Meta­analysis of the efficacy of venetoclax and azacitidine combination therapy and azacitidine monotherapy for treating acute myeloid leukemia.

The present study aimed to compare the efficacy of combination therapy with venetoclax and azacitidine with that of azacytidine monotherapy in the treatment of acute myeloid leukemia (AML). The Web of Science, PubMed, Embase, The Cochrane Library, Weipu Database, Wanfang Digital Periodicals, Sinomed, China National Knowledge Infrastructure, ProQuest Dissertations and Theses and Cumulative Index to Nursing and Allied Health Literature were searched for publications on the treatment of AML with venetoclax combined with azacitidine or with azacitidine monotherapy. A total of 5,271 relevant studies were retrieved, of which 10 were included. Literature quality was evaluated according to the Cochrane systematic review methodology, and data were extracted for meta-analysis using Review Manager 5.4. The combination of venetoclax and azacitidine demonstrated greater overall efficacy than azacitidine monotherapy for AML treatment. Notably, combination therapy resulted in a higher frequency of complete remission. By contrast, combined treatment and monotherapy showed no significant differences in partial remission, whereas there was a statistically significant decrease in the frequency of no remission in the combination therapy group compared with in the monotherapy group. The results also revealed a significantly higher incidence of adverse reactions when venetoclax and azacitidine were combined in the treatment of AML compared with the observed rates in response to azacitidine monotherapy. Moreover, subgroup analyses showed that no statistically significant differences were observed between the two groups regarding adverse events, including hypokalemia and liver insufficiency. In conclusion, the combination of venetoclax and azacitidine was more effective than azacitidine alone, and had a good clinical application value in the treatment of AML. Although some adverse reactions occurred in response to the combination therapy, they did not significantly affect the prognosis of AML. To better evaluate the efficacy and safety of this treatment regimen, multicenter clinical studies with larger sample sizes are required.

Chirality Induction and Memory of Pillar[4]arene[1]quinone Derivatives in Visible-Light Range.

Pillar[4]arene[1]quinone derivatives (PQXs) were synthesized by the oxidation of pillar[5]arenes, which exhibited notable charge transfer (CT) transitions at approximately 485 nm. Successful chiral resolution of two pairs of enantiomeric conformers was achieved. Despite reduced binding affinity, PQXs demonstrated slower racemization kinetics. Visible-light chiroptical induction with a significant dissymmetry factor was attained by complexing PQXs with a chiral guest. The induced enantiomeric excess could be maintained through competitive binding with an achiral guest, offering a promising strategy for chiral sensing and memory.

Activation of the JNK/COX-2/HIF-1α axis promotes M1 macrophage via glycolytic shift in HIV-1 infection.

Chronic inflammation is recognized as a major risk factor for the severity of HIV infection. Whether metabolism reprogramming of macrophages caused by HIV-1 is related to chronic inflammatory activation, especially M1 polarization of macrophages, is inconclusive. Here, we show that HIV-1 infection induces M1 polarization and enhanced glycolysis in macrophages. Blockade of glycolysis inhibits M1 polarization of macrophages, indicating that HIV-1-induced M1 polarization is supported by enhanced glycolysis. Moreover, we find that this immunometabolic adaptation is dependent on hypoxia-inducible factor 1α (HIF-1α), a strong inducer of glycolysis. HIF-1α-target genes, including HK2, PDK1, and LDHA, are also involved in this process. Further research discovers that COX-2 regulates HIF-1α-dependent glycolysis. However, the elevated expression of COX-2, enhanced glycolysis, and M1 polarization of macrophages could be reversed by inactivation of JNK in the context of HIV-1 infection. Our study mechanistically elucidates that the JNK/COX-2/HIF-1α axis is activated to strengthen glycolysis, thereby promoting M1 polarization in macrophages in HIV-1 infection, providing a new idea for resolving chronic inflammation in clinical AIDS patients.

Asymmetric Photoreactions in Supramolecular Assemblies.

ConspectusStereochemical control of excited-state asymmetric photoreactions has been one of the most challenging topics of modern photochemistry. The short-lived character of electronically excited photosubstrates and their low activation energy barriers to form both enantiomers are the major obstacles to achieving significant enantioselectivity in excited-state asymmetric photochemistry. Recent research demonstrated that the supramolecular strategy is promising to control the stereochemical outcome of asymmetric photoreaction through relatively strong and long-lasting noncovalent interaction at both ground and excited states. In this methodology, chiral hosts/assemblies provide the chiral environment for photochemically transferring chirality to the complexed photosubstrate in both the ground and the excited states by virtue of relatively strong supramolecular interactions, such as hydrogen bonding, van der Waals, π-π, electrostatic, and hydrophobic interactions. The orientation and conformation of the photosubstrate can be critically manipulated by the supramolecular complexation to ensure the subsequent effective stereoselective photochemical conversion.This Account describes our recent advance in asymmetric photoreactions in supramolecular assemblies. Several chiral photoreactions, including photoisomerization of cycloolefins and photocyclodimerization of anthracene and naphthalene derivatives, have been mediated by various supramolecular hosts, such as cyclodextrin (CD), cucurbituril, pillararene, and chiral polymer. The following advantages of supramolecular asymmetric photochemistry were evidenced: (1) The improvement of stereoselectivity can be enabled by the careful design and fabrication of chiral host molecules. (2) Supramolecular complexation could effectively regulate the orientation and conformation of photosubstrates, thus resulting in novel reaction pathways which create unusual photoproducts that are not achievable through traditional reaction conditions. (3) Asymmetric photoreactions in supramolecular systems showed strong correlations with the external environmental variants, such as temperature, solvent, irradiation wavelength, and pressure, which therefore provide a powerful tool for the regulation of stereoselectivities of excited-state photoreactions. (4) Utilizing supramolecular complexation can dramatically speed up photoreactions, a combination of appropriate photosensitizers/photocatalysts being able to drive catalyzed chiral photoreactions effectively. (5) Photoisomerization in chiral supramolecular systems has been applied to chiroptical molecular devices, which exhibited multiple stimulus-response functions and advanced switching performances. We believe that these concepts, methods, and principles derived therefrom are instructive in designing chiral supramolecular hosts, elucidating the stereodifferentiation mechanisms in the ground and excited states, and analyzing and improving the stereochemical outcomes of a diverse range of supramolecular chiral photoreactions.

GCN5 regulates ZBTB16 through acetylation, mediates osteogenic differentiation, and affects orthodontic tooth movement.

In the process of orthodontic tooth movement (OTM), periodontal ligament fibroblasts (PDLFs) must undergo osteogenic differentiation. OTM increased the expression of Zinc finger and BTB domain-containing 16 (ZBTB16), which is implicated in osteogenic differentiation. Our goal was to investigate the mechanism of PDLF osteogenic differentiation mediated by ZBTB16. The OTM rat model was established, and PDLFs were isolated and exposed to mechanical force. Hematoxylin-eosin staining, Alizarin Red staining, immunofluorescence, and immunohistochemistry were carried out. The alkaline phosphatase (ALP) activity was measured. Dual-luciferase reporter gene assay and chromatin immunoprecipitation assay were conducted. In OTM models, ZBTB16 was significantly expressed. Additionally, there was an uneven distribution of PDLFs in the OTM group, as well as an increase in fibroblasts and inflammatory infiltration. ZBTB16 interference hindered PDLF osteogenic differentiation and decreased Wnt and ß-catenin levels. Meanwhile, ZBTB16 activated the Wnt/ß-catenin pathway. ZBTB16 also enhanced the expression of the osteogenic molecules osterix, osteocalcin (OCN), osteopontin (OPN), and bone sialo protein (BSP) at mRNA and protein levels. The interactions between Wnt1 and ZBTB16, as well as GCN5 and ZBTB16, were also verified. The adeno-associated virus-shZBTB16 injection also proved to inhibit osteogenic differentiation and reduce tooth movement distance in in vivo tests. ZBTB16 was up-regulated in OTM. Through acetylation modification of ZBTB16, GCN5 regulated the Wnt/ß-catenin signaling pathway and further mediated PDLF osteogenic differentiation.

Nanobodies: a new potential for prostate cancer treatment.

BACKGROUND: The current progressive increase in the cancer burden of prostate cancer requires the exploration of new diagnostic and therapeutic approaches. Nanobodies are single-domain antibodies with the advantages of small size, high stability, easy processing and modification, which are increasingly used in the treatment of many types of cancer. METHODS: This review analyzed the relevant literature in PubMed and other databases. RESULT: In the retrieved literature, nanobodies are widely used in the treatment of prostate cancer. The preparation of nanobodies targeting PSA or PSMA is straightforward. For diagnostic purposes, nanobodies can be used in the preparation of biosensors for more sensitive identification of prostate cancer; for therapeutic purposes, nanobodies are used in the preparation of immunotoxic and ADC drugs. Preclinical in vivo and in vitro experiments have shown that this therapeutic approach is feasible. This article is a review of the above to provide new ideas for the treatment of prostate cancer. CONCLUSION: Compared with traditional antibodies, nano-antibodies have the advantages of small size, high stability, and high penetration. These advantages make nano-antibodies worthy to be widely used. Current studies have shown that nanobodies have advantages and future in the diagnosis and treatment of prostate cancer.

The global burden of cardiovascular diseases and type 2 diabetes attributable to low physical activity, 1990-2019: an analysis from the global burden of disease study.

Background: Cardiovascular diseases (CVD) and type 2 diabetes (T2D) account for the majority of the burden of noncommunicable disease caused by low physical activity (LPA). In order to inform future interventions, this study aims to assess the burden and trends in mortality and disability-adjusted life years (DALYs) of CVD and T2D attributable to LPA by year, location, sex, and age from 1990 to 2019. Methods: Mortality, DALYs, and their age-standardised rates (ASMR, ASDR) for CVD and T2D attributable to LPA were retrieved from Global Burden of Disease (GBD) 2019. The estimated annual percentage changes (EAPCs) were calculated using linear regression model to describe the trend over time. Results: From 1990 to 2019, the number of deaths caused by both CVD and T2D due to LPA increased significantly globally. However, the overall ASMR and ASDR for CVD declined over this same period [EAPC for ASMR (CVD) = -1.44 (95% CI: -1.50-1.38), EAPC for ASDR (CVD) = -1.30 (95% CI: -1.35 to -1.25)]. In terms of disparities, ASMR (CVD) and ASDR (CVD) in North Africa and the Middle East were consistently higher than the global average; also, the sex difference in ASMR was greatest in Central Asia. ASMR among people aged 25-44 in high Socio-Demographic Index (SDI) region has increased significantly over the past three decades. ASMR (T2D) due to LPA showed an increasing trend year by year, with EAPC = 0.26 (95% CI: 0.13-0.39), and this rate increased faster in males than in females. Consistent with cardiovascular diseases, ASMR of type 2 diabetes attributable to LPA increased among people aged 25-44, while decreased in other age groups in high SDI region. Conclusion: Interventions targeting LPA are warranted in controlling the burden of cardiovascular diseases and type 2 diabetes. Countries should adapt strategies to their local contexts, considering the sex and age differences among their populations. The 25-44 age group should be given special attention to prevent the disease burden from worsening among younger people.

Synthesis of cyclodextrin derivatives for enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate.

Photochemical methods are increasingly being used in organic synthesis. They are especially useful for preparing many compounds that are not readily accessible through thermal or enzymatic reactions. The supramolecular strategy has proved highly promising in recent years for manipulating the stereochemical outcome of chiral photoreactions through relatively strong and long-lasting noncovalent interactions in both ground and excited states. Among the numerous chiral photochemical reactions, photocyclodimerization of 2-anthracenecarboxylate (AC) is the most comprehensively studied supramolecular chiral photoreaction and has essentially become a benchmark reaction for evaluating supramolecular photochirogenesis. Cyclodextrin (CD) derivatives were the earliest and are the most widely applied chiral host for mediating photoreactions. Herein, we use CD-mediated photocyclodimerization of AC as an example to introduce the operation process of supramolecular chiral photoreactions. The protocol includes the following contents: (i) the preparation, purification and characterization of ß-CD derivatives; (ii) methods for investigating the host-guest inclusion behavior between AC and ß-CD derivatives; (iii) the photochemical reaction operation flow under different solvent and temperature conditions; (iv) chiral high-performance liquid chromatography (HPLC) analyses of the product distribution and enantioselectivity. The protocol is introduced by using representative examples of the synthesis of ß-CD derivatives and the manipulation of environmental factors that give excellent regio- and enantioselectivities in the photocyclodimerization of AC. The synthesis and purification of ß-CD derivatives require 3-5 d of work. The photoirradiation of AC with ß-CD derivatives can be done within 1 h. The product analysis requires 5 h.

The More the Slower: Self-Inhibition in Supramolecular Chirality Induction, Memory, Erasure, and Reversion.

Self-inhibition has been observed widely in hierarchical biochemical processes but has yet to be demonstrated in pure molecular physical rather than chemical or biological processes. Herein, we report an unprecedented example of self-inhibition during the supramolecular chirality induction, memory, erasure, and inversion processes of pillar[5]arene (P[5]) derivatives. The addition of chiral alanine ethyl ester to bulky substituent-modified P[5]s led to time-dependent chirality induction due to the shift in the equilibrium of the SP and RP conformers P[5]. Intriguingly, more chiral inducers led to more intensive final chiroptical properties but lower chiral induction rates. Thus, the chiral inducer plays the role of both activator and inhibitor. Such self-inhibition essentially arises from kinetics manipulation of three tandem equilibria. Moreover, the chiroptical properties could be memorized by replacing the chiral inducer with an achiral competitive binder, and the chiroptical signal could be erased and reversed by an antipodal chiral inducer, which also showed the self-inhibition property.

[Detection of microcalcification clusters regions in mammograms combining discriminative deep belief networks].

In order to overcome the shortcomings of high false positive rate and poor generalization in the detection of microcalcification clusters regions, this paper proposes a method combining discriminative deep belief networks (DDBNs) to automatically and quickly locate the regions of microcalcification clusters in mammograms. Firstly, the breast region was extracted and enhanced, and the enhanced breast region was segmented to overlapped sub-blocks. Then the sub-block was subjected to wavelet filtering. After that, DDBNs model for breast sub-block feature extraction and classification was constructed, and the pre-trained DDBNs was converted to deep neural networks (DNN) using a softmax classifier, and the network is fine-tuned by back propagation. Finally, the undetected mammogram was inputted to complete the location of suspicious lesions. By experimentally verifying 105 mammograms with microcalcifications from the Digital Database for Screening Mammography (DDSM), the method obtained a true positive rate of 99.45% and a false positive rate of 1.89%, and it only took about 16 s to detect a 2 888 × 4 680 image. The experimental results showed that the algorithm of this paper effectively reduced the false positive rate while ensuring a high positive rate. The detection of calcification clusters was highly consistent with expert marks, which provides a new research idea for the automatic detection of microcalcification clusters area in mammograms.

A Supramolecular Strategy for Enhancing Photochirogenic Performance through Host/Guest Modification: Dicationic γ-Cyclodextrin-Mediated Photocyclodimerization of 2,6-Anthracenedicarboxylate.

Possessing an extra anionic handle for chiral supramolecular interactions, 2,6-anthracenedicarboxylate exhibited greater photochirogenic performance than 2-anthracenecarboxylate to afford the anti-cyclodimer in up to 94% yield and -72% enantiomeric excess upon photoirradiation with dicationic γ-cyclodextrins.

Construction a Long-Circulating Delivery System of Liposomal Curcumin by Coating Albumin.

Although the bioavailability and stability of curcumin can be greatly improved by liposomes encapsulation, its application is still limited due to the short circulating time. In this present work, we aim to construct a long-circulating delivery system of liposomal curcumin (Cur-Lips) by coating bovine serum albumin (BSA), namely, BSA-coated liposomal curcumin (BSA-Cur-Lips). The effects of coating albumin on the physicochemical properties of Cur-Lips were investigated. It was found that BSA-Cur-Lips was more spherical, more homogeneous in size, and significantly larger than Cur-Lips. Combining sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Coomassie bright blue staining, and X-ray photoelectron spectroscopy analysis (XPS), we confirmed that albumin molecules were stably located on the surface of BSA-Cur-Lips. In addition, the impacts of the coating albumin on the Cur-Lips release and phagocytosis by mouse macrophages Raw264.7 in vitro were investigated. We found that no significant initial burst drug release effect was observed for both Cur-Lips and BSA-Cur-Lips and the presence of albumin can enhance the liposome structure stability and slow down the release of Cur. More importantly, the macrophage phagocytosis of Cur-Lips was significantly reduced after coating albumin. In conclusion, coating albumin is a promising approach for developing a long-circulating delivery system of liposomal curcumin, and its properties including low phagocytosis, slow drug release, enhanced stability, and nontoxicity give this system great prospects for practical use.

[Chondrocyte cocultures with stromal vascular fraction of adipose tissue promote cartilage regeneration in vivo].

OBJECTIVE: This study aimed to compare the cartilage regeneration of the stromal vascular fraction (SVF) cells and adipose-derived mesenchymal stem cells (ASCs) cocultured with chondrocytes seeded on the scaffolds. METHODS: The cellular morphologies and proliferation capabilities on the scaffolds were evaluated. The scaffolds with the cocul-ture of ASCs/SVF and chondrocytes were implanted into the full thickness cartilage defective rabbit joints for 10 weeks. RESULTS: The cells seeded into the scaffolds showed good adhesion and proliferation. Implantation with SVF and chondrocytes revealed desirable in vitro healing outcomes. CONCLUSIONS: The SVF cells were better than ASCs in terms of the formation of cartilage matrix in a coimplantation model. Without in vitro expansion, the SVF cells are good cell sources for cartilage repair.

Synergetic effects in the enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylic acid mediated by ß-cyclodextrin-pillar[5]arene-hybridized hosts.

Tri-cavity hosts consisting of one pillar[5]arene (P5) sandwiched by two ß-cyclodextrins (CDs) were synthesized, and their diastereoseparation was successfully accomplished. Photocyclodimerization of 2-anthracenecarboxylate with these hybrid hosts demonstrated the critical dependence of stereoselectivity on the absolute configuration of the central P5 and the conjugating positions on the ß-CD, and gave the non-classical HT photodimers in up to 87% ee.

pH-Controlled Chirality Inversion in Enantiodifferentiating Photocyclodimerization of 2-Antharacenecarboxylic Acid Mediated by γ-Cyclodextrin Derivatives.

Several γ-cyclodextrin (γ-CDx) derivatives were used as chiral hosts for the photocyclodimerization of 2-anthracenecarboxylic acid (AC). The effect of pH on photoreactivity and stereochemical outcome of photoproducts was investigated. Upon changing the solution pH, the stereochemical outcome of HH cyclodimer 3 was inverted from 25.2% to -64.4% and 41.2% to -76.2%, respectively, in the photocyclodimerization of AC mediated by bis-quinoline-modified γ-CDx 7 and its N-methylated derivative 8.

Enantioselective photoinduced cyclodimerization of a prochiral anthracene derivative adsorbed on helical metal nanostructures.

The generation of molecular chirality in the absence of any molecular chiral inductor is challenging and of fundamental interest for developing a better understanding of homochirality. Here, we show the manipulation of molecular chirality through control of the handedness of helical metal nanostructures (referred to as nanohelices) that are produced by glancing angle deposition onto a substrate that rotates in either a clockwise or counterclockwise direction. A prochiral molecule, 2-anthracenecarboxylic acid, is stereoselectively adsorbed on the metal nanohelices as enantiomorphous anti-head-to-head dimers. The dimers show either Si-Si or Re-Re facial stacking depending on the handedness of the nanohelices, which results in a specific enantiopreference during their photoinduced cyclodimerization: a left-handed nanohelix leads to the formation of (+)-cyclodimers, whereas a right-handed one gives (-)-cyclodimers. Density functional theory calculations, in good agreement with the experimental results, point to the enantioselectivity mainly arising from the selective spatial matching of either Si-Si or Re-Re facial stacking at the helical surface; it may also be influenced by chiroplasmonic effects.

Improving the Stability of Liposomal Curcumin by Adjusting the Inner Aqueous Chamber pH of Liposomes.

Curcumin (CURC) is a hydrophobic molecule and its water solubility can be greatly improved by liposome encapsulation. However, investigations on the stability of pH-sensitive molecules incorporated into liposomal membranes are limited. In this study, CURC-loaded liposomes with varied internal pH values (pH 2.5, 5.0, or 7.4) were prepared and designated as CURC-LP (pH 2.5), CURC-LP (pH 5.0), and CURC-LP (pH 7.4). Physical properties including particle size, ζ-potential, morphology, entrapment efficiency, and physical stabilities of these CURC-LPs were assessed. In addition, the chemical stability of liposomal CURC to different external physiological environments and internal microenvironmental pH levels were investigated. We found that among these CURC-LPs, CURU-LP (pH 2.5) has the highest entrapment efficiency (73.7%), the best physical stabilities, and the slowest release rate in vitro. Liposomal CURC remains more stable in an acid external environment. In the physiological environment, the chemical stability of liposomal CURC is microenvironmental pH-dependent. In conclusion, we prove that the stability of liposomal CURC is external physiological environment- and internal microenvironmental pH-dependent. These findings suggest that creating an acidic microenvironment in the internal chamber of liposomes is beneficial to the stability of liposomal CURC, as well as for other pH-sensitive molecules.

Reversal of Regioselectivity during Photodimerization of 2-Anthracenecarboxylic Acid in a Water-Soluble Organic Cavitand.

The value of octa acid (OA) as a reaction vessel in steering a photoreaction toward a less favored product was established. Photodimerization of 2-anthracenecarboxylic acid within OA yields exclusively head-to-head dimers, while in media such as solution, cyclodextrins (CD) and related hosts yield predominantly head-to-tail dimers. Further, OA enhances the chiral selectivity on the product dimers. The difference between OA and CD is attributed to the variation in the dimensions of their entry ports.

Chondrocyte Co-cultures with the Stromal Vascular Fraction of Adipose Tissue in Polyhydroxybutyrate/Poly-(hydroxybutyrate-co-hydroxyhexanoate) Scaffolds: Evaluation of Cartilage Repair in Rabbit.

Chondral defects are challenging to repair because of the poor self-healing capacity of articular cartilage. The aim of this study was to compare and investigate the cartilage regeneration of stromal vascular fraction (SVF) cells and adipose-derived stem cells (ASCs) co-cultured with chondrocytes seeding on scaffolds composed of polyhydroxybutyrate (PHB)/poly-(hydroxybutyrate-co-hydroxyhexanoate) (PHBHHx). In this study, the cellular morphologies and proliferation capabilities on scaffolds were evaluated. Next, scaffolds with 1:1 co-culture of ASCs/SVF and chondrocytes were implanted into the full-thickness cartilage defects in rabbit knee for 10 weeks. Cells seeded on the scaffolds showed better adhesion, migration, and proliferation in vitro. Importantly, implantation with scaffolds with SVF and chondrocytes revealed more desirable in vivo healing outcomes. Our results illustrate a one-step surgical procedure for the regeneration of focal cartilage defects using a mixture of SVF from adipose tissue and uncultured chondrocytes.

An Ultimate Stereocontrol in Supramolecular Photochirogenesis: Photocyclodimerization of 2-Anthracenecarboxylate Mediated by Sulfur-Linked ß-Cyclodextrin Dimers.

Stereoisomeric ß-cyclodextrin (CD) dimers linked with a sulfur atom or an arene spacer were designed to create a tethered dual CD capsule for precisely manipulating the regio- and enantioselectivities of the photocyclodimerization of 2-anthracenecarboxylate (AC) to four stereoisomeric classical 9,10:9',10'-cyclodimers and two nonclassical 5,8:9',10'-cyclodimers. Among the dimeric CD hosts prepared, exo-3-thia-ß-CD dimer formed 1:1 and 1:2 host-guest complexes with AC in aqueous solutions, the former of which hindered but the latter facilitated the AC photocyclodimerization with regio- and enantioselectivities much higher than those obtained with native ß-CD or the rest of the ß-CD dimers. The stereochemical outcomes turned out to be highly sensitive to and hence critically manipulable by the linking position and configuration of the connected saccharide units and the linker length, as well as the external variants, such as temperature, pH, and added salt. Eventually, the photocyclodimerization of AC mediated by the dimeric ß-CD host gave enantiopure syn-head-to-tail-9,10:9',10'-cyclodimer in 97-98% yield in a pH 5.1 buffer solution at 0.5 °C and also in an aqueous CsCl solution at -20 °C.