Acceptor-Reactivity-Controlled Stereoconvergent Synthesis and Immunological Activity of a Unique Pentasaccharide from the Cell Wall Polysaccharide of Cutibacterium acnes C7.

Bacterial cell-surface polysaccharides are involved in various biological processes and have attracted widespread attention as potential targets for developing carbohydrate-based drugs. However, the accessibility of structurally well-defined polysaccharide or related active oligosaccharide domains remains challenging. Herein, we describe an efficiently stereocontrolled approach for the first total synthesis of a unique pentasaccharide repeating unit containing four difficult-to-construct 1,2-cis-glycosidic linkages from the cell wall polysaccharide of Cutibacterium acnes C7. The features of our approach include: 1) acceptor-reactivity-controlled glycosylation to stereoselectively construct   two challenging rare 1,2-cis-ManA2,3(NAc)2 (ß-2,3-diacetamido-2,3-dideoxymannuronic acid) linkages, 2) combination use of 6-O-tert-butyldiphenylsilyl (6-O-TBDPS)-mediated steric shielding effect and ether solvent effect to stereoselectively install a 1,2-cis-glucosidic linkage, 3) bulky 4,6-di-O-tert-butylsilylene (DTBS)-directed glycosylation to stereospecifically construct a 1,2-cis-galactosidic linkage, 4) stereoconvergent [2+2+1] and one-pot chemoselective glycosylation to rapidly assemble the target pentasaccharide. Immunological activity tests suggest that the pentasaccharide can induce the production of proinflammatory cytokine TNF-α in a dose-dependent manner.

Total Synthesis and Anti-Inflammatory Evaluation of Osajin, Scandenone and Analogues.

In this study, the total synthesis of osajin, scandenone and their analogues have been accomplished. The key synthetic steps include aldol/intramolecular iodoetherification/elimination sequence reactions and a Suzuki coupling reaction to assemble the tricyclic core, chemoselective propargylation and Claisen rearrangement reactions to obtain natural compounds. In addition, we also designed and synthesized twenty-five natural product analogues. All synthetic compounds were screened for anti-inflammatory activity against tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Collectively, Compound 39e and 39d were considered as promising lead compounds for further development.

A Dual-Function Hemicyanine Material with Highly Efficient Photothermal and Photodynamic Effect Used for Tumor Therapy.

Small molecular organic optical agents with synergistic effects of photothermal therapy (PTT) and photodynamic therapy (PDT), hold credible promise for anti-tumor therapy by overcoming individual drawbacks and enhancing photon utilization efficiency. However, developing effective dual-function PTT-PDT photosensitizers (PSs) for efficient synergistic phototherapy remains challenging. Here, a benz[c,d]indolium-substituted hemicyanine named Rh-BI, which possesses a high photothermal conversion efficiency of 41.67% by exhaustively suppressing fluorescence emission, is presented. Meanwhile, the rotating phenyl group at meso-site induces charge recombination to enhance the molar extinction coefficient up to 13.58 × 104 M-1cm-1, thereby potentiating the photodynamic effect. Under 808 nm irradiation, Rh-BI exhibits significant phototoxicity in several cancer cell types in vitro with IC50 values as low as ≈0.5 µM. Moreover, treatment of 4T1 tumor-bearing mice with Rh-BI under laser irradiation successfully inhibits tumor growth. In a word, an effective strategy is developed to build PTT-PDT dual-functional optical materials based on hemicyanine backbone for tumor therapy by modulating conjugation system interaction to adjust the energy consumption pathway.

Non-Anticoagulant Activities of Low Molecular Weight Heparins-A Review.

Low molecular weight heparins (LMWHs) are derived from heparin through chemical or enzymatic cleavage with an average molecular weight (Mw) of 2000-8000 Da. They exhibit more selective activities and advantages over heparin, causing fewer side effects, such as bleeding and heparin-induced thrombocytopenia. Due to different preparation methods, LMWHs have diverse structures and extensive biological activities. In this review, we describe the basic preparation methods in this field and compare the main principles and advantages of these specific methods in detail. Importantly, we focus on the non-anticoagulant pharmacological effects of LMWHs and their conjugates, such as preventing glycocalyx shedding, anti-inflammatory, antiviral infection, anti-fibrosis, inhibiting angiogenesis, inhibiting cell adhesion and improving endothelial function. LMWHs are effective in various diseases at the animal level, including cancer, some viral diseases, fibrotic diseases, and obstetric diseases. Finally, we briefly summarize their usage and potential applications in the clinic to promote the development and utilization of LMWHs.

Combination Therapy with Resveratrol and Celastrol Using Folic Acid-Functionalized Exosomes Enhances the Therapeutic Efficacy of Sepsis.

Overactivated macrophages are a prominent feature of many inflammatory and autoimmune diseases, including sepsis. Attention and regulation of macrophages activity is of great significance for sepsis treatment. Herein, this study shows that folic acid-functionalized exosomes accumulate in the lung of septic mice and specifically target inflammatory macrophages. Therefore, FA-functionalized exosomes co-loaded with resveratrol (an anti-inflammatory polyphenol) and celastrol (an immunosuppressive pentacyclic triterpenoid; FA-Exo/R+C), which exhibit powerful anti-inflammatory and immunosuppressive activities against LPS-stimulated macrophages in vitro by regulating NF-κB and ERK1/2 signaling pathways, are designed. Encouraged by these positive data, the efficacy of FA-Exo/R+C is systematically investigated in an LPS-induced mouse sepsis model. FA-Exo/R+C shows striking therapeutic benefits in terms of attenuated cytokine storm, reduced acute lung injury, and increased survival of septic mice by inhibiting the inflammation and proliferation of proinflammatory M1 macrophages. Importantly, multiple administrations of FA-Exo/R+C significantly enhance and prolong the protective effect, and resist rechallenge to LPS. Collectively, the strategy of co-delivering drugs combination through functionalized exosomes offers a new avenue for sepsis treatment.

A three-dimensional measurement study of fracture displacement in Garden I femoral neck fracture: a retrospective study.

BACKGROUND: Garden I femoral neck fractures are nondisplaced femoral neck fractures. Nonoperative treatment and in situ fixation are the preferred treatments. However, the postoperative outcome is not satisfactory and the incidence of complications remains high, which raises doubts about the accuracy of the diagnosis of nondisplaced Garden I fractures. Recently, three-dimensional (3D) reconstruction has been reported as a mature technology for reconstructing the bone structure of patients. We further extended this technique in the measurement of the fracture spatial displacement to verify the accuracy of Garden I femoral neck fractures. METHODS: This was a retrospective study of patients with Garden I femoral neck fractures from January 2013 to December 2018 at our institution, who were included according to specified criteria. A bilateral proximal femur model of each patient was established based on computed tomography (CT) data. The displacement of the deepest portion of the femoral head fovea, the displacement of the center of the femoral head and the rotation of the femoral head were measured in the bilateral model. RESULTS: A total of 102 patients diagnosed with Garden I fractures were included in this study. The cohort included 32 men and 70 women, with an average age of 55.88 ± 15.32 years. In these patients, the average displacement of the deepest portion of the femoral head fovea was 16.43 ± 7.69 mm. The minimum and maximum displacement was 3.58 and 44.32 mm, respectively. The average displacement of the center of the femoral head was 10.39 ± 5.47 mm and ranged from 2.16 to 34.42 mm. The rotational angle was 23.81 ± 10.15 ° and ranged from 3.71 ° to 61.19 °. CONCLUSIONS: Garden I fractures have large spatial displacement and cannot be considered incomplete or nondisplaced fractures. Therefore, we suggest that anatomical reduction should be considered during treatment.

Mechanical analysis of the femoral neck dynamic intersection system with different nail angles and clinical applications.

BACKGROUND: The femoral neck dynamic intersection system (FNS) is mechanically more stable than other internal fixation techniques. Current studies have confirmed that the structural design of FNS has good biomechanical properties in European and American populations. However, whether the suitability of the FNS's 130° main nail angle design for Asian populations has been thoroughly investigated remains unclear. AIM: To compare the biomechanical stability differences among different main nail angles of the FNS in the treatment of femoral neck fractures in Asian populations. METHODS: Computed tomography data of the femur of healthy adult male volunteers were imported into Mimics software to create a three-dimensional model of the femur. The model was adapted to the curve using Geomagic software and imported into Solidworks software to construct the Pauwels I femoral neck fracture model and design the FNS internal fixation model using different main nail angles. Afterward, the models were assembled with the FNS fracture model and meshed using the preprocessing Hypermesh software. Subsequently, they were imported into Abaqus software to analyze and evaluate the biomechanical effects of different angles of the FNS main nail on the treatment of femoral neck fractures. RESULTS: The peak displacement of the proximal femur under different angles of FNS fixation under stress was 7.446 millimeters in the 120° group and 7.416 millimeters in the 125° group; in the 130°, 135°, and 140° FNS fixation groups, the peak displacement was 7.324 millimeters, 8.138 millimeters, and 8.246 millimeters, respectively. In the 120° and 125° FNS fixation groups, the maximum stresses were concentrated at the main nail and the anti-rotation screw, which intersected the fracture line of the femur neck, resulting in peak stresses of 200.7 MPa and 138.8 MPa, respectively. Peak stresses of 208.8 MPa, 219.8 MPa, and 239.3 MPa were observed on the angular locking plate distal to the locking screw in the 130°, 135°, and 140° fixation groups. CONCLUSION: FNS has significant stress distribution properties, a minimal proximal femoral displacement, and an optimal stability for treating femoral neck fractures in Asian populations when performed with a 130° main nail angle.

Total Synthesis of Lineaflavones A, C, D, and Analogues.

The first total synthesis of lineaflavones A, C, D, and their analogues has been accomplished. The key synthetic steps include aldol/oxa-Michael/dehydration sequence reactions to assemble the tricyclic core, Claisen rearrangement and Schenck ene reaction to construct the key intermediate, and selective substitution or elimination of tertiary allylic alcohol to obtain natural compounds. In addition, we also explored five new routes to synthesize fifty-three natural product analogues, which can contribute to a systematic structure-activity relationship during biological evaluation.

An Overview of Antitumour Activity of Polysaccharides.

Cancer incidence and mortality are rapidly increasing worldwide; therefore, effective therapies are required in the current scenario of increasing cancer cases. Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties, and they have become the focus of current antitumour drug research owing to their significant antitumour effects. In addition to the direct antitumour activity of some natural polysaccharides, their structures offer versatility in synthesizing multifunctional nanocomposites, which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues. This review aims to highlight recent advances in natural polysaccharides and polysaccharide-based nanomedicines for cancer therapy.

Exosomes as CNS Drug Delivery Tools and Their Applications.

Central nervous system (CNS) diseases threaten the health of people all over the world. However, due to the structural and functional particularities of the brain and spinal cord, CNS-targeted drug development is rather challenging. Exosomes are small cellular vesicles with lipid bilayers that can be secreted by almost all cells and play important roles in intercellular communication. The advantages of low immunogenicity, the ability to cross the blood-brain barrier, and the flexibility of drug encapsulation make them stand out among CNS drug delivery tools. Herein, we reviewed the research on exosomes in CNS drug delivery over the past decade and outlined the impact of the drug loading mode, administration route, and engineered modification on CNS targeting. Finally, we highlighted the problems and prospects of exosomes as CNS drug delivery tools.

Biomechanical evaluation of the reconstruction of the calcar femorale in femoral neck fractures: a comparative finite element analysis.

OBJECTIVE: Femoral neck fractures are common. We evaluated the biomechanical performance of an internal fixation method based on traditional three cannulated screws (3CS) inserted from below the fracture in the direction of the calcar femorale in the treatment of Pauwels III femoral neck fracture. METHODS: We constructed and evaluated a three-dimensional model of a Pauwels III femoral neck fracture with four models of internal fixation (3CS, and 150°, 155°, and 160° nailing angles) for reconstruction of the calcar femorale, by finite element analysis (FEA). RESULTS: The peak stress values at the fracture ends in the 3CS, 150°, 155°, and 160° nailing angle models were 30.052 MPa, 33.382 MPa, 34.012 MPa, and 29.858 MPa; peak stress values for internal fixed stress were 315.121 MPa, 228.819 MPa, 198.173 MPa, and 208.798 MPa; and the maximum displacement of the femoral head was 13.190 mm, 13.183 mm, 12.443 mm, and 12.896 mm, respectively. CONCLUSION: FEA showed that the new nailing methods and the 160° nailing angle for reconstruction of the calcar femorale showed better performance in resisting shearing force for Pauwels III femoral neck fracture, with better mechanical properties, than those with the other three models. These findings can provide a clinical reference.

An efficient anticoagulant candidate: Characterization, synthesis and in vivo study of a fondaparinux analogue Rrt1.17.

Fondaparinux, a synthetic pentasaccharide anticoagulant based on heparin antithrombin-binding domain, is derived from a chemical synthesis with more than 50 steps. Herein, we identified nine analogues separated from commercially available crude fondaparinux sodium, and tested their anticoagulant activity in vitro. Based on the activity results, the most active derivative Rrt1.17 was chemically synthesized. Biological properties in vitro and in vivo indicated that the well-defined derivative Rrt1.17 was a more efficient anticoagulant candidate compared with fondaparinux.

Intensity-symmetric accelerating caustic beams.

We construct and generate symmetric accelerating caustic beams (ACBs) by using 3/2-order phase-only masks with elliptical contour based on optical caustics and diffraction theory. The symmetric ACBs are a type of bimodal accelerating caustic beam with two quasi-constant intensity peaks, very similar to the combination of two face-to-face Airy-like beams judging by appearance. Their fundamental optical morphology and force properties of particles in ACBs are subsequently provided. The unique optical properties of ACBs can be exploited for practical uses, such as accelerating electrons and clearing micrometer-sized particles as a laser micrometer-sized "water pump" instead of a laser micrometer-sized "snowblower" of accelerating Airy beams.

Fast algorithm for reliability-guided phase unwrapping in digital holographic microscopy.

A fast reliability-guided phase unwrapping algorithm, using an optimized quality map and combining it with look-up table operation, is proposed for digital holographic microscopy. First, by detecting the residues in the wrapped phase map, an intensity threshold is calculated in the normalized intensity image and the measured region is distinguished into the reliable region and the doubtful region. An optimized quality map is derived by the method in which the intensity values in the reliable region are set to 1 and those in the doubtful region remain unchanged. Then the flood fill algorithm by look-up table is implemented with the optimized quality map to retrieve true phase map. The experimental results demonstrate that not only does the proposed algorithm perform well, but also the speed is significantly faster than that of the conventional flood fill algorithm using insert sorting.

Spatially induced spatiotemporally nonspreading Airy-Bessel wave packets.

By studying the effect of spatially induced group velocity dispersion (SIGVD) during the propagation of ultrashort pulsed Bessel beams in free space, we numerically prove that third-order SIGVD can temporally cause Gaussian distribution of pulsed Bessel beams to gradually evolve as unsymmetrical trailing oscillatory structures. The pulse shape is confirmed to be temporal Airy distributions on the basis of the cross-correlation function. Therefore, it is demonstrated that the scheme of generating spatiotemporally nonspreading Airy-Bessel wave packets in free space is possible by using a precompensating second-order SIGVD. The results of numerical simulation show that the quasi-Airy pulses induced by third-order SIGVD are temporally nonspreading during propagation in dispersive media. The reasons for nonspreading of such Airy distribution pulses are phenomenologically analyzed by a time-frequency Wigner distribution function of the pulse.

Partition calculation for zero-order and conjugate image removal in digital in-line holography.

Conventional digital in-line holography requires at least two phase-shifting holograms to reconstruct an original object without zero-order and conjugate image noise. We present a novel approach in which only one in-line hologram and two intensity values (namely the object wave intensity and the reference wave intensity) are required. First, by subtracting the two intensity values the zero-order diffraction can be completely eliminated. Then, an algorithm, called partition calculation, is proposed to numerically remove the conjugate image. A preliminary experimental result is given to confirm the proposed method. The method can simplify the procedure of phase-shifting digital holography and improve the practical feasibility for digital in-line holography.

High-speed and dense three-dimensional surface acquisition using defocused binary patterns for spatially isolated objects.

The three-dimensional (3-D) shape measurement using defocused Ronchi grating is advantageous for the high contrast of fringe. This paper presents a method for measuring spatially isolated objects using defocused binary patterns. Two Ronchi grating with horizontal position difference of one-third of a period and an encoded pattern are adopted. The phase distribution of fringe pattern is obtained by Fourier analysis method. The measurement depth and range is enlarged because the third harmonic component and background illumination is eliminated with proposed method. The fringe order is identified by the encoded pattern. Three gray levels are used and the pattern is converted to binary image with error diffusion algorithm. The tolerance of encoded pattern is large. It is suited for defocused optical system. We also present a measurement system with a modified DLP projector and a high-speed camera. The 3-D surface acquisition speed of 60 frames per second (fps), with resolution of 640 × 480 points and that of 120 fps, with resolution of 320 × 240 points are archived. If the control logic of DMD was modified and a camera with higher speed was employed, the measurement speed would reach thousands fps. This makes it possible to analyze dynamic objects.

Practical method for color computer-generated rainbow holograms of real-existing objects.

A novel method for computer-generated rainbow holograms (CGRHs) of full-color objects is proposed. First, a new algorithm for fabricating full-color CGRHs of real-existing objects is proposed based on the interrelationship between coding of a CGRH and reconstruction of the hologram. Second, a color rainbow hologram for a real-existing object is generated by combining the proposed algorithm and computer-generated hologram generating system. Finally, the hologram is outputted by an auto-microfilming system. The principle of the algorithm, the process of hologram calculation, and the hologram generating system for real-existing objects and experimental results are presented. The experimental results demonstrate that the new method is feasible.