BACKGROUND:Ongoing neuropathic pain is difficult to treat. The authors examined whether dermorphin D-Arg2, Lys4 (1–4) amide, a peripherally acting μ-opioid receptor agonist, attenuates ongoing ...pain-associated manifestations after nerve injury in rats and mice.
METHODS:Using conditioned place preference assay, the authors tested whether animals show a preference to the environment associated with drug treatment. Wide-dynamic range and dorsal root ganglion neuronal activities were measured by electrophysiology recording and calcium imaging.
RESULTS:Nerve-injured animals stayed longer in dermorphin D-Arg2, Lys4 (1–4) amide–paired chamber after conditioning than during preconditioning (rats402.4 ± 61.3 vs. 322.1 ± 45.0 s, 10 mg/kg, n = 9, P = 0.009; mice437.8 ± 59.4 vs. 351.3 ± 95.9 s, 2 mg/kg, n = 8, P = 0.047). Topical ganglionic application of dermorphin D-Arg2, Lys4 (1–4) amide (5 μM, 1 μl, n = 5) reduced the numbers of small-diameter dorsal root ganglion neurons that showed spontaneous activity (1.1 ± 0.4 vs. 1.5 ± 0.3, P = 0.044) and that were activated by test stimulation (15.5 ± 5.5 vs. 28.2 ± 8.2, P = 0.009) after injury. In neuropathic rats, dermorphin D-Arg2, Lys4 (1–4) amide (10 mg/kg, n = 8) decreased spontaneous firing rates in wide-dynamic range neurons to 53.2 ± 46.6% of predrug level, and methylnaltrexone (5 mg/kg, n = 9) blocked dermorphin D-Arg2, Lys4 (1–4) amide–induced place preference and inhibition of wide-dynamic range neurons. Dermorphin D-Arg2, Lys4 (1–4) amide increased paw withdrawal threshold (17.5 ± 2.2 g) from baseline (3.5 ± 0.7 g, 10 mg/kg, n = 8, P = 0.002) in nerve-injured rats, but the effect diminished after repeated administrations.
CONCLUSIONS:Peripherally acting μ-opioids may attenuate ongoing pain-related behavior and its neurophysiologic correlates. Yet, repeated administrations cause antiallodynic tolerance.
The high tendency of bio-oil towards polymerization renders bio-oil with the application as the precursor for carbon materials. However, the pathway of the cross-polymerization of the major ...components of bio-oil was still unclear. Therefore, the cross-polymerization of furfural and the typical carbohydrates (monosaccharides and oligosaccharides) in bio-oil was studied. The results suggested that the cross-polymerization between furfural and sugars existed and proceeded to a significant extent, producing a much higher yield solid polymer than that of single feedstock and the soluble polymers with the varied π-conjugated structure. In addition, the characterization also indicated that the polymerization of furfural was accompanied with the substantial deoxygenation reactions such as dehydration, forming the polymer with a higher carbon content than that from the sugars. Although sugars contain multiple hydroxyl group, the dehydration reactions for elimination of the hydroxyl group did not take place to a remarkable extent during the polymerization, retaining significant hydrogen and oxygen content of polymer. In addition, the cross-polymerization of furfural and the sugars significantly changed the elemental composition, functionalities, thermal stability, and morphologies of the polymer, owing to the varied pathway from the polymerization of the single feedstock.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ferroptosis drugs often induce oxidative damage or block antioxidant defense due to the key mechanism of ferroptosis involved in cancer treatment, regulating the intracellular redox balance. However, ...these ferroptosis drugs are unstable during systemic circulation, and they lack tumor-targeting capability. Herein, we developed a stimuli-responsive and cell membrane-coated nanodrug for the simultaneous delivery of two ferroptosis drugs, an iron-chelating drug as a ROS inducer and sorafenib as an antioxidase inhibitor. The coating of the cancer cell membrane over the nanodrug can enhance the tumor-targeting capability and improve the stability in the blood circulation. In addition, the nanodrug exhibits sensitive drug release profiles in response to glutathione (GSH) and reactive oxygen species (ROS) in tumor microenvironments due to the dynamic diselenide bonds. The released iron-chelating drug and sorafenib not only produce hydroxyl radicals (&z.rad;OH) to induce ferroptosis, but also inhibit the expression of GPX4 to mitigate the ferroptosis resistance. Excitingly, the systemic administration of this biomimetic nanodrug displays superior antitumor and anti-metastatic effects in tumor-bearing mice. Our findings provide a promising therapeutic strategy for the co-delivery of ferroptosis inducers and antioxidase inhibitors to strengthen the therapeutic efficacy of ferroptosis.
A cancer cell membrane-coated nanodrug that can generate intercellular &z.rad;OH and inhibit ferroptosis resistance for enhanced ferroptosis therapy.
As the novel serum biomarkers, it has not been clearly clarified that the diagnostic accuracy of prostate health index (PHI) and prostate health index density (PHID) are superior to that of ...percentage free prostate-specific antigen (%fPSA) in detection of clinically significant prostate cancer (csPCa), especially in the gray zone. Therefore, this study aimed to compare the diagnostic value of PHI, PHID, and %fPSA for csPCa in the patients with prostate-specific antigen (PSA) >4 ng/mL and those with PSA within 4-10 ng/mL.
In this study, the serum samples and clinicopathological features were prospectively obtained from the patients who underwent prostate biopsy between September 2019 and December 2020. According to the inclusion criteria, the patients with total PSA (tPSA) >4 ng/mL, prostate magnetic resonance imaging or ultrasound clearly suggesting an occupying lesion were enrolled in this study. The patients with Gleason score ≥7 indicated csPCa. The receiver operating characteristic curves and the area under the curve (AUC) values were used to assess the diagnostic performance.
Among the 296 patients (mean age 67.5 years, median tPSA 7.94 ng/mL) included in this study, there were 54 in the csPCa group (mean age 70.4 years, median tPSA 11.0 ng/mL) and 242 in the non-csPCa group (mean age 66.8 years, median tPSA 7.67 ng/mL). Based on the PSA level, there were 198 patients with PSA within the gray zone, which included 40 patients in the csPCa group and 158 in the non-csPCa group. In all patients, the sensitivity of PHID for detecting csPCa was 96.30%, and the specificity was 33.06% with the cut-off value of 0.51. Moreover, both PHID and PHI did better in the diagnosis of csPCa (AUC: 0.880 and 0.867, respectively) compared with other PSA derivative markers. Similarly, in the patients with PSA level in the gray zone, the diagnostic accuracy of PHID and PHI in predicting csPCa (AUC: 0.788 and 0.777, respectively) were better than other PSA derivative markers.
PHID presented the better diagnostic accuracy in predicting csPCa in patients with PSA in the gray zone than other PSA derivative markers, which could be a promising biomarker for making the biopsy strategy.
Highlights • The cells death of keratinocytes and reduction of corneous layer cause capecitabine-induced HFS. • Capecitabine evoke HFS through mitochondria dysfunction that activating ...caspase-dependent apoptosis. • An alternative hypothesis concentrated on skelemin or ionic channel may be more appropriate to explain capecitabine-induced HFS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A novel method for facile fabrication of glycopolymer-based iron oxide nanoparticles (GIONs) is developed. Via perfluorophenylazide photochemically induced C–H insertion, alkynyl groups were ...introduced onto the polymer which was precoated on the iron oxide nanoparticle surface. GIONs were then prepared by conjugating the azide-functionalized carbohydrate to the introduced alkynyl groups via click chemistry. Polyvinyl alcohol-coated and dextran-coated iron oxide NPs were chosen as scaffolds to attach two different carbohydrates, α- d -mannose and β- d -glucose, to fabricate multivalent GIONs, respectively. The multivalent GIONs demonstrated high binding affinities towards the corresponding lectins in both protein and cell chips. As a proof of concept, fluorescent GIONs (Gal-RhB-IONPs) were fabricated, which showed selective and efficient internalization by ASGP-R overexpressing HepG2 cells targeted.
The purpose of this present study is to assess if addition of the synthetic polymers in maturation medium can influence cryotolerance and subsequently embryonic development of mammalian oocytes. We ...examined the roles of two polymers, including polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), on in vitro maturation (IVM), embryonic developmental capacity, and cryotolerance of goat oocytes. The present study includes two parts. At first, goat cumulus−oocyte complexes (COCs) were matured in a medium supplemented with 10% fetal bovine serum (FBS), 3 mg/ml PVP, or 1 mg/ml PVA, respectively. Data of oocyte with first polar body, cleavage, and blastocyst following parthenogenetic activation (PA) were recorded. Secondly, after maturation in the above medium, oocytes were vitrified using the Cryotop technique and then the morphology, cleavage and blastocyst formation of vitrified oocytes have been checked. The results demonstrated that the adding of PVP or PVA in maturation medium can't affect IVM of goat oocytes in comparison with FBS, as concern cumulus cell expansion, first polar body formation, and embryonic development. Additionally, without plunging into liquid nitrogen, only exposure to the vitrification and warming solutions cannot also influence the quality of oocytes, in terms of morphology, cleavage, and blastocyst formation. However, after IVM with synthetic polymers and vitrification, the ratio of oocytes with standard morphology in PVP or PVA group was only 59.47% ± 3.56% or 54.86% ± 5.19%, respectively, and was significantly less than that in the FBS group (89.37% ± 4.52%, P < 0.05). Furthermore, the cleavage ratio of oocytes in PVP or PVA group was 37.41% ± 4.17% or 27.71% ± 3.91% and was considerably less than that in the FBS group (64.97% ± 4.69%, P < 0.05). In addition, the cleavage ratio in PVP group was statistically higher than that in PVA group (P < 0.05). In terms of blastocyst development, a significant difference was observed between the synthetic polymer group and the FBS group (24.96% ± 3.62%, P < 0.05). However, the blastocyst ratio in the PVA group (7.51% ± 1.68%) was statistically less than the PVP groups (13.20% ± 4.59%, P < 0.05) and the FBS group (P < 0.05). In conclusion, two potential serum replacements, either PVP or PVA, can support IVM and embryonic development of goat oocytes at the concentration used in this study. But IVM with synthetic polymers supplemented to maturation medium may reduce the cryotolerance of oocytes. Additionally, the supportive function of PVP on embryonic development of vitrified oocytes might be better than that of PVA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Despite significant progress made in past decades, it is still challenging to elucidate dynamics mechanisms for polyatomic reactions, in particular, involving complex formation. The reaction of O(1D) ...with methane has long been regarded as a prototypical polyatomic system of direct insertion reaction in which the O(1D) atom can insert into the C–H bond of methane to form a “hot” methanol intermediate before decomposition. Here, we report a combined theoretical and experimental study on the O(1D) + CHD3 reaction, on which good agreement between theory and experiment is achieved. Our study revealed that this complex-forming reaction actually proceeds via a trapped abstraction mechanism, rather than an insertion mechanism as has long been thought. We anticipate that this reaction mechanism should also be responsible for the reaction of O(1D) with ethane and propane, as well as many other chemical reactions with deep wells in the interaction region.
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IJS, KILJ, NUK, PNG, UL, UM
ObjectiveInfection is a major cause of death in patients with SLE. This study aimed to explore the infection rate in patients with SLE receiving a low dose of intravenous cyclophosphamide ...(IV-CYC).MethodsClinical parameters of 1022 patients with SLE from 24 hospitals in China were collected. Patients were divided into the short-interval and lower-dose (SILD, 400 mg every 2 weeks) IV-CYC group and the high-dose (HD, 500 mg/m2 of body surface area every month) IV-CYC group. The clinical data and infection rate between the two groups were compared.ResultsCompared with HD IV-CYC, the infection rate of the SILD IV-CYC group was significantly lower (13.04% vs 22.27%, p=0.001). Respiratory tract infection (10.28% vs 15.23%, p=0.046) and skin/soft tissue infection (1.78% vs 4.3%, p=0.040) were significantly decreased in the SILD IV-CYC group. Moreover, infections occurred most likely in patients with SLE with leucopenia (OR 2.266, 95% CI 1.322 to 3.887, p=0.003), pulmonary arterial hypertension (OR 2.756, 95% CI 1.249 to 6.080, p=0.012) and >15 mg/day of glucocorticoid (OR 2.220, 95% CI 1.097 to 4.489, p=0.027).ConclusionsSILD IV-CYC showed a lower frequency of infection events than high-dose IV-CYC in patients with SLE.
Chemotherapy is the only therapy option for the majority of AML patients, however, there are several limitations for this treatment. Our aim was to find a new chemotherapy strategy that is more ...effective and less toxic.
MTT assays and a xenograft mouse model were employed to evaluate the synergistic activity of all-trans retinoic acid (ATRA) combined with topotecan (TPT). Drug-induced DNA damage and apoptosis were determined by flow cytometry analysis with PI and DAPI staining, the comet assay and Western blots. Short hairpin RNA (shRNA) and a RARα plasmid were used to determine whether RARα expression influenced DNA damage and apoptosis.
We found that ATRA exhibited synergistic activity in combination with Topotecan in AML cells, and the enhanced apoptosis induced by Topotecan plus ATRA resulted from caspase pathway activation. Mechanistically, ATRA dramatically down regulated RARα protein levels and led to more DNA damage and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of Topotecan combined with ATRA was further validated in the HL60 xenograft mouse model.
Our data demonstrated, for the first time, that the combination of TPT and ATRA showed potential benefits in AML, providing a novel insight into clinical treatment strategies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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