Heterochromatin formation and remodeling by IRTKS condensates counteract cellular senescence.

Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS droplets can infiltrate heterochromatin condensates composed of HP1α and diverse DNA-bound nucleosomes. IRTKS can stabilize HP1α by recruiting the E2 ligase Ubc9 to SUMOylate HP1α, which enables it to form larger phase-separated droplets than unmodified HP1α. Furthermore, IRTKS deficiency leads to loss of heterochromatin, resulting in genome-wide changes in chromatin accessibility and aberrant transcription of repetitive DNA elements. This leads to activation of cGAS-STING pathway and type-I interferon (IFN-I) signaling, as well as to the induction of cellular senescence and senescence-associated secretory phenotype (SASP) responses. Collectively, our findings establish a mechanism by which IRTKS condensates consolidate constitutive heterochromatin, revealing an unexpected role of IRTKS as an epigenetic mediator of cellular senescence.

[Discovery and activity verification of reniformin A as an anti-tumor leading compound].

Reverse prediction and molecular docking techniques were employed to evaluate the feasibility of reniformin A(RA) as an anti-tumor leading compound. Based on the reverse prediction, network pharmacology was used to construct a "disease-compound-target-pathway" network. Thirty-nine tumor-related targets of RA were predicted, which participated in the regulation of multiple cellular activities such as apoptosis, cell cycle, and tumor metastasis, and regulated estrogen signal transduction and inflammatory response. Discovery Studio 2020 was adopted for molecular docking and toxicity prediction(TOPKAT). As revealed by the results, the binding affinity of RA with the tumor-related targets ABL1, ESR1, SRC and BCL-XL was stronger than that of oridonin(OD), while its mutagenicity, rodent carcinogenesis, and oral LD_(50) in rats were all inferior to that of OD. Furthermore, in vitro experiments were performed to confirm the anti-tumor activity of RA, and the mechanism was preliminarily discussed. The results demonstrated that RA was superior to OD in cytotoxicity, inhibition of cell colony formation, and induction of apoptosis. RA, possessing potent anti-tumor activity, is expected to be a new anti-tumor leading compound.

Myeloid neoplasms in the setting of sickle cell disease: an intrinsic association with the underlying condition rather than a coincidence; report of 4 cases and review of the literature.

Myeloid neoplasms occasionally occur in patients with sickle cell disease, and the underlying connection between the two diseases is unclear. Herein, we retrospectively analyzed four cases of sickle cell disease patients who developed myeloid neoplasm. Age at time of diagnosis ranged from 27 to 59 years with a median of 35.5 years. Two patients were treated with hydroxyurea and the other two with supportive care alone, with one out of the four patients receiving additional treatment with hematopoietic stem cell transplant. Three patients presented with leukocytosis, and the remaining patient presented with pancytopenia. Two patients were diagnosed with myelodysplastic syndrome/myeloproliferative neoplasm, one with myelodysplastic syndrome, and the other with acute myeloid leukemia. All four cases demonstrated certain degrees of myelodysplasia and complex cytogenetic abnormalities with - 7/7q- and/or - 5/5q- or with 11q23 (KMT2A) rearrangement. This cytogenetic profile resembles that seen in therapy-related myeloid neoplasm, suggesting that myeloid neoplasm in the setting of sickle cell disease may represent a subcategory of the disease distinct from de novo myeloid neoplasm in general. Extensive literature review further demonstrates this similarity in cytogenetic profile, as well as in other associated pathologic features. Potential etiology includes therapy for sickle cell disease, disease-related immunomodulation, or disease-related chronic inflammation. We hypothesize that constant hematopoietic hyperplasia, stimulated by a hemolysis-induced cytokine storm, may increase the chance of somatic mutations/cytogenetic aberrations, resulting in transformation of myeloid precursors. This group of myeloid neoplasms seems to herald a dismal clinical outcome, with median survival <1 year, although the exact pathogenesis and biology of the disease remain to be investigated by large cohorts in future studies.

Correction to: Axin gene methylation status correlates with radiosensitivity of lung cancer cells.

Following publication of the original article.

Effects of gene knockdown of CNP on ventricular remodeling after myocardial ischemia-reperfusion injury through NPRB/Cgmp signaling pathway in rats.

This study aimed to explore effects of CNP on ventricular remodeling following myocardial ischemia-reperfusion (I/R) injury through the NPRB/cGMP signaling pathway. Rat cardiomyocytes were assigned into: control, I/R, I/R + CNP, and I/R + 8-Br-cGMP groups. ELISA, qRT-PCR, and Western blotting were used to detect cGMP content and expression, respectively. After model establishment of I/R rats, normal control, CNP-/- control, I/R, and CNP-/- groups were set. Indexes of heart were detected using echocardiography and hemodynamics. ELISA was used to measure serum CNP, cGMP, LDH, cTn I, CK-MB, TNF-α, and IL-6 levels. Myocardial infarct was identified by TTC staining, and apoptosis conditions by TUNEL staining. QRT-PCR and Western blotting were adopted to detect expressions of CNP, NPRB, cGMP, and apoptosis-related genes. Compared with control group, cGMP contents and expression in the I/R, I/R + CNP and I/R + 8-Br-cGMP groups were decreased. Levels of LVEDV, LVESV, LVDS, LVDD, IVSD, LVM, LVEDP, and LVSP were higher in the I/R, CNP-/- control, and CNP-/- groups than normal control group while LVEF, SV, CO, and ±dp/dtmax were lower. Compared with the normal control group, LDH, cTn I, CK-MB, TNF-α, and IL-6 were higher in the I/R, CNP-/- control and CNP-/- groups; pathological changes and myocardial infarction were observed in the I/R, CNP-/- control, and CNP-/- groups; expressions of apoptosis-related genes in those groups were higher; while CNP, NPRB, cGMP, and Bcl-2 expressions were decreased. We came to the conclusion that gene knockdown of CNP blocks the NPRB/cGMP signaling pathway, thereby aggravating myocardial I/R injury and causing ventricular remodeling in rats.

Construction and cellular uptake behavior of redox-sensitive docetaxel prodrug-loaded liposomes.

A redox-responsive docetaxel (DTX) prodrug consisting of a disulfide linkage between DTX and vitamin E (DTX-SS-VE) was synthesized in our laboratory and was successfully formulated into liposomes. The aim of this study was to optimize the formulation and investigate the cellular uptake of DTX prodrug-loaded liposomes (DPLs). The content of DTX-SS-VE was determined by ultrahigh-performance liquid chromatography (UPLC). The formulation and process were optimized using entrapment efficiency (EE), drug-loading (DL), particle size and polydispersity index (PDI) as the evaluation indices. The optimal formulation was as follows: drug/lipid ratio of 1:12, cholesterol/lipid ratio of 1:10, hydration temperature of 40 °C, sonication power and time of 400 W and 5 min. The EE, DL and particle size of the optimized DPLs were 97.60 ± 0.03%, 7.09 ± 0.22% and 93.06 ± 0.72 nm, respectively. DPLs had good dilution stability under the physiological conditions over 24 h. In addition, DPLs were found to enter tumor cells via different pathways and released DTX from the prodrug to induce apoptosis. Taken together, the optimized formulation and process were found to be a simple, stable and applicable method for the preparation of DPLs that could successfully escape from lysosomes.

IQ-domain GTPase-activating protein 1 promotes the malignant phenotype of invasive ductal breast carcinoma via canonical Wnt pathway.

IQ-domain GTPase-activating protein 1 is a scaffolding protein with multidomain which plays a role in modulating dishevelled (Dvl) nuclear translocation in canonical Wnt pathway. However, the biological function and mechanism of IQ-domain GTPase-activating protein 1 in invasive ductal carcinoma (IDC) remain unknown. In this study, we found that IQ-domain GTPase-activating protein 1 expression was elevated in invasive ductal carcinoma, which was positively correlated with tumor grade, lymphatic metastasis, and poor prognosis. Coexpression of IQ-domain GTPase-activating protein 1 and Dvl in the nucleus and cytoplasm of invasive ductal carcinoma was significantly correlated but not in the membrane. Postoperative survival in the patients with their coexpression in the nucleus and cytoplasm was obviously lower than that without coexpression. The positive expression rates of c-myc and cyclin D1 were significantly higher in the patients with nuclear coexpression of Dvl and IQ-domain GTPase-activating protein 1 than that with cytoplasmic coexpression, correlating with poor prognosis. IQ-domain GTPase-activating protein 1 significantly enhanced cell proliferation and invasion in invasive ductal carcinoma cell lines by interacting with Dvl in cytoplasm to promote Dvl nuclear translocation so as to upregulate the expression of c-myc and cyclin D1. Collectively, our data suggest that IQ-domain GTPase-activating protein 1 may promote the malignant phenotype of invasive ductal carcinoma via canonical Wnt signaling, and it could be used as a potential prognostic biomarker for breast cancer patients.

Cerebellar hemangioblastoma with perivascular pseudorosette formation and glial differentiation: A case report.

Hemangioblastoma is a well-circumscribed, highly vascular, lipid-rich and low-grade tumor of uncertain histogenesis. Its histopathological features have been well established. Herein, we present a case of cerebellar hemangioblastoma in a 43-year-old woman. Histologically, the tumor was predominantly composed of cellular areas showing eosinophilic or vacuolated stromal cells arranged in nests and sheets. Focally, conventional reticular areas could be seen. Additionally, in some areas, the stromal cells were arranged radially around blood vessels, exhibiting perivascular pseudorosette structures, which were similar mostly to those of ependymomas. Immunohistochemically, the stromal cells markedly showed diffused staining for Vimentin, S-100, CD56, NSE, inhibin-a, podoplanin, alpha-Thalassemia/mental retardation syndrome X and carbonic anhydrase IX, and were negative for cytokeratin, epithelial membrane antigen, oligodendrocyte transcription factor 2, neuronal nuclear antigen, synaptophysin, isocitrate dehydrogenase 1 (R132H), P53 and CD34. Interestingly, the reticular and cellular areas either showed no or individual scattering of the GFAP-positive cells, respectively, while, the perivascular pseudorosette areas strongly and diffusely expressed GFAP. Nuclear mitosis and necrosis were not observed. The MIB-1 antibody labeling index was especially low (about 3%). Based on these findings, the patient was diagnosed with cerebellar hemangioblastoma. In the present case, we documented a distinctive histological appearance of perivascular pseudorosettes in hemangioblastoma and provided the evidence for stromal cells with glial differentiation.

Insecticidal activities of constituents of Litsea cubeba fruit extracts effective against the maize weevil (Coleoptera: Curculionidae).

In this study, we investigated the insecticidal activities, including contact toxicity, fumigant toxicity, and repellent activity, of Litsea cubeba fruit extracts against Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae). The extracts, obtained by liquid-liquid extraction in n-hexane, ethyl acetate, chloroform, and water were analyzed by gas chromatography-mass spectrometry. Among the different extract types, chloroform extracts exhibited the strongest repellent, contact, and fumigant activities against S. zeamais. The main components of the chloroform extracts were identified as laurine (21.15%) and 2,6-diisopropyl aniline (16.14%), followed by chlorobutanol (10.54%), 3-O-methyl-N-acetyl-d-glucosamine (10.03%), and 6-methyl-5-hepten-2-one (8.33%). Among the identified components of the chloroform extracts, chlorobutanol showed the strongest fumigant toxicity (LD50 = 21.91 mg/liter), contact toxicity (LD50 = 54.25 µg/adult), and repellent activity against S. zeamais. These results indicate that L. cubeba fruit extracts possess natural insecticide-like activities against S. zeamais.

[Research and Application of Narrowband Polarizing Beam Splitter in the Optical Fiber Communication].

In fiber-optic communications, in order to achieve more data channels in the wavelength division multiplexing (WDM) system without changing the modulation wavelength range, a new type of small-sized narrowband polarizing beam splitter was designed. It can be used for data communication network expansion and improve the Signal to Noise Ratio (SNR) of the optical signal. Two kinds new film system designed were deposited on the polarizing beam splitter. One layer is narrowband filter film, while the other layer is polarizing beam splitter film. TFCalc software was used for simulation analysis, and the results shown that the bandwidth of the narrowband filter film was about 0.4 nm, and the permeability of p light from the polarizing beam splitter film was better than 99.8% in the range of 1 530～1 560 nm. Based on the above film system design, two groups film system was made on BK7 optical glass. In the experiment, light through film was spectral analysis with Agilent 8164-A type optical measuring instrument. Experimental results show that the actual bandwidth of the narrowband filter film is better than 0.4 nm, gain flatness is not less than -0.05 dB. It has a narrower bandwidth compared to the existing common 0.8 nm filter film, and it can be realized to increase the amount of data channels in the wavelength division multiplexing system with the same modulation wavelength range. Actual transmittance of p light was 99.6% through polarizing filter film, and it's slightly lower than the simulated values, but it remains better than the design requirements. Compared to conventional polarizing beam splitter, its optical signal was stronger, and it has a higher SNR. In summary, the polarizing beam splitter has better application value and practical significance.

The high expression of TC1 (C8orf4) was correlated with the expression of ß-catenin and cyclin D1 and the progression of squamous cell carcinomas of the tongue.

Thyroid cancer 1 (TC1, C8orf4) plays important roles in many signaling pathways, such as Wnt/ß-catenin signaling pathway, and is involved in the development of many cancers. The objective of this study was to examine the expression of TC1 and investigate the associations among TC1, ß-catenin, Chibby, cyclin D1, and the clinicopathological factors of oral tongue squamous cell carcinomas (OTSCCs). The expressions of TC1, ß-catenin, Chibby, and cyclin D1 were examined in 109 cases of OTSCCs using immunohistochemistry. The expression of TC1 was observed in all cases of OTSCCs but was negative or weak in normal squamous epithelial tissues of tongue. The high expression of TC1 was correlated with the advanced TNM stage (P = 0.042), the abnormal expression of ß-catenin (correlation coefficient = 0.314, P = 0.001) and the expression of cyclin D1 (correlation coefficient = 0.274, P = 0.006) in OTSCCs. But we did not find any associations between TC1 and Chibby. The abnormal expression of ß-catenin was correlated with the poor differentiation (P = 0.035), advanced TNM stage (P = 0.048) and the expression of cyclin D1 (correlation coefficient = 0.422, P < 0.001). In conclusion, the high expression of TC1 was common in OTSCCs and correlated with the expression of ß-catenin and cyclin D1 and the progression of OTSCCs. The high expression level of TC1 might promote the progression of OTSCCs by enhancing the activity of Wnt signaling pathway.

Multifunctional Poly(methyl vinyl ether-co-maleic anhydride)-graft-hydroxypropyl-ß-cyclodextrin Amphiphilic Copolymer as an Oral High-Performance Delivery Carrier of Tacrolimus.

In order to improve oral bioavailability of tacrolimus (FK506), a novel poly(methyl vinyl ether-co-maleic anhydride)-graft-hydroxypropyl-ß-cyclodextrin amphiphilic copolymer (CD-PVM/MA) is developed, combining the bioadhesiveness of PVM/MA, P-glycoprotein (P-gp), and cytochrome P450-inhibitory effect of CD into one. The FK506-loaded nanoparticles (CD-PVM/MA-NPs) were obtained by solvent evaporation method. The physiochemical properties and intestinal absorption mechanism of FK506-loaded CD-PVM/MA-NPs were characterized, and the pharmacokinetic behavior was investigated in rats. FK506-loaded CD-PVM/MA-NPs exhibited nanometer-sized particles of 273.7 nm, with encapsulation efficiency as high as 73.3%. FK506-loaded CD-PVM/MA-NPs maintained structural stability in the simulated gastric fluid, and about 80% FK506 was released within 24 h in the simulated intestinal fluid. The permeability of FK506 was improved dramatically by CD-PVM/MA-NPs compared to its solution, probably due to the synergistic inhibition effect of P-gp and cytochrome P450 3A (CYP3A). The intestinal biodistribution of fluorescence-labeled CD-PVM/MA-NPs confirmed its good bioadhesion to the rat intestinal wall. Two endocytosis pathways, clathrin- and caveolae-mediated endocytosis, were involved in the cellular uptake of CD-PVM/MA-NPs. The important role of lymphatic transport in nanoparticles' access to the systemic circulation, about half of the contribution to oral bioavailability, was observed in mesenteric lymph duct ligated rats. The AUC0-24 of FK506 loaded in nanoparticles was enhanced up to 20-fold compared to FK506 solutions after oral administration. The present study suggested that the novel multifunctional CD-PVM/MA is a promising efficient oral delivery carrier for FK506, due to its ability in solubilization, inhibitory effects on both P-gp and CYP 3A, high bioadhesion, and sustained release capability.

Enteric polymer based on pH-responsive aliphatic polycarbonate functionalized with vitamin E to facilitate oral delivery of tacrolimus.

To improve the bioavailability of orally administered drugs, we synthesized a pH-sensitive polymer (poly(ethylene glycol)-poly(2-methyl-2-carboxyl-propylene carbonate)-vitamin E, mPEG-PCC-VE) attempting to integrate the advantages of enteric coating and P-glycoprotein (P-gp) inhibition. The aliphatic polycarbonate chain was functionalized with carboxyl groups and vitamin E via postpolymerization modification. Optimized by comparison and central composite design, mPEG113-PCC32-VE4 exhibited low critical micelle concentration of 1.7 × 10(-6) mg/mL and high drug loading ability for tacrolimus (21.2% ± 2.7%, w/w). The pH-responsive profile was demonstrated by pH-dependent swelling and in vitro drug release. Less than 4.0% tacrolimus was released under simulated gastric fluid after 2.5 h, whereas an immediate release was observed under simulated intestinal fluid. The mPEG113-PCC32-VE4 micelles significantly increased the absorption of P-gp substrate tacrolimus in the whole intestine. The oral bioavailability of tacrolimus micelles was 6-fold higher than that of tacrolimus solution in rats. This enteric polymer therefore has the potential to become a useful nanoscale carrier for oral delivery of drugs.

Neuroprotective effects of daphnetin against NMDA receptor-mediated excitotoxicity.

The accumulation of glutamate can excessively activate the N-methyl-d-aspartate (NMDA) receptors and cause excitotoxicity. Daphnetin (Dap), a coumarin derivative, is a protein kinase inhibitor that exhibits antioxidant and neuroprotective properties. However, little is known about the neuroprotective effects of Dap on glutamate-induced excitotoxicity. We evaluated the neuroprotective activities in the primary cultured cortical neurons against NMDA-induced excitotoxicity. Pretreatment with Dap significantly prevented NMDA-induced neuronal cell loss. Dap significantly inhibited the neuronal apoptosis by regulating balance of Bcl-2 and Bax expression. Furthermore, pretreatment of Dap reversed the up-regulation of NR2B-containing NMDA receptors and inhibited the intracellular Ca2+ overload induced by NMDA exposure. In addition, Dap prevented cerebral ischemic injury in mice induced via a 2 h middle cerebral artery occlusion and a 24 h reperfusion in vivo. The findings suggest that Dap prevents the excitotoxicity through inhibiting the NR2B-containing NMDA receptors and the subsequent calcium overload in cultured cortical neurons.

[Resource investigation on rare and endangered She medicine Tetrastigma hemsleyanum in Zhejiang Province].

OBJECTIVE: To investigate the resource of Tetrastigma hemsleyanum which was rare and endangered plant in She nationality in Zhejiang Province. METHODS: Using literature method, survey method, plots method and line method, the resource situation of artificial planting and wild resource in Zhejiang Province were investigated. RESULTS: It was a scarce and precious medicinal herb that wild resource was rare and endangered. There were artificial planting area about 104.55 hm2 which expected to produce 173.91 tons in Zhejiang Province. CONCLUSION: In the wild,it is relatively harsh to environmental requirements for growth. Generally speaking, it takes 3 - 5 years growth period to achieve the medicinal value. The wild resource is scarce and the market demand is increasing, which brings about artificial planting to develop rapidly.

A microneedle patch realizes weight loss through photothermal induction of fat browning.

As a globally prevalent disease, obesity leads to many chronic diseases, so it is important to develop safe and effective treatments with fewer side effects and lasting weight loss. In this study, we developed a biodegradable hyaluronic acid microneedle patch loaded with polydopamine nanoparticles and mirabegron, which directly acted on subcutaneous white adipose tissue, and then induced browning of white adipose tissue through mild photothermal therapy. The approach showed excellent browning-promoting ability and biocompatibility. It is noteworthy that the weight of untreated mice increased by 9%, while the weight of obese mice decreased by nearly 19% after photothermal treatment. In addition, when mirabegron was used in combination with photothermal therapy, the weight loss of obese mice was more significant, with a weight loss of about 22%. This microneedle patch exhibited attractive potential for body slimming.

Recent Advances in the Fabrication and Performance Optimization of Polyvinyl Alcohol Based Vascular Grafts.

Cardiovascular disease is one of the diseases with the highest morbidity and mortality rates worldwide, and coronary artery bypass grafting (CABG) is a fast and effective treatment. More researchers are investigating in artificial blood vessels due to the limitations of autologous blood vessels. Despite the availability of large-diameter vascular grafts (Ø > 6 mm) for clinical use, small-diameter vascular grafts (Ø < 6 mm) have been a challenge for researchers to overcome in recent years. Vascular grafts made of polyvinyl alcohol (PVA) and PVA-based composites have excellent biocompatibility and mechanical characteristics. In order to gain a clearer and more specific understanding of the progress in PVA vascular graft research, particularly regarding the preparation methods, principles, and functionality of PVA vascular graft, this article discusses the mechanical properties, biocompatibility, blood compatibility, and other properties of PVA vascular graft prepared or enhanced with different blends using various techniques that mimic natural blood vessels. The findings reveal the feasibility and promising potential of PVA or PVA-based composite materials as vascular grafts.

Advancements in the study of glucose metabolism in relation to tumor progression and treatment.

Sugar serves as the primary energy source for mammals, with glucose metabolism facilitating energy acquisition in human cells. The proper functioning of intracellular glucose metabolism is essential for the maintenance of orderly and healthy physiological activities. Tumor cells, characterized by uncontrolled growth, exhibit dysregulated proliferation and apoptosis processes, leading to abnormal alterations in glucose metabolism. Specifically, tumor cells exhibit a shift towards aerobic glycolysis, resulting in the production of lactic acid that can be utilized as a metabolic intermediate for sustained tumor cell growth. This article provides a comprehensive overview of the enzymes involved in glucose metabolism and the alterations in gene expression that occur during tumor progression. It also examines the current research on targeting abnormal glucose metabolism processes for tumor treatment and discusses potential future directions for utilizing glucose metabolism as a therapeutic target.