Search

Brucellosis is a global zoonotic infection caused by Brucella bacteria, which poses a significant burden on society. While transmission prevention is currently the most effective method, the absence of a licenced vaccine for humans necessitates the urgent development of a safe and effective vaccine. Recombinant protein-based subunit vaccines are considered promising options, and in this study, the Brucella BP26 protein is expressed using prokaryotic expression systems. The immune responses are evaluated using the well-established adjuvant CpG-ODN. The results demonstrate that rBP26 supplemented with a CpG adjuvant induces M1 macrophage polarization and stimulates cellular immune responses mediated by Th1 cells and CD8+ T cells. Additionally, it generates high levels of rBP26-specific antibodies in immunized mice. Furthermore, rBP26 immunization activates, proliferates, and produces cytokines in T lymphocytes while also maintaining immune memory for an extended period of time. These findings shed light on the potential biological function of rBP26, which is crucial for understanding brucellosis pathogenesis. Moreover, rBP26 holds promise as an effective subunit vaccine candidate for use in endemic areas.

Alveolar echinococcosis (AE) is a highly lethal helminth infection. Current chemotherapeutic strategies for AE primarily involve the use of benzimidazoles (BZs) such as mebendazole (MDZ) and albendazole (ABZ), which exhibit limited efficacy. In a previous study, the vaccine of recombinant Echinococcus granulosus P29 (rEgP29) showed significant immunoprotection against E. granulosus in both mice and sheep. In the current study, we utilized hybridoma technology to generate five monoclonal antibodies (mAbs) against P29, among which 4G10F4 mAb exhibited the highest antigen-specific binding capacity. This mAb was selected for further investigation of anti-AE therapy, both in vivo and in vitro. In vitro, 4G10F4 inhibited a noteworthy inhibition of E. multilocularis protoscoleces and primary cells viability through complement-dependent cytotoxicity (CDC) mechanism. In vivo, two experiments were conducted. In the first experiment, mice were intraperitoneally injected with Em protoscoleces, and subsequently treated with 4G10F4 mAb (2.5/5/10 mg/kg) at 12 weeks postinfection once per week for 8 times via tail vein injection. Mice that were treated with 4G10F4 mAb only in dosage of 5mg/kg exhibited a significant lower mean parasite burden (0.89±0.97 g) compared to isotype mAb treated control mice (2.21±1.30 g). In the second experiment, mice were infected through hepatic portal vein and treated with 4G10F4 mAb (5mg/kg) at one week after surgery once per week for 8 times. The numbers of hepatic metacestode lesions of the 4G10F4 treatment group were significantly lower in comparison to the isotype control group. Pathological analysis revealed severe disruption of the inner structure of the metacestode in both experiments, particularly affecting the germinal and laminated layers, resulting in the transformation into infertile vesicles after treatment with 4G10F4. In addition, the safety of 4G10F4 for AE treatment was confirmed through assessment of mouse weight and evaluation of liver and kidney function. This study presents antigen-specific monoclonal antibody immunotherapy as a promising therapeutic approach against E. multilocularis induced AE. Author summary: Echinococcosis encompasses two significant zoonotic tapeworm diseases, cystic echinococcosis (CE) and alveolar echinococcosis (AE), caused by Echinococcus granulosus and Echinococcus multilocularis, respectively. AE is widely acknowledged as the most fatal helminth infection, with a mortality rate exceeding 90% within 10–15 years of diagnosis if left untreated or inadequately treated. Two benzimidazole carbamates, albendazole and mebendazole, are the only anti-infective drugs that are clinically efficient in interrupting the larval growth of Echinococcus spp. However, due to their toxicity and limited efficacy, there is a pressing need to explore novel therapeutic strategies for AE. In this study, a therapeutic antibody named 4G10F4 was produced against hydatid P29 using hybridoma technology. This candidate antibody significantly inhibited E. multilocularis both in vitro and in vivo, representing a potentially efficacious and safe antigen-specific monoclonal antibody immunotherapy for the treatment of AE. Additionally, it has been identified as a promising antibody drug and molecular target for the development of anti-AE therapy. [ABSTRACT FROM AUTHOR]

Aging is generally associated with declining somatosensory function, which seems at odds with the high prevalence of chronic pain in older people. This discrepancy is partly related to the high prevalence of degenerative diseases such as osteoarthritis in older people. However, whether aging alters pain processing in the primary somatosensory cortex (S1), and if so, whether it promotes pain chronification is largely unknown. Herein, we report that older mice displayed prolonged nociceptive behavior following nerve injury when compared with mature adult mice. The expression of peroxisome proliferator‐activated receptor‐gamma coactivator‐1α (PGC‐1α) in S1 was decreased in older mice, whereas PGC‐1α haploinsufficiency promoted prolonged nociceptive behavior after nerve injury. Both aging and PGC‐1α haploinsufficiency led to abnormal S1 neural dynamics, revealed by intravital two‐photon calcium imaging. Manipulating S1 neural dynamics affected nociceptive behavior after nerve injury: chemogenetic inhibition of S1 interneurons aggravated nociceptive behavior in naive mice; chemogenetic activation of S1 interneurons alleviated nociceptive behavior in older mice. More interestingly, adeno‐associated virus‐mediated expression of PGC‐1α in S1 interneurons ameliorated aging‐associated chronification of nociceptive behavior as well as aging‐related S1 neural dynamic changes. Taken together, our results showed that aging‐associated decrease of PGC‐1α promotes pain chronification, which might be harnessed to alleviate the burden of chronic pain in older individuals. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a degenerative disease that affects synovial joints and leads to significant pain and disability, particularly in older adults. Infiltration of macrophages plays a key role in the progression of OA. However, the mechanisms underlying macrophage recruitment in OA are not fully understood. Methods: The Serglycin (SRGN) expression pattern was analyzed, along with its association with macrophage infiltration in OA, using bioinformatic methods. SRGN expression in chondrocytes was altered by small interfering RNA (siRNA) and plasmids. Conditioned media (CM) was obtained from transfected chondrocytes to establish a co-culture model of chondrocytes and THP-1 derived macrophages. The impact of SRGN on macrophage recruitment was evaluated using a transwell assay. Furthermore, the regulatory effect of SRGN on CCL3 was validated through qPCR, WB, and ELISA experiments. Results: In OA patients, the upregulation of SRGN positively correlated with K-L grade and macrophage infiltration. It was found that SRGN expression and secretion were up-regulated in OA and that it can promote macrophage migration in vitro. Further investigation showed that SRGN affects macrophage migration by regulating the expression of CCL3. Conclusion: SRGN in chondrocytes plays a role in promoting the recruitment of THP-1 derived macrophages in vitro by regulating production of CCL3. [ABSTRACT FROM AUTHOR]

Highlights: Naturally crosslinked carbonaceous liquid metal aqueous printable ink mediated by biopolymers. E-textile with conductivity, stability, wearability, and aesthetic characteristics. Multi-applications in health monitoring, pressure sensing, and energy harvesting. Achieving flexible electronics with comfort and durability comparable to traditional textiles is one of the ultimate pursuits of smart wearables. Ink printing is desirable for e-textile development using a simple and inexpensive process. However, fabricating high-performance atop textiles with good dispersity, stability, biocompatibility, and wearability for high-resolution, large-scale manufacturing, and practical applications has remained challenging. Here, water-based multi-walled carbon nanotubes (MWCNTs)-decorated liquid metal (LM) inks are proposed with carbonaceous gallium–indium micro-nanostructure. With the assistance of biopolymers, the sodium alginate-encapsulated LM droplets contain high carboxyl groups which non-covalently crosslink with silk sericin-mediated MWCNTs. E-textile can be prepared subsequently via printing technique and natural waterproof triboelectric coating, enabling good flexibility, hydrophilicity, breathability, wearability, biocompatibility, conductivity, stability, and excellent versatility, without any artificial chemicals. The obtained e-textile can be used in various applications with designable patterns and circuits. Multi-sensing applications of recognizing complex human motions, breathing, phonation, and pressure distribution are demonstrated with repeatable and reliable signals. Self-powered and energy-harvesting capabilities are also presented by driving electronic devices and lighting LEDs. As proof of concept, this work provides new opportunities in a scalable and sustainable way to develop novel wearable electronics and smart clothing for future commercial applications. [ABSTRACT FROM AUTHOR]

Background: To investigate whether accurate placement of sustentaculum tali screws have the impacts on the clinical efficacy of calcaneal fractures. Methods: A retrospective analysis of 72 cases (73 feet) of calcaneal fractures from September 2015 to September 2019 treated with open reduction and internal fixation with sustentaculum tali screws was conducted. Patients were divided into the sustentaculum tali fixation group (ST group) and the sustentaculum fragment fixation group (STF group) according to the location of the sustentaculum tali screw placement. The functional outcomes at preoperative, 7 days and 1 year postoperative were collected and analyzed. Results: In the ST group (40 feet), the Gissane's angle altered from (109.89 ± 12.13)° to (121.23 ± 9.34)° and (119.08 ± 8.31)° at 7 days and 1 year postoperative, respectively. For Böhler’s angles altered from (11.44 ± 5.94)°, to (31.39 ± 7.54)°, and (30.61 ± 7.94)° at 7 days and 1 year postoperative, respectively. In the STF group (33 feet), Gissane’s angle altered from (110.47 ± 14.45)°, to (122.08 ± 8.84)°, and (120.67 ± 9.07)° and Böhler’s angle altered from (11.32 ± 6.77)°, to (28.82 ± 8.52)°, and (28.25 ± 9.13)° (P < 0.001). However, there was no statistically significant difference in functional outcomes at 1 week after surgery and 1 year after surgery (P > 0.05). The AOFAS scores at the final follow-up of the two groups: ST group (88.95 ± 6.16) and STF group (89.78 ± 8.76); VAS scores, ST group (0.83 ± 0.98) and STF group (1.03 ± 1.59), all differences were not statistically significant (P > 0.05). Conclusion: The position of sustentaculum tali screws has no significant difference on the short-term clinical outcome in patients with calcaneal fractures, while reliable fixation of screws to sustentaculum tali fragment can achieve similar clinical outcome. Level of evidence V. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is marked by cartilage deterioration, subchondral bone changes, and an inflammatory microenvironment. The study introduces the Microneedle-Delivered Polydopamine-Exosome (PDA@Exo MN), a therapeutic that not only preserves cartilage and promotes bone regeneration but also improves localized drug delivery through enhanced penetration capabilities. PDA@Exo MN shows strong reactive oxygen species (ROS) scavenging abilities and high biocompatibility, fostering osteogenesis and balancing anabolic and catabolic processes in cartilage. It directs macrophage polarization from M0 to the anti-inflammatory M2 phenotype. RNA sequencing of treated chondrocytes demonstrates restored cellular function and activated antioxidant responses, with modulated inflammatory pathways. The PI3K-AKT-mTOR pathway's activation, essential for PDA@Exo's effects, is confirmed via bioinformatics and Western blot. In vivo assessments robustly validate that PDA@Exo MN prevents cartilage degradation and OA progression, supported by histological assessments and micro-CT analysis, highlighting its disease-modifying impact. The excellent biocompatibility of PDA@Exo MN, verified through histological (H&E) and blood tests showing no organ damage, underscores its safety and efficacy for OA therapy, making it a novel and multifunctional nanomedical approach in orthopedics, characterized by organ-friendliness and biosecurity., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Osteosarcoma is one of the most dreadful bone neoplasms in young people, necessitating the development of innovative therapies that can effectively eliminate tumors while minimizing damage to limb function. An ideal therapeutic strategy should possess three essential capabilities: antitumor effects, tissue-protective properties, and the ability to enhance osteogenesis. In this study, self-assembled Ce-substituted molybdenum blue (CMB) nanowheel crystals are synthesized and loaded onto 3D-printed bioactive glass (CMB@BG) scaffolds to develop a unique three-in-one treatment approach for osteosarcoma. The CMB@BG scaffolds exhibit outstanding photothermally derived tumor ablation within the near-infrared-II window due to the surface plasmon resonance properties of the CMB nanowheel crystals. Furthermore, the photothermally synergistic catalytic effect of CMB promotes the rapid scavenging of reactive oxygen species caused by excessive heat, thereby suppressing inflammation and protecting surrounding tissues. The CMB@BG scaffolds possess pro-proliferation and pro-differentiation capabilities that efficiently accelerate bone regeneration within bone defects. Altogether, the CMB@BG scaffolds that combine highly efficient tumor ablation, tissue protection based on anti-inflammatory mechanisms, and enhanced osteogenic ability are likely to be a point-to-point solution for the comprehensive therapeutic needs of osteosarcoma., (© 2024 Wiley‐VCH GmbH.)

Osteosarcoma, recognized for its aggressiveness and resistance to chemotherapy, notably doxorubicin, poses significant treatment challenges. This comprehensive study investigated the CXCR4-CARM1-YAP signaling axis and its pivotal function in controlling aerobic glycolysis, which plays a crucial role in doxorubicin resistance. Detailed analysis of Dox-resistant 143b/MG63-DoxR cells has uncovered the overexpression of CXCR4. Utilizing a combination of molecular biology techniques including gene silencing, aerobic glycolysis assays such as Seahorse experiments, RNA sequencing, and immunofluorescence staining. The study provides insight into the mechanistic pathways involved. Results demonstrated that disrupting CXCR4 expression sensitizes cells to doxorubicin-induced apoptosis and alters glycolytic activity. Further RNA sequencing revealed that CARM1 modulated this effect through its influence on glycolysis, with immunofluorescence of clinical samples confirming the overexpression of CXCR4 and CARM1 in drug-resistant tumors. Chromatin immunoprecipitation studies further highlighted the role of CARM1, showing it to be regulated by methylation at the H3R17 site, which in turn affected YAP expression. Crucially, in vivo experiments illustrated that CARM1 overexpression could counteract the tumor growth suppression that resulted from CXCR4 inhibition. These insights revealed the intricate mechanisms at play in osteosarcoma resistance to doxorubicin and pointed toward potential new therapeutic strategies that could target this metabolic and signaling network to overcome drug resistance and improve patient outcomes., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Alveolar echinococcosis is considered to be one of the most potentially lethal parasitic zoonotic diseases. However, the molecular mechanisms by which Echinococcus multilocularis interacts with hosts are poorly understood, hindering the prevention and treatment of this disease. Due to the great advantages of cell culture systems for molecular research, numerous attempts have been made to establish primary cell cultures for E. multilocularis. In this study we developed a simple, rapid, and economical method that allows E. multilocularis metacestode tissue blocks to generate daughter vesicles without the continuous presence of host feeder cells in a regular medium. We performed anaerobic, hypoxic (1% O2), normoxic, and semi-anaerobic (in sealed tubes) cultures and found that E. multilocularis metacestode tissues can produce daughter vesicles only in the sealed tubes after 4 wk of incubation. The daughter vesicles cultivated in this system were remarkably enlarged under anaerobic conditions after 8 days of culture, whereas vesicles cultured under hypoxic (1% O2) and normoxic conditions showed only a mild increase in volume. Our in vitro cultivated vesicles showed strong viability and could be used to test antiparasitic drugs, isolate primary cells, and infect animals., (© American Society of Parasitologists 2024.)

Alveolar echinococcosis (AE) is a zoonotic parasitic disease caused by infection with the larval stage of Echinococcus multilocularis and a major challenge to human public health. Vaccines are the most effective way to prevent and control infectious diseases. We previously revealed that the Echinocuccus granulosus recombinant protein P29 is a good vaccine candidate against E . granulosus . However, the protective and immunological mechanism of rEg.P29 against E . multilocularis remain unclear. In this study, CD4 + T cell-deficient mice are transferred with spleen CD4 + T cells isolated from wild-type mice and subjected to rEg.P29 immunization, and then these immunized mice are infected with E . multilocularis . The cyst inhibition rate is calculated by weighing the body and cyst weights. The level of antibody is detected by ELISA. Flow cytometry is used to detect the level of IFN-γ production by CD4 + T and CD8 + T cells. The cytokines in culture supernatant are detected by ELISA. The expressions of CD44 and CD62L on memory T cells are determined by flow cytometry. The results show the cyst inhibition rate is 41.52% after adoptive transfer of CD4 + T cells. Furthermore, the levels of IgG, IgM, IgA and IgE in serum are significantly increased compared with those in the PBS group. The IFN-γ-secretion by CD8 + T cells and the level of IFN-γ in culture supernatant are obviously increased; and the number of CD4 + T cells is increased, but the number of IFN-γ producing CD4 + T cells has no significant difference compared with PBS group. In addition, the number of CD44 + CD62L ‒ CD8 + memory T cells in the spleen is significantly increased, while the number of CD44 ‒ CD62L + CD8 + memory T cells is not significantly altered. Collectively, rEg.P29 can alleviate E . multilocularis infection by inducing humoral immune responses and CD8 + T cell responses.

Flexible and stretchable triboelectric nanogenerators (TENGs) have been rapidly advanced owing to the demand for portable and wearable electronic devices that can work under universal or motional circumstances. While versatile materials can be applied in a TENG as dielectric materials, flexible and cost-effective electrodes are crucially important for the output performance of TENGs. Herein, we developed a poly(vinyl alcohol) (PVA) hydrogel TENG doped with a novel two-dimensional material, graphitic carbon nitride (g-C 3 N 4 ), which could act as both a cost-effective flexible electrode and a positive dielectric for TENG with different morphologies. The measured peak-to-peak open-circuit voltage of the TENG reached 80 V at a dopant concentration of 2.7 wt % in single-electrode mode, which is far higher than that of the pristine PVA hydrogel TENG. As a demonstration of the application, the g-C 3 N 4 /PVA hydrogel TENG can be adopted as electronic skin to monitor the movement of the human body. Low-frequency mechanical energy-harvesting devices in different morphologies including discoid flake shape, tube shape, and spiral shape in the single-electrode mode or contact-separation mode have been designed, fabricated, and evaluated. All of these merits of the proposed hydrogel TENG after doping two-dimensional (2D) material g-C 3 N 4 have demonstrated their promising potential for versatile applications in biomechanical energy harvesting and self-powered sensing.