obtained after periosteal prestress release was able to significantly promote the migration ability of PDCs within 24 h. Enzyme-linked immunosorbnent assay (ELISA) experiments showed that the expression of stroma-derived factor-1α (SDF-1α) and vascular endothelial growth factor (VEGF) in the supernatant increased significantly after 3 h and 12 h of stress release, respectively. Furthermore, periosteal stress release promoted the high expression of osteogenic markers osteocalcin (OCN), osteopontin (OPN), and collagen type I of PDCs. The change in stress environment caused by the release of periosteal prestress was sensed by integrin ß1, a mechanoreceptor on the membrane of PDCs, which further stimulated the expression of YAP in the nucleus. These investigations provided a novel method to evaluate the importance of mechanical stimulation in periosteum, which is also of great significance for the design and fabrication of artificial periosteum with mechanical regulation function.

Hydroxyl silicone oil grafting onto a rough thermoplastic polyurethane surface created durable super-hydrophobicity.

Indwelling medical catheters are frequently utilized in medical procedures, but they are highly susceptible to infection, posing a vital challenge for both health workers and patients. In this study, the superhydrophobic micro-nanostructure surface was constructed on the surface of thermoplastic polyurethane (TPU) membrane using heavy calcium carbonate (CaCO3) template. To decrease the surface free energy, hydroxyl silicone oil was grafted onto the surface, forming a super-hydrophobic surface. The water contact angle (WCA) increased from 91.1° to 143 ± 3° when the concentration of heavy calcium CaCO3 was 20% (weight-to-volume (w/v)). However, the increased WCA was unstable and tended to decrease over time. After grafting hydroxyl silicone oil, the WCA rose to 152.05 ± 1.62° and remained consistently high for a period of 30 min. Attenuated total reflection infrared spectroscopy (ATR-FTIR) analysis revealed a chemical crosslinking between silicone oil and the surface of TPU. Furthermore, Scanning electron microscope (SEM) image showed the presence of numerous nanoparticles on the micro surface. Atomic force microscope (AFM) testing indicated a significant improvement in surface roughness. This method of creating a hydrophobic surface demonstrated several advantages, including resistance to cell, bacterial, protein, and platelet adhesion and good biosecurity. Therefore, it holds promising potential for application in the development of TPU-based medical catheters with antibacterial properties.

Molecular mechanism analysis of apoptosis induced by silk fibroin peptides.

Silk fibroin derived from silkworm cocoons exhibits excellent mechanical properties, good biocompatibility, and low immunogenicity. Previous studies showed that silk fibroin had an inhibitory effect on cells, suppressing proliferation and inducing apoptosis. However, the source of the toxicity and the mechanism of apoptosis induction are still unclear. In this study, we hypothesized that the toxicity of silk fibroin might originate from the crystalline region of the heavy chain of silk fibroin. We then verified the hypothesis and the specific induction mechanism. A target peptide segment was obtained from α-chymotrypsin. The potentially toxic mixture of silk fibroin peptides (SFPs) was separated by ion exchange, and the toxicity was tested by an MTT assay. The results showed that SFPs obtained after 4 h of enzymatic hydrolysis had significant cytotoxicity, and SFPs with isoelectric points of 4.0-6.8 (SFPα II) had a significant inhibitory effect on cell growth. LC-MS/MS analysis showed that SFPα II contained a large number of glycine-rich and alanine-rich repetitive sequence polypeptides from the heavy-chain crystallization region. A series of experiments showed that SFPα II mediated cell death through the apoptotic pathway by decreasing the expression of Bcl-2 protein and increasing the expression of Bax protein. SFPα II mainly affected the p53 pathway and the AMPK signaling pathway in HepG2 cells. SFPα II may indirectly increase the expression of Cers2 by inhibiting the phosphorylation of EGFR, which activated apoptotic signaling in the cellular mitochondrial pathway and inhibited the Akt/NF-κB pathway by increasing the expression of PPP2R2A.

Fine-Scale Genetic Structure of Curculio chinensis (Coleoptera: Curculionidae) Based on Mitochondrial COI: The Role of Host Specificity and Spatial Distance.

The Camellia weevil, Curculio chinensis (Chevrolat, 1978), is a dominant oligophagous pest that bores into the fruit of oil-tea Camellia. Genetic differentiation among populations in various hosts can easily occur, which hinders research on pest management. In this study, the genetic structure, genetic diversity, and phylogenetic structure of local C. chinensis populations were examined using 147 individuals (from 6 localities in Jiangxi), based on 2 mitochondrial COI markers. Results indicated that the C. chinensis population in Jiangxi exhibits a high haplotype diversity, especially for the populations from Cam. meiocarpa plantations. Structural differentiation was observed between Haplogroup 1 (73 individuals from Ganzhou, Jian, and Pingxiang) in the monoculture plantations of Cam. meiocarpa and Haplogroup 2 (75 individuals from Pingxiang and Jiujiang) in Cam. oleifera. Two haplogroups have recently undergone a demographic expansion, and Haplogroup 1 has shown a higher number of effective migrants than Haplogroup 2. This suggests that C. chinensis has been spreading from Cam. meiocarpa plantations to other oil-tea Camellia, such as Cam. oleifera. The increased cultivation of oil-tea Camellia in Jiangxi has contributed to a unique genetic structure within the C. chinensis population. This has, in turn, expanded the distribution of C. chinensis and increased migration between populations.

[Efficacy, safety, and mechanism of Huangkui Capsules in treating chronic kidney disease: Meta-analysis and integrative bioinformatics].

Meta-analysis and integrative bioinformatics were employed to comprehensively study the efficacy, safety, and mechanism of Huangkui Capsules in treating chronic kidney disease(CKD). CNKI, Wanfang, VIP, SinoMed, Cochrane Library, PubMed, EMbase, and Web of Science were searched for randomized controlled trial(RCT) of Huangkui Capsules for CKD from inception to January 3, 2023. The outcome indicators included urine protein, serum creatinine(Scr), and blood urea nitrogen(BUN) levels, and Cochrane Handbook 5.1 and RevMan 5.3 were employed to perform the Meta-analysis of the included RCT. The active ingredients of Huangkui Capsules were retrieved from CNKI, and the targets of CKD from GeneCards, OMIM, and TTD. Cytoscape 3.8.0 was used to build a "component-disease" network and a protein-protein interaction(PPI) network for the screening of core components and targets. Next, a differential analysis of the core targets of Huangkui Capsules for treating CKD was conducted with the clinical samples from GEO to identify the differentially expressed core targets, and correlation analysis and immune cell infiltration analysis were then performed for these targets. A total of 13 RCTs were included for the Meta-analysis, involving 2 372 patients(1 185 in the observation group and 1 187 in the control group). Meta-analysis showed that the Huangkui Capsules group and the losartan potassium group had no significant differences in reducing the urinary protein levels after 12(MD=19.60, 95%CI[-58.66, 97.86], P=0.62) and 24 weeks(MD=-66.00, 95%CI[-264.10, 132.11], P=0.51) of treatment. Huangkui Capsules in combination with conventional treatment was superior to conventional treatment alone(MD=-0.55, 95%CI[-0.86,-0.23], P=0.000 6). Huangkui Capsules combined with conventional treatment was superior to conventional treatment alone in recovering Scr(MD=-9.21, 95%CI[-15.85,-2.58], P=0.006) and BUN(MD=-1.02, 95%CI[-1.83,-0.21], P=0.01). Five patients showed clear adverse reactions, with abdominal or gastrointestinal discomfort. Huangkui Capsules had 43 active ingredients and 393 targets, and the core ingredients were myricetin, quercetin, gossypin, elaidic acid, dihydromyricetin, isochlorogenic acid B, and caffeic acid. CKD and Huangkui Capsules shared 247 common targets, including 25 core targets. The GEO differential analysis predicted 18 differentially expressed core targets, which were mainly positively correlated with immune cell expression and involved in immune inflammation, oxidative stress, pyroptosis, lipid metabolism, sex hormone metabolism, and cell repair. Conclusively, Huangkui Capsules combined with conventional treatment significantly reduced urine protein, Scr, and BUN. Huangkui Capsules alone and losartan potassium had no significant difference in reducing urine protein. This efficacy of Huangkui Capsules may be associated with the multi-component, multi-target, and multi-pathway responses to immune inflammation and oxidative stress. The included RCT had small sample sizes and general quality. More clinical trial protocols with large sample sizes and rigorous design and in line with international norms are needed to improve the evidence quality, and the results of bioinformatics analysis remain to be confirmed by further studies.

Estimation of Wideband Multi-Component Phasors Considering Signal Damping.

Harmonic and interharmonic content in power system signals is increasing with the development of renewable energy generation and power electronic devices. These multiple signal components can seriously degrade power quality, trip thermal generators, cause oscillations, and threaten system stability, especially the interharmonic tones with positive damping factors. The first step to mitigate these adverse effects is to accurately and quickly monitor signal features, including frequency, damping factor, amplitude, and phase. This paper proposes a concise and robust index to identify the number of modes present in the signal using the singular values of the Hankel matrix and discusses the scope of its application by testing the influence of various factors. Next, the simplified matrix pencil theory is employed to estimate the signal component frequency and damping factor. Then their estimates are considered in the modified least-squares algorithm to extract the wideband multi-component phasors accurately. Finally, this paper designs a series of scenarios considering varying signal frequency, damping factor, amplitude, and phase to test the proposed algorithm thoroughly. The results verify that the proposed method can achieve a maximum total vector error of less than 1.5%, which is more accurate than existing phasor estimators in various signal environments. The high accuracy of the proposed method is because it considers both the estimation of the frequency number and the effect of signal damping.

Cell Transdifferentiation: A Challenging Strategy with Great Potential.

With the discovery and development of somatic cell nuclear transfer, cell fusion, and induced pluripotent stem cells, cell transdifferentiation research has presented unique advantages and stimulated a heated discussion worldwide. Cell transdifferentiation is a phenomenon by which a cell changes its lineage and acquires the phenotype of other cell types when exposed to certain conditions. Indeed, many adult stem cells and differentiated cells were reported to change their phenotype and transform into other lineages. This article reviews the differentiation of stem cells and classification of transdifferentiation, as well as the advantages, challenges, and prospects of cell transdifferentiation. This review discusses new research directions and the main challenges in the use of transdifferentiation in human cells and molecular replacement therapy. Overall, such knowledge is expected to provide a deep understanding of cell fate and regulation, which can change through differentiation, dedifferentiation, and transdifferentiation, with multiple applications.

Preparation of a modified silk-based gel/microsphere composite as a potential hepatic arterial embolization agent.

Transcatheter arterial chemoembolization (TACE) is an effective method for treating hepatocellular carcinoma (HCC). In this study, chitosan (CS), sodium glycerophosphate (GP), and sodium alginate (SA) were used as the main raw materials to develop clinically non-degradable embolization microspheres (Ms). Chitosan/sodium alginate embolization Ms. were generated using an emulsification cross-linking method. The Ms. were then uniformly dispersed in CS/GP temperature-sensitive gels to produce Gel/Ms. composite embolic agents. The results showed that Gel/Ms. had good morphology and a neatly arranged three-dimensional structure, and the Ms. dispersed in the Gel as evidenced by SEM. Furthermore, Gel/Ms. has good blood compatibility, with a hemolysis rate of ≤5 %. The cytotoxicity experiments have also proven its excellent cell compatibility. The degradation rate of Gel/Ms. was 58.869 ± 1.754 % within 4 weeks, indicating that Gel/Ms. had good degradation performance matching its drug release purpose. The Gel/Ms. adheres better at the target site than Ms. alone and releases the drug steadily over a long period, and the maximum release rate of Gel/Ms. within 8 h was 38.33 ± 1.528 %, and within 168 h was 81.266 ± 1.193 %. Overall, Gel/Ms. demonstrate better slow drug release, reduced sudden drug release, prolonged drug action time at the target site, and reduced toxic side effects on the body compared to Gel alone.

Postbiotics as potential new therapeutic agents for sepsis.

Sepsis is the main cause of death in critically ill patients and gut microbiota dysbiosis plays a crucial role in sepsis. On the one hand, sepsis leads to the destruction of gut microbiota and induces and aggravates terminal organ dysfunction. On the other hand, the activation of pathogenic gut flora and the reduction in beneficial microbial products increase the susceptibility of the host to sepsis. Although probiotics or fecal microbiota transplantation preserve gut barrier function on multiple levels, their efficacy in sepsis with intestinal microbiota disruptions remains uncertain. Postbiotics consist of inactivated microbial cells or cell components. They possess antimicrobial, immunomodulatory, antioxidant and antiproliferative activities. Microbiota-targeted therapy strategies, such as postbiotics, may reduce the incidence of sepsis and improve the prognosis of patients with sepsis by regulating gut microbial metabolites, improving intestinal barrier integrity and changing the composition of the gut microbiota. They offer a variety of mechanisms and might even be superior to more conventional 'biotics' such as probiotics and prebiotics. In this review, we present an overview of the concept of postbiotics and summarize what is currently known about postbiotics and their prospective utility in sepsis therapy. Overall, postbiotics show promise as a viable adjunctive therapy option for sepsis.

Fasudil promotes polyploidization of megakaryoblasts in an acute megakaryocyte leukemia model.

Acute megakaryocytic leukemia (AMKL) is a rare neoplasm caused by abnormal megakaryoblasts. Megakaryoblasts keep dividing and avoid undergoing polyploidization to escape maturation. Small-molecule probes inducing polyploidization of megakaryocytic leukemia cells accelerate the differentiation of megakaryocytes. This study aims to determine that Rho kinase (ROCK) inhibition on megakaryoblasts enhances polyploidization and the inhibition of ROCK1 by fasudil benefits AMKL mice. The study investigated fasudil on the megakaryoblast cells in vitro and in vivo. With the differentiation and apoptosis induction, fasudil was used to treat 6133/MPLW515L mice, and the differentiation level was evaluated. Fasudil could reduce proliferation and promote the polyploidization of megakaryoblasts. Meanwhile, fasudil reduced the disease burden of 6133/MPLW515L AMKL mice at a dose that is safe for healthy mice. Combination therapy of ROCK1 inhibitor fasudil and reported clinical AURKA inhibitor MLN8237 achieved a better antileukemia effect in vivo, which alleviated hepatosplenomegaly and promoted the differentiation of megakaryoblast cells. ROCK1 inhibitor fasudil is a good proliferation inhibitor and polyploidization inducer of megakaryoblast cells and might be a novel rationale for clinical AMKL treatment.

Mechanism of the Impact-Sensitivity Reduction of Energetic CL-20/TNT Cocrystals: A Nonequilibrium Molecular Dynamics Study.

High-energy low-sensitivity explosives are research objectives in the field of energetic materials, and the formation of cocrystals is an important method to improve the safety of explosives. However, the sensitivity reduction mechanism of cocrystal explosives is still unclear. In this study, CL-20/TNT, CL-20 and TNT crystals were taken as research objects. On the basis of the ReaxFF-lg reactive force field, the propagation process of the wave front in the crystals at different impact velocities was simulated. The molecular dynamics data were used to analyze the molecular structure changes and initial chemical reactions, and to explore the sensitivity reduction mechanism of the CL-20/TNT cocrystal. The results showed that the chemical reaction of the CL-20/TNT cocrystal, compared with the CL-20 single crystal, is different under different impact velocities. At an impact velocity of 2 km/s, polymerization and separation of the component molecules weakened the decomposition of CL-20. At an impact velocity of 3 km/s, the decay rates of CL-20 and TNT in the cocrystal decreased, and the intermediate products were enhanced, such as nitrogen oxides. At an impact velocity of 4 km/s, the cocrystal had little effect on the decay rates of the molecules and formation of CO2, but it enhanced formation of N2 and H2O. This may explain the reason for the impact-sensitivity reduction of the CL-20/TNT cocrystal.

Differentiation therapy for murine myelofibrosis model with MLN8237 loaded low-density lipoproteins.

Primary myelofibrosis (PMF) is a severe myeloproliferative neoplasm that is characterized by low-differentiation megakaryoblasts and progressive bone marrow fibrosis. Although an Aurora kinase A (AURKA) targeting small-molecule inhibitor MLN8237 has been approved in clinical trials for differentiation therapy of high-risk PMF patients, its off-target side effects lead to a partial remission and serious complications. Here, we report a dual-targeting therapy agent (rLDL-MLN) with great clinical translation potential for differentiation therapy of PMF disease. In particular, the reconstituted low-density lipoprotein (rLDL) nanocarrier and the loaded MLN8237 can actively target malignant hematopoietic stem/progenitor cells (HSPCs) via LDL receptors and intracellular AURKA, respectively. In contrast to free MLN8237, rLDL-MLN effectively prohibits the proliferation of PMF cell lines and abnormal HSPCs and significantly induces their differentiation, as well as prevents the formation of erythrocyte and megakaryocyte colonies from abnormal HSPCs. Surprisingly, even at a 1500-fold lower dosage (0.01 mg/kg) than that of free MLN8237, rLDL-MLN still exhibits a much more effective therapeutic effect, with the PMF mice almost clear of blast cells. More importantly, rLDL-MLN promotes hematological recovery without any toxic side effects at the effective dosage, holding great promise in the targeted differentiation therapy of PMF patients.

Surface grafting of sericin onto thermoplastic polyurethanes to improve cell adhesion and function.

Thermoplastic polyurethane (TPU) membrane has super physical-mechanical properties and biocompatibility, but the surface is inert and lack of active groups which limit its application in cell culture. Silk sericin (SS) can improve cell adhesion, proliferation, growth and metabolism. In this paper, SS was grafted onto the surface of TPU membrane by -NH2 bridge to build a high efficiency cell culture membrane. The FT-IR spectrum results indicated SS was grafted by chemical bond. According to the SEM and AFM results, we found that the grafting of SS reduced the water contact angle by 43.31% and increased the surface roughness by about four times. When TPU-SS was used for HepG2 cell culture, the cell adhesion rate of TPU-SS was significantly higher than that of the general TCPS cell culture plate, and the cell proliferation rate was close to that of TCPS. FDA/EB staining showed that HepG2 cells remained a better cellular growth behavior. HepG2 cells had higher cell vitality including the albumin secretion and the intracellular total protein synthesis. Grafting SS maintained the stability of cell and significantly decreased the cytotoxicity by decreased LDH release. In conclusion, SS grafting is beneficial to cell culture in vitro, and provides a key material for bioartificial liver culture system.

Sericin-reinforced dual-crosslinked hydrogel for cartilage defect repair.

Articular cartilage is essential for normal daily joint function activities. However, it is difficult for articular cartilage to repair itself after injury due to the lack of nerves and blood vessels, so an effective cartilage repair method is necessary. As a three-dimensional polymer network structure with high water content, hydrogel is a good candidate material for cartilage repair, and it is also a research hotspot in the treatment of cartilage injury. Here, a porous dual-crosslinked hydrogel containing sodium alginate (SA) and silk sericin (SS) was designed for in situ repair of cartilage damage. The degradation rate of the hydrogel was regulated by changing the content of SS to match the rate of cartilage regeneration. The hydrogel had excellent mechanical properties (compressive strength≈245 kPa, compressibility≈60%), high water content (85%-88%) and porosity(>20%), and when the content of SS is 1%, the scaffold has the best comprehensive performance. Existing excellent cytocompatibility, the scaffold can promote the adhesion and proliferation of chondrocytes while reducing inflammatory cell infiltration. The cartilage defect repair experiments in vivo showed that artificial cartilage was formed at 4 weeks with molecular structure similar to natural cartilage. It is expected to be applied to clinical cartilage repair through the dual-crosslinked three-dimensional cartilage scaffold.

Highly efficient removal of hexavalent chromium by magnetic Fe-C composite from reed straw and electric furnace dust waste.

Reed straw and electric furnace dust (EFD) waste were used to prepare magnetic Fe-C composite (EFD&C) by co-precipitation and high-temperature activation method to remove Cr(VI) from water. The magnetic EFD&C owned a large specific surface (536.61 m2/g) and a porous structure (micropores and mesopores), and had an efficient removal capacity for Cr(VI). Under conditions of pH (2), the addition amount of EFD&C (1 g/L), the adsorption time (760 min), and the temperature (45 °C), the maximum adsorption capacity reached 111.94 mg/g. The adsorption mechanism mainly attributed to chemical adsorption (redox), Cr(VI) reduced to Cr(III) by Fe(II) and Fe(0) (from Fe3O4 and Fe components in EFD) and surface functional groups of -OH, C = C, C-C and O-C = O (from biochar), and secondary attributed to physical adsorption, Cr(VI) and Cr(III) (from reduced Cr(VI)) adsorbed into the porous structure of EFD&C. This study provided a feasible solution for the preparation of adsorbents for adsorbing heavy metals from iron-containing metallurgical solid waste and biomass waste, which contributed to reducing the environmental pollution and lowering the cost of adsorbent preparation.

Heat shock protein 90 inhibitors induce cell differentiation via the ubiquitin-dependent aurora kinase A degradation in a MPLW515L mouse model of primary myelofibrosis.

Primary myelofibrosis (PMF) is characterized by immature megakaryocytic hyperplasia, splenomegaly, extramedullary hematopoiesis and bone marrow fibrosis. Our preclinical study had demonstrated that aurora kinase A (AURKA) inhibitor MLN8237 reduced the mutation burden of PMF by inducing differentiation of immature megakaryocytes. However, it only slightly alleviated splenomegaly, reduced tissue fibrosis, and normalized megakaryocytes in PMF patients of the preliminary clinical study. So enhancing therapeutic efficacy of PMF is needed. In this study, we found that AURKA directly interacted with heat shock protein 90 (HSP90) and HSP90 inhibitors promoted the ubiquitin-dependent AURKA degradation. We demonstrated that HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), normalized peripheral blood counts, improved splenomegaly, attenuated extramedullary hematopoiesis, decreased tissue fibrosis and reduced mutant burden in a MPLW515L mouse model of PMF. Importantly, both 17-AAG and 17-DMAG treatment at effective doses in vivo did not influence on hematopoiesis in healthy mice. Collectively, the study demonstrates that HSP90 inhibitors induce cell differentiation via the ubiquitin-dependent AURKA and also are safe and effective for the treatment of a MPLW515L mouse model of PMF, which may provide a new strategy for PMF therapy. Further, we demonstrate that combined therapy shows superior activity in acute megakaryocytic leukemia mouse model than single therapy.

Density Functional Theory Analysis of the Copolymerization of Cyclopropenone with Ethylene Using a Palladium Catalyst.

Density functional theory has been used to elucidate the mechanism of Pd copolymerization of cyclopropenone with ethylene. The results reveal that introducing ethylene and cyclopropenone to Pd catalyst is thermodynamically feasible and generates the α,ß-unsaturated ketone unit (UnitA). Cis-mode insertion and Path A1a are the most favorable reaction routes for ethylene and cyclopropenone, respectively. Moreover, cyclopropenone decomposition can generate CO in situ without a catalyst or with a Pd catalyst. The Pd-catalyzed decomposition of cyclopropenone exhibits a lower reaction barrier (22.7 kcal/mol) than its direct decomposition. Our study demonstrates that incorporating CO into the Pd catalyst can generate the isolated ketone unit (UnitB). CO is formed first; thereafter, UnitB is generated. Therefore, the total energy barrier of UnitB generation, accounting for the CO barrier, is 22.7 kcal/mol, which is slightly lower than that of UnitA generation (24.0 kcal/mol). Additionally, the possibility of copolymerizing ethylene, cyclopropenone, and allyl acetate (AAc) has been investigated. The free energy and global reactivity index analyses indicate that the cyclopropenone introduction reaction is more favorable than the AAc insertion, which is consistent with the experimental results. Investigating the copolymerization mechanism will help to develop of a functionalization strategy for polyethylene polymers.

Combination of AURKA inhibitor and HSP90 inhibitor to treat breast cancer with AURKA overexpression and TP53 mutations.

Breast cancer is the most common cancer among women worldwide. Researches show that Aurora kinase A (AURKA) is highly expressed in approximately 73% of breast cancer patients, which induces drug resistance in breast cancer patients and decreases the median survival time. AURKA regulates spindle assembly, centrosome maturation, and chromosome alignment. AURKA overexpression affects the occurrence and development of breast cancer. Besides AURKA overexpression, heat shock protein 90 (HSP90) maintains the survival and proliferation of tumor cells by stabilizing the structure of oncoproteins, including P53 mutants (mtP53). TP53 mutations accounted for approximately 13%, 40%, 80%, 33%, 71%, and 82% of luminal A, Luminal B, Luminal C, normal basal-like, HER2-amplified, and basal-like breast cancers, respectively. TP53 mutation can aggravate cell genome instability and enhance the invasion, migration, and resistance of cancer cell. This review describes the research status of AURKA and HSP90 in breast cancer, summarizes the structure, function, and the chaperone cycle of HSP90, elaborates the interrelation between HSP90, mtP53, P53, and AURKA, and proposes the combination of HSP90 inhibitor and AURKA inhibitor to treat breast cancer. Targeting AURKA and HSP90 to treat cancer with AURKA overexpression and TP53 mutations will help improve the specificity and efficiency of breast cancer treatment and solve the problem of drug resistance.