Azido- and Triazolyl-modified Nucleoside/tide Analogues: Chemistry, Fluorescent Properties, and Anticancer Activities

Two classes of C5 azido-modified pyrimidine nucleosides were synthesized and explored as radiosensitizers. The 5-azidomethyl-2\u27-deoxyuridine (AmdU) was prepared from thymidine and converted to its cytosine counterpart (AmdC). The 5-(1-azidovinyl) modified 2\u27-deoxyuridine (AvdU) and 2\u27-deoxycytidine (AvdC) were prepared employing regioselective Ag-catalyzed hydroazidation of 5-ethynyl pyrimidine substrates with TMSN3. AmdU and AmdC were converted to 5\u27-triphosphates AmdUTP and AmdCTP, and incorporated into DNA-fragments via polymerase-catalyzed reaction during DNA replication and base excision repair. Radiation-mediated prehydrated electrons formed in homogeneous aqueous glassy (7.5 M LiCl) systems in the absence of oxygen at 77 K led to site-specific formation of π-type aminyl radicals (RNH•) from AmdU, AmdC, AvdU, and AvdC. The ESR spectral studies and DFT calculations showed RNH• undergo facile conversion to thermodynamically more stable σ-type iminyl radicals, R=N•. For AmdU, conversion of RNH• to R=N• was bimolecular involving α-azidoalkyl radical as intermediate; however, for AvdU, RNH• tautomerized to R=N•. Our work provides the first evidence for the formation of RNH• attached to C5 position of azidopyrimidine nucleoside and its facile conversion to R=N• under reductive environment. These aminyl and iminyl radicals can generate DNA damage via oxidative pathways. The azido-nucleosides were successfully applied as radiosensitizers in EMT6 cancer cells in both hypoxic and normoxic conditions. To explore the generation and reactivity of 2\u27‑deoxyguanosin-N2-yl radical (dG(N2-H)•) postulated to generate from guanine moiety towards •OH, 2-azido-2\u27-deoxyinosine (2-N3dI) was prepared by conversion of 2-amino group in protected dG into 2-azido via diazotization with tert-butyl nitrite followed by displacement with azide and deprotection. The investigation of dG(N2-H)• generated from 2-N3dI and its subsequent reactions using ESR will be discussed. Cycloaddition between 5-ethynylpyrimidine or 8-ethynylpurine nucleosides and TMSN3 in the presence of Ag2CO3, CuI, or CuSO4/sodium ascorbate provided N-unsubstituted 1,2,3-triazol-4-yl analogues of the parental DNA bases (i.e. 5-TrzdU, 5‑TrzdC, 8-TrzdA, and 8-TrzdG). These novel triazolyl nucleosides showed excellent fluorescent properties: 8-TrzdA exhibits the highest quantum yield (ΦF) of 44% while 8‑TrzdG had ΦF of 9%. The 5-TrzdU and 5-TrzdC showed a large Stokes shift of ~110 nm. The application of these fluorescent nucleosides to cell imaging and DNA modifications will also be discussed

Taraxerol exerts potent anticancer effects via induction of apoptosis and inhibition of Nf-kB signalling pathway in human middle ear epithelial cholesteatoma cells

Purpose: To investigate the effect of taraxerol on the proliferation of middle ear epithelial cholesteatoma cells.Methods: The anti-proliferative effect of taraxerol was investigated by cell counting kit-8 (CCK8) and clonogenic assays. Apoptosis was measured using DAPI, while mitochondrial membrane potential was determined with the aid of rhodamine 123 staining. Protein expression was studied by western blotting.Results: Taraxerol induced concentration-dependent anti-proliferative effects on the middle ear epithelial cholesteatoma cells, and also inhibited their colony formation potential. The drug induced apoptosis in the middle ear epithelial cholesteatoma cells by reducing mitochondrial membrane potential, and also triggered sub-G1 cell cycle arrest in these cells. Moreover, taraxerol inhibited the expression of Nf-kB.Conclusion: These findings reveal that taraxerol may be a potential lead compound for the treatment of middle ear cholesteatoma.Keywords: Cholesteatoma, Epithelial tissues, Taraxerol, Apoptosis, Cell cycle arres

One-Bit-Aided Modulo Sampling for DOA Estimation

Modulo sampling or unlimited sampling has recently drawn a great deal of attention for cutting-edge applications, due to overcoming the barrier of information loss through sensor saturation and clipping. This is a significant problem, especially when the range of signal amplitudes is unknown or in the near-far case. To overcome this fundamental bottleneck, we propose a one-bit-aided (1bit-aided) modulo sampling scheme for direction-of-arrival (DOA) estimation. On the one hand, one-bit quantization involving a simple comparator offers the advantages of low-cost and low-complexity implementation. On the other hand, one-bit quantization provides an estimate of the normalized covariance matrix of the unquantized measurements via the arcsin law. The estimate of the normalized covariance matrix is used to implement blind integer-forcing (BIF) decoder to unwrap the modulo samples to construct the covariance matrix, and subspace methods can be used to perform the DOA estimation. Our approach named as 1bit-aided-BIF addresses the near-far problem well and overcomes the intrinsic low dynamic range of one-bit quantization. Numerical experiments validate the excellent performance of the proposed algorithm compared to using a high-precision ADC directly in the given set up

Possible mechanisms of treatment for spinal cord injury repair with tanshinone IIA

Tanshinone IIA serves as a coenzyme for certain biochemical reactions, exhibiting various pharmacological effects in the treatment of neurological diseases including spinal cord injury (SCI), however, its working mechanism in the treatment of SCI is not clear. Based on previous research, we believe that tanshinone IIA promotes the survival and repair of nerves after spinal cord injury through its pharmacological effects such as anti-inflammatory, antioxidant, and prevention of cellular apoptosis in the spinal cord

Predictive value of cystatin C-based estimated glomerular filtration rate combined with thromboelastogram for clinical prognosis of acute-on-chronic liver failure

Objective To investigate the value of cystatin C-based estimated glomerular filtration rate （eGFR-CysC） combined with thromboelastogram （TEG） to predict clinical prognosis of patients with acute-on-chronic liver failure （ACLF）. Methods 34 patients with ACLF （ACLF group）， 26 patients with chronic hepatitis （chronic hepatitis group） and 30 patients with cirrhosis （cirrhosis group） were selected. Laboratory parameters within 24 h after admission， TEG parameters and eGFR-CysC value were collected and compared among three groups. All patients were divided into different groups according to the incidence of complications and prognosis. The risk factors affecting clinical prognosis of ACLF patients were analyzed by binary logistic regression analysis. The predictive value of these risk factors for clinical prognosis of ACLF patients was assessed by the receiver operating characteristic （ROC）curve. Results There were significant differences in the white blood cell count （WBC）， alanine aminotransferase （ALT）， total bilirubin （TBIL）， albumin （ALB）， C-reactive protein （CRP）， prothrombin time activity （PTA）， prothrombin time （PT）， international normalized ratio （INR）， reaction time of TEG （R）， maximum amplitude （MA） and eGFR-CysC among different groups （all P < 0.05）. ACLF intra-group analysis showed that MA and eGFR-CysC were significantly different between patients with or without acute renal injury （both P < 0.05）， R and MA were significantly different between patients with or without upper gastrointestinal bleeding （both P < 0.05）， MA and eGFR-CysC significantly differed between the death and survival groups （both P < 0.05）. Binary logistic regression analysis suggested that MA （OR=0.439， 95%CI 0.231-0.833， P = 0.012） and eGFR-CysC （OR=0.931， 95%CI 0.878-0.988， P = 0.018） were the risk factors affecting short-term prognosis of ACLF. MA combined with eGFR-CysC yielded similar prognostic value in patients with ACLF （AUC=0.933， 95%CI 0.792-0.990） compared with Model for End-Stage Liver Disease （MELD） （AUC=0.839， 95%CI 0.672-0.942） （P > 0.05）. Conclusion MA and eGFR-CysC can predict clinical prognosis of ACLF patients. MA combined with eGFR-CysC yield similar predictive value for ACLF compared with MELD