Recent trends in preparation and biomedical applications of iron oxide nanoparticles.

The iron oxide nanoparticles (IONPs), possessing both magnetic behavior and semiconductor property, have been extensively used in multifunctional biomedical fields due to their biocompatible, biodegradable and low toxicity, such as anticancer, antibacterial, cell labelling activities. Nevertheless, there are few IONPs in clinical use at present. Some IONPs approved for clinical use have been withdrawn due to insufficient understanding of its biomedical applications. Therefore, a systematic summary of IONPs' preparation and biomedical applications is crucial for the next step of entering clinical practice from experimental stage. This review summarized the existing research in the past decade on the biological interaction of IONPs with animal/cells models, and their clinical applications in human. This review aims to provide cutting-edge knowledge involved with IONPs' biological effects in vivo and in vitro, and improve their smarter design and application in biomedical research and clinic trials.

[Diurnal differences in acute gout attacks: A clinical study of male gout patients].

OBJECTIVE: To observe the diurnal difference of acute gout attacks in men, and provide reference for accurate clinical prevention and treatment. METHODS: Using a single-center, cross-sectional study design, the patients diagnosed with gout in the outpatient department of Rheumatology and Immuno-logy of PLA Joint Logistic Support Force No.980 Hospital from October 2021 to April 2022 were selected. The information about the patient's current/last acute gout attacks (less than 2 weeks from visit), date and time of attacks, joint symptoms and signs, medication use, and relevant biochemical tests on the day of visit was recorded. The diurnal time difference of acute gout attacks in male patients was analyzed, and univariate comparison and multivariate Logistic regression analyses were conducted to compare the diurnal difference of acute gout attacks with clinical characteristics and biochemical indicators. RESULTS: A total of 100 male gout patients were included, and 100 acute attacks were recorded. Diurnal distribution of acute gout attacks: morning (6:00~11:59, 18, 18%), afternoon (12:00~17:59, 11, 11%), the first half of the night (18:00~23:59, 22, 22%), the second half of the night (0:00~05:59, 49, 49%); During the day (included morning and afternoon, 29, 29%) and at night (included the first half of the night and the second half of the night, 71, 71%). The rate of acute gout attack was significantly higher at night than in the day (about 2.5 ∶1). No matter the first or recurrent gout, no matter the duration of the disease, the number of acute gout attacks had the difference of less in the day and more in the night. Serum urate (SU) level was higher in the patients with nocturnal attack than in those with daytime attack (P=0.044). Comorbidities were significantly different in the day-night ratio of the number of acute gout attack (P=0.028). Multiple Logistic regression analysis showed that SU level (OR=1.005, 95%CI: 1.001-1.009) and comorbidities (OR=3.812, 95%CI: 1.443-10.144) were the correlative factors of nocturnal acute gout attacks. CONCLUSION: No matter the first or recurrent gout, no matter the duration of the disease, it has a diurnal variation characterized by multiple attacks at night, increased SU level and comorbidities are correlative factors for nocturnal acute attack of gout.

Radical Acylalkylation of 1,3-Enynes To Access Allenic Ketones via N-Heterocyclic Carbene Organocatalysis.

An N-heterocyclic carbene organocatalytic 1,4-difunctionalization of 1,3-enynes was developed. This organocatalytic strategy was suitable for a broad spectrum of substrates to efficiently synthesize allenic ketones bearing diverse substituents. Preliminary mechanistic studies suggest a radical reaction pathway for this organocatalytic acylalkylation process.

Asymmetric organocatalysis: an enabling technology for medicinal chemistry.

The efficacy and synthetic versatility of asymmetric organocatalysis have contributed enormously to the field of organic synthesis since the early 2000s. As asymmetric organocatalytic methods mature, they have extended beyond the academia and undergone scale-up for the production of chiral drugs, natural products, and enantiomerically enriched bioactive molecules. This review provides a comprehensive overview of the applications of asymmetric organocatalysis in medicinal chemistry. A general picture of asymmetric organocatalytic strategies in medicinal chemistry is firstly presented, and the specific applications of these strategies in pharmaceutical synthesis are systematically described, with a focus on the preparation of antiviral, anticancer, neuroprotective, cardiovascular, antibacterial, and antiparasitic agents, as well as several miscellaneous bioactive agents. The review concludes with a discussion of the challenges, limitations and future prospects for organocatalytic asymmetric synthesis of medicinally valuable compounds.

Remote C(sp3 )-H Acylation of Amides and Cascade Cyclization via N-Heterocyclic Carbene Organocatalysis.

The direct functionalization of inert C(sp3 )-H bonds under environmentally benign catalytic conditions remains a challenging task in synthetic chemistry. Here, we report an organocatalytic remote C(sp3 )-H acylation of amides and cascade cyclization through a radical-mediated 1,5-hydrogen atom transfer mechanism using N-heterocyclic carbene as the catalyst. Notably, a diversity of nitrogen-containing substrates, including simple linear aliphatic carbamates and ortho-alkyl benzamides, can be successfully applied to this organocatalytic system. With the established protocol, over 120 examples of functionalized δ-amino ketones and isoquinolinones with diverse substituents were easily synthesized in up to 99 % yield under mild conditions. The robustness and generality of the organocatalytic strategy were further highlighted by the successful acylation of unactivated C(sp3 )-H bonds and late-stage modification of pharmaceutical molecules. Then, the asymmetric control of the radical reaction was attempted and proven feasible by using a newly designed chiral thiazolium catalyst, and moderate enantioselectivity was obtained at the current stage. Preliminary mechanistic investigations including several control reactions, KIE experiments, and computational studies shed light on the organocatalytic radical reaction mechanism.

Oxidative Radical NHC Catalysis: Divergent Difunctionalization of Olefins through Intermolecular Hydrogen Atom Transfer.

Oxidative N-heterocyclic carbene (NHC) organocatalysis, typically leading to the formation of acyl azolium reactive intermediates, constitutes one of the most important activation strategies for the NHC-catalyzed chemical transformations. Here, we report an unprecedented oxidative radical NHC catalysis by using peroxyester as the external single-electron oxidant to realize divergent difunctionalization of olefins. The key to success of this chemistry is the catalytic generation of oxygen radicals that could trigger an intermolecular hydrogen atom transfer to activate the inert C-H bonds, thereby enabling the productive radical relay process. With this protocol, commonly used general chemicals could serve as radical precursors to allow efficient synthesis of value-added products in a straightforward and cost-effective manner. Preliminary mechanistic investigations, including control experiments and DFT calculations, shed light on the NHC organocatalytic radical reaction mechanism.

Double-Walled Metal-Organic Framework with Regulable Pore Environments for Efficient Removal of Radioactive Cesium Cations.

An anion double-walled metal-organic framework [Co2Li4(BTC)3(DMF)(H2O)·(CH3)2N]n (1) based on heterobimetallic Li+ and Co2+ ions was successfully constructed. Utilizing selective destruction and formation of Co-O/Co-N bonds in the metal chains, [Co2Li4(BTC)3(py)(H2O)·(CH3)2N]n (2) and [Co2Li4(BTC)3(pi)(H2O)·(CH3)2N]n (3) with the same skeleton but distinct pore structures can be surprisingly obtained. Additionally, compounds 2 and 3 can be transformed into [Co2Li4(BTC)3(H2O)2·(CH3)2N]n (4) by soaking them in an ethanol solution. This kind of single-crystal-to-single-crystal transformation successfully regulates the pore structure of MOFs and enriches the diversity of the pore wall on the premise of retaining the original framework. Most impressively, compound 1 shows high adsorption capacity for Cs+ cations and is a good candidate to selectively accommodate Cs+ among the common alkali metal ions, which is future identified by single-crystal X-ray diffraction and inductively coupled plasma mass spectrometry (ICP-MS) test. Meanwhile, compound 1 can selectively adsorb methylene blue (MB) and crystal violet (CV) molecules over Rhodamine B (RMB).

Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways.

Melanoma is the deadliest form of skin cancer, and its incidence has continuously increased over the past 20 years. Therefore, the discovery of a novel targeted therapeutic strategy for melanoma is urgently needed. In our study, MTT-based cell proliferation assay, cell cycle, and apoptosis assays through flow cytometry, protein immunoblotting, protein immunoprecipitation, designing of melanoma xenograft models, and immunohistochemical/immunofluorescent assays were carried out to determine the detailed molecular mechanisms of a novel HSP90-PI3K dual inhibitor. Our compound, named DHP1808, was found to suppress A375 cell proliferation through apoptosis induction by activating the Fas/FasL signaling pathway; it also induced cell-cycle arrest and inhibited the cell migration and invasion of A375 cells by interfering with Hsp90-EGFR interactions and downstream signaling pathways. Our results indicate that DHP1808 could be a promising lead compound for the Hsp90/PI3K dual inhibitor.

[Significance of Dynamic Risk Assessment in the Follow-up of Non-distant Metastatic Differentiated Thyroid Cancer Patients with Intermediate and High Risk].

Objective To tailor the subsequent treatment and follow-up strategy,this study dynamically assessed the response to initial therapy in non-distant metastatic differentiated thyroid cancer (DTC) patients with intermediate and high risk. Methods A total of 184 non-distant metastatic DTC patients (intermediate-risk 111 cases and high-risk 73 cases) were retrospectively enrolled in this study. Based on the results of initial response assessment (6-12 months after initial therapy),patients were divided into two groups:excellent response (ER) group (n=113) and non-excellent response (non-ER) group (n=71). We compared the differences in clinicopathological features between these 2 groups and evaluated the changes of dynamic response to therapy at the initial and final assessments after initial therapy in all patients. Results Compared with the ER group,the non-ER group showed a larger tumor size (U=2771.500,P=0.000),higher proportion of extrathyroidal invasion (χ 2=4.070,P=0.044),and higher preablative-stimulated thyroglobulin levels (U=1367.500,P=0.000). ER was achieved in 31% of patients in the initial non-ER group [including indeterminate response (IDR) and biochemical incomplete response (BIR)] at the final follow-up only by thyroid stimulating hormone (TSH) suppression therapy,among which 63.6% were with intermediate risk (especially the patients with IDR) and 36.4% at high risk. In addition,5.2%(6/113) of patients in the initial ER group were reassessed as IDR,BIR,or even structural incomplete response at the end of the follow-up (among which one patient developed into cervical lymph node recurrence,as confirmed by pathology);the TSH level in these patients fluctuated at 0.56-10.35 µIU/ml and was not corrected in time during the follow-up after initial therapy. Conclusions Some of non-distant metastatic DTC patients with intermediate and high risks who presented initial non-ER may achieve ER only by TSH suppression therapy over time;in contrast,the patients presented initial ER may develop into non-ER without normalized TSH suppression therapy. The dynamic risk assessment system may provide a real-time assessment of recurrence risk and tailor the subsequent treatment and follow-up strategies.

Radical Acylfluoroalkylation of Olefins through N-Heterocyclic Carbene Organocatalysis.

Fluorinated ketones are widely prevalent in numerous biologically interesting molecules, and the development of novel transformations to access these structures is an important task in organic synthesis. Herein, we report the multicomponent radical acylfluoroalkylation of a variety of olefins in the presence of various commercially available aromatic aldehydes and fluoroalkyl reagents through N-heterocyclic carbene organocatalysis. With this protocol, over 120 examples of functionalized ketones with diverse fluorine substituents have been synthesized in up to 99 % yield with complete regioselectivity. The generality of this catalytic strategy was further highlighted by its successful application in the late-stage functionalization of pharmaceutical skeletons. Excellent diastereoselectivity could be achieved in the reactions forging multiple stereocenters. In addition, preliminary results have been achieved on the catalytic asymmetric variant of the olefin difunctionalization process.

1,25-(OH)2D3/Vitamin D receptor alleviates systemic lupus erythematosus by downregulating Skp2 and upregulating p27.

BACKGROUND: Recent evidence has suggested that the 1,25(OH)2D3/Vitamin D receptor (VDR) acts to suppress the immune response associated with systemic lupus erythematosus (SLE), a serious multisystem autoimmune disease. Hence, the aim of the current study was to investigate the mechanism by which 1,25-(OH)2D3/VDR influences SLE through regulating the Skp2/p27 signaling pathway. METHODS: Initially, the levels of 1,25(OH)2D3, VDR, Skp2, and p27 were measured in collected renal tissues and peripheral blood. Meanwhile, the levels of inflammatory factors, biochemical indicators (BUN, Cr, anti-nRNP IgG, anti-dsDNA IgG) and urinary protein levels were assayed in in VDRinsert and VDR-knockout mice in response to 1,25(OH)2D3 supplement. In addition, the distribution of splenic immune cells was observed in these mice. RESULTS: Among the SLE patients, the levels of 1,25(OH)2D3, VDR and p27 were reduced, while the levels of Skp2 were elevated. In addition, the levels of anti-nRNP IgG and anti-dsDNA IgG were increased, suggesting induction of inflammatory responses. Notably, 1,25(OH)2D3/VDR mice had lower concentrations of BUN and Cr, urinary protein levels, precipitation intensity of the immune complex and complement, as well as the levels of anti-nRNP IgG and anti-dsDNA IgG in SLE mice. Additionally, 1,25(OH)2D3 or VDR reduced the degree of the inflammatory response while acting to regulate the distribution of splenic immune cells. CONCLUSION: This study indicated that 1,25-(OH)2D3/VDR facilitated the recovery of SLE by downregulating Skp2 and upregulating p27 expression, suggesting the potential of 1,25-(OH)2D3/VDR as a promising target for SLE treatment.

UNFAVORABLE RESPONSES TO RADIOIODINE THERAPY IN N1B PAPILLARY THYROID CANCER: A PROPENSITY SCORE MATCHING STUDY.

Objective: Regional nodal metastases carry prognostic significance in papillary thyroid cancer (PTC). However, whether different locational nodal metastases correlate with different therapeutic responses remains controversial. We innovatively applied the response to therapy restratification system to evaluate the dynamic disease status after surgery and radioactive iodine (RAI) therapy in PTC patients with different locational nodal metastases. Methods: A total of 585 nondistant-metastatic PTC patients who underwent total thyroidectomy and RAI therapy were retrospectively enrolled. Patients with nodal metastases were categorized into N1a and N1b groups. Propensity score matching was used to balance the bias between the 2 groups. Therapeutic responses were dynamically evaluated, and responses to RAI therapy were classified into excellent (ER), indeterminate (IDR), biochemical incomplete (BIR) and structural incomplete response (SIR). Results: N1b group patients showed a significantly higher pre-ablation stimulated thyroglobulin (Ps-Tg) level than N1a group patients (7.4 ng/mL versus 3.2ng/mL, P<.001). After RAI therapy, N1b group patients took a longer time to achieve ER (9.86 months versus 3.29 months, P<.001) and exhibited a higher proportion of non-ER (IDR, BIR, and SIR) (39.15% versus 17.46%, P<.001) compared to N1a group patients. In logistic regression, N1b and Ps-Tg ≥10 ng/mL were confirmed to be independent factors predicting non-ER (odds ratio: 2.591, and 9.196, respectively). In Cox regression, patients with N1b disease and Ps-Tg ≥10 ng/mL showed significantly lower hazards for achieving ER (hazard ratio: 0.564, and 0.223, respectively). Conclusion: N1b PTC patients showed inferior responses to surgery and RAI therapy compared to N1a patients. N1b was confirmed to be an independent factor predicting unfavorable responses to RAI therapy. Abbreviations: AJCC = American Joint Committee on Cancer; ATA = American Thyroid Association; BIR = biochemical incomplete response; BRAFV600E = proto-oncogene B-Raf V600E mutation; CI = confidence interval; CT = computed tomography; DNA = deoxyribonucleic acid; DTC = differentiated thyroid cancer; ER = excellent response; ETE = extrathyroidal extension; HR = hazard ratio; IDR = indeterminate response; LNM = lymph node metastasis; N1a = central cervical LNM; N1b = lateral cervical LNM; OR = odds ratio; PSM = propensity score matching; Ps-Tg = pre-ablation stimulated thyroglobulin; PTC = papillary thyroid cancer; RAI = radioactive iodine; SIR = structural incomplete response; Tg = thyroglobulin; TgAb = thyroglobulin antibody; TSH = thyroid-stimulating hormone.

Bulleyaconitine A attenuates hyperexcitability of dorsal root ganglion neurons induced by spared nerve injury: The role of preferably blocking Nav1.7 and Nav1.3 channels.

Background Oral administration of Bulleyaconitine A, an extracted diterpenoid alkaloid from Aconitum bulleyanum plants, is effective for treating chronic pain in rats and in human patients, but the underlying mechanisms are poorly understood. Results As the hyperexcitability of dorsal root ganglion neurons resulting from the upregulation of voltage-gated sodium (Nav) channels has been proved critical for development of chronic pain, we tested the effects of Bulleyaconitine A on Nav channels in rat spared nerve injury model of neuropathic pain. We found that Bulleyaconitine A at 5 nM increased the threshold of action potentials and reduced the firing rate of dorsal root ganglion neurons in spared nerve injury rats but not in sham rats. Bulleyaconitine A preferably blocked tetrodotoxin-sensitive Nav channels over tetrodotoxin-resistant ones in dorsal root ganglion neurons of spared nerve injury rats. Bulleyaconitine A was more potent for blocking Nav1.3 and Nav1.7 than Nav1.8 in cell lines. The half maximal inhibitory concentration (IC50) values for resting Nav1.3, Nav1.7, and Nav1.8 were 995.6 ± 139.1 nM, 125.7 ± 18.6 nM, and 151.2 ± 15.4 µM, respectively, which were much higher than those for inactivated Nav1.3 (20.3 ± 3.4 pM), Nav1.7 (132.9 ± 25.5 pM), and Nav1.8 (18.0 ± 2.5 µM). The most profound use-dependent blocking effect of Bulleyaconitine A was observed on Nav1.7, less on Nav1.3, and least on Nav1.8 at IC50 concentrations. Bulleyaconitine A facilitated the inactivation of Nav channels in each subtype. Conclusions Preferably blocking tetrodotoxin-sensitive Nav1.7 and Nav1.3 in dorsal root ganglion neurons may contribute to Bulleyaconitine A's antineuropathic pain effect.

Direct Sulfide-Catalyzed Diastereoselective [4+1] Annulations of ortho-Quinone Methides and Bromides.

Direct sulfide organocatalysis is an emerging topic in research on synthetic chemistry. Here, an unprecedented sulfide-catalyzed diastereoselective [4+1] annulation of (in situ generated) ortho-quinone methides and bromides is reported. Notably, the robustness of such sulfide organocatalysis was demonstrated by performing the catalytic reaction under oxidative conditions without significantly affecting the reaction outcome. Various dihydrobenzofurans with diverse substituents were obtained with high isolated yields of up to 98% and remarkable diastereoselectivity (>19:1 dr in general).

Congenital Loss of Permanent Teeth in a Patient With Congenital Insensitivity to Pain With Anhidrosis due to 2 Novel Mutations in the NTRK1 Gene.

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV, is an extremely rare autosomal recessive disorder. This study investigated the oral and craniofacial manifestations of a 7-year-old Chinese boy affected by CIPA and identified 2 novel mutations in the NTRK1 gene, and a new feature of the disorder was identified. The patient had typical features, including insensitivity to pain, anhidrosis, and mental retardation; recurrent fractures and osteoporosis also were noted. His oral and craniofacial manifestations included congenital blepharoptosis, a large number of missing teeth, serious tooth abrasion, severe soft tissue injuries, and dental caries. Radiographic examination showed congenital loss of the permanent tooth germs, thin and weak alveolar bone of the mandible, and a fracture of the right mandible. This study extends the spectrum of NTRK1 mutations observed in patients with a diagnosis of CIPA and is the first to propose that congenital loss of permanent teeth may occur in CIPA patients. Furthermore, it highlights the importance of including an oral and maxillofacial surgeon and a pediatric dentist on the multidisciplinary team.

Early diagnosis and severity assessment of acute pancreatitis (AP) using MR elastography (MRE) with spin-echo echo-planar imaging.

PURPOSE: To evaluate the accuracy of magnetic resonance elastography (MRE) in comparison to contrast-enhanced computed tomography (CE-CT) for early diagnosis and prediction of severity in acute pancreatitis (AP). MATERIALS AND METHODS: This cross-sectional prospective study included 76 patients with suspected AP who underwent both CE-CT and 3.0T MRE within 24 hours of hospital admission. Pancreatic stiffness, CT severity index (CTSI), Acute Physiology and Chronic Health Evaluation (APACHE)-II, and Bedside Index for Severity in AP (BISAP) scores were comparatively evaluated using data from the first 24 hours of admission, and diagnosis and severity of AP were confirmed according to the revised Atlanta Classification (2012). The accuracy of MRE for predicting disease severity was compared with that of CE-CT and the clinical scoring systems using area under the receiver-operating curve (AUC) analysis. RESULTS: AP was confirmed in 56/76 patients (73.7%). Pancreatic stiffness values of >1.47 kPa showed significantly better diagnostic performance than CE-CT (AUC: 0.993 vs. 0.818, P < 0.001) along with greater sensitivity (96.4% vs. 78.6%, P = 0.006) and accuracy (96.1% vs. 81.6%, P = 0.007). Ten patients (10/76; 13.2%) had clinically severe AP. The accuracy of pancreatic stiffness >2.47 kPa was comparable to that of the CTSI, APACHE-II and BISAP scores for predicting severe AP (accuracy = 85.5%, 75.0%, 88.2%, and 78.9%, respectively). The pairwise comparisons were not significant after Bonferroni correction (P < 0.008 [0.05/6]), with P values of 0.008 (MRE vs. CTSI), 0.823 (MRE vs. APACHE-II) and 0.414 (MRE vs. BISAP). CONCLUSION: Early MRE is a useful, noninvasive method for both diagnosis and early severity assessment of AP. We recommend MRE at hospital admission for initial evaluation of AP. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1311-1319.

Control of Activation Mode To Achieve Diastereodivergence in Asymmetric Syntheses of Chiral Spiropiperidinone Derivatives.

An efficient organocatalytic cascade reaction has been developed involving a Michael-hemiaminalization relay for the asymmetric synthesis of spiropiperidinone derivatives bearing adjacent quaternary and tertiary chiral centers via LUMO or HOMO activation. Importantly, this methodology demonstrates that applying distinct activation modes to different substrates in the same reaction can diverge diastereoselectivity. To our knowledge, this is also one of the few published cases of primary amine catalytic [3 + 3] cycloaddition reactions involving α-branched ß-ketoamides.

Evaluation of the Morphology and Function of Medial Collateral Ligament afterTotal Knee Arthroplasty with High-frequency Ultrasound.

Objective To explore the feasibility and clinical value of ultrasonography in evaluating the morphology and function of medial collateral ligaments (MCL) after total knee arthroplasty (TKA). Methods Totally 38 patients undergoing routine KTA (group A) and 22 patients undergoing constrained condylar knee arthroplasty KTA with MCL injury (group B) were included. Long axis views of MCL were taken and the MCL thickness was measured on femur side and tibial side 1 cm away from the joint line, respectively. The thicknesses were compared between the two groups. Subsequently, the gap between the metal part of the femoral prosthesis and the spacer after dynamic valgus stress was measured. The distribution and composition of the gap between the two groups were compared. Results High-frequency ultrasound clearly showed the prosthesis and MCL after TKA. MCL fiber structures of both groups were intact. The MCL thickness on the tibial side in group B was (0.25±0.06)cm, which was significantly thinner than group A [(0.32±0.14)cm] (t=2.12, P=0.040).For the femur side, there was no significant difference (t=1.65, P=0.110) between these two groups [(0.37±0.09) cm in group B versus (0.42±0.12)cm in group A]. Under the condition of valgus stress, the gaps between the metal part of the femoral prosthesis and the spacer could be found in 11 cases in group B but only in 1 case in group A. The proportion of gaps in group B was significantly higher than that in group A (Fisher's exact test, P=0.000). Conclusions High-frequency ultrasound can clearly show the prosthesis and MCL after TKA. The injured MCL can be well joined but the thickness is thinner. Under the condition of valgus stress of the knee, the stability of the TKA can be evaluated according to the gap between the prosthesis and the spacer.