Deferoxamine-Loaded Injectable Chitosan-Grafted Chlorogenic Acid/Oxidized Hyaluronic Acid Hybrid Hydrogel with Antibacterial, Anti-inflammatory, and Angiogenesis-Promoting Properties for Diabetic Wound Repair.

Diabetic chronic wounds are notoriously difficult to heal as a result of their susceptibility to infection. To address this issue, we constructed an innovated and adaptable solution in the form of injectable chitosan (CS) hydrogel, denoted as CCOD, with enhanced antibacterial and anti-inflammatory properties. This hydrogel is created through a Schiff base reaction that combines chitosan-grafted chlorogenic acid (CS-CGA) and oxidized hyaluronic acid (OHA) with deferoxamine (DFO) as a model drug. The combination of CS and CGA has demonstrated excellent antibacterial and anti-inflammatory properties, while grafting played a pivotal role in making these positive effects stable. These unique features make it possible to customize injectable hydrogel and fit any wound shape, allowing for more effective and personalized treatment of complex bacterial infections. Furthermore, the hydrogel system is not only effective against inflammation and bacterial infections but also possesses antioxidant and angiogenic abilities, making it an ideal solution for the repair of chronic wounds that have been previously thought of as unmanageable.

Alginate microspheres encapsulating hox transcript antisense RNA siRNA regulate the Hedgehog-Gli1 pathway to alleviate epidermal growth factor receptor tyrosine kinase inhibitors resistance.

The long non-coding RNA HOTAIR and the Hedgehog-Gli1 signaling pathway are closely associated with tumor occurrence and drug resistance in various cancers. However, their specific roles in the development of EGFR-TKIs resistance in non-small cell carcinoma remain unclear. To address the issue of EGFR-TKIs resistance, this study utilized the electrospray method to prepare sodium alginate microspheres encapsulating HOTAIR siRNA (SA/HOTAIR siRNA) and investigated its effects on RNA interference (RNAi) in the gefitinib-resistant cell line PC9/GR. Furthermore, the study explored whether HOTAIR could modulate EGFR-TKIs resistance through the Hedgehog-GLi1 signaling pathway. The experimental results showed that sodium alginate (SA) microspheres demonstrated excellent biocompatibility with high encapsulation efficiency and drug-loading capacity, effectively enhancing the silencing efficiency of siRNA. HOTAIR siRNA significantly inhibited the proliferation, migration, and invasion abilities of PC9/GR cells while promoting apoptosis. Additionally, HOTAIR siRNA effectively suppressed tumor growth and downregulated the Hedgehog-GLi1 pathway and anti-apoptotic proteins, which were confirmed in animal experiments. Moreover, SA/HOTAIR siRNA exhibited superior inhibition of cellular and tumor functions compared to using HOTAIR siRNA alone. Clinical research findings indicated that monitoring the expression level of HOTAIR in the serum and urine samples of NSCLC patients before and after receiving EGFR-TKIs treatment can predict the efficacy of EGFR-TKIs to a certain extent. This study provided evidence that HOTAIR siRNA effectively mitigated the development of acquired resistance to EGFR-TKIs by inhibiting the Hedgehog-GLi1 pathway. Furthermore, it introduced a reliable and long-lasting drug delivery system for combating acquired resistance to EGFR-TKIs.

Preparation, characterization, and in vitro/vivo evaluation of a multifunctional electrode coating for cochlear implants.

Cochlear implantation (CI) is the primary intervention for patients with sensorineural hearing loss to restore their hearing. However, approximately 90 % of CI recipients experience unexpected fibrosis around the inserted electrode arrays due to acute and chronic inflammation. This fibrosis leads to progressive residual hearing loss. Addressing this complication is crucial for enhancing CI outcomes, yet an effective treatment has not yet been found. In this study, we developed a multifunctional dexamethasone (DXM)-loaded polytrimethylene carbonate (PTMC) electrode coating to mitigate inflammatory reactions and fibrosis after CI. This thin and flexible coating could preserve the mechanical performance of the electrode and reduce the implantation resistance for CI. The in vitro release studies demonstrated the DXM-PTMC coating's efficient drug loading and sustained release capability over 90 days. DXM-PTMC also showed long-term stability, high biocompatibility, and effective anti-inflammatory effects in vitro and in vivo. Compared with the uncoated group, DXM-PTMC coating significantly inhibited the expression of inflammatory factors, such as NO, TNF-α, IL-1ß, and IL-6. DXM-PTMC coating suppressed fibrosis in rat implantation models for 3 weeks by reducing both acute and chronic inflammation. Our findings suggest that DXM-PTMC coating is a novel strategy to improve the outcomes of CI.

Enhanced external counterpulsation treatment regulates blood flow and wall shear stress metrics in femoral artery: An in vivo study in healthy subjects.

As a non-invasive assisted circulation therapy, enhanced external counterpulsation (EECP) has demonstrated potential in treatment of lower-extremity arterial disease (LEAD). However, the underlying hemodynamic mechanism remains unclear. This study aimed to conduct the first prospective investigation of the EECP-induced responses of blood flow behavior and wall shear stress (WSS) metrics in the femoral artery. Twelve healthy male volunteers were enrolled. A Doppler ultrasound-basedapproach was introduced for the in vivo determination of blood flow in the common femoral artery (CFA) and superficial femoral artery (SFA) during EECP intervention, with incremental treatment pressures ranging from 10 to 40 kPa. Three-dimensional subject-specific numerical models were developed in 6 subjects to quantitatively assess variations in WSS-derived hemodynamic metrics in the femoral bifurcation. A mesh-independence analysis was performed. Our results indicated that, compared to the pre-EECP condition, both the antegrade and retrograde blood flow volumes in the CFA and SFA were significantly augmented during EECP intervention, while the heart rate remained constant. The time average shear stress (TAWSS) over the entire femoral bifurcation increased by 32.41%, 121.30%, 178.24%, and 214.81% during EECP with treatment pressures of 10 kPa, 20 kPa, 30 kPa, and 40 kPa, respectively. The mean relative resident time (RRT) decreased by 24.53%, 61.01%, 69.81%, and 77.99%, respectively. The percentage of area with low TAWSS in the femoral artery dropped to nearly zero during EECP with a treatment pressure greater than or equal to 30 kPa. We suggest that EECP is an effective and non-invasive approach for regulating blood flow and WSS in lower extremity arteries.

Visible-Light-Driven Photocatalytic Dehydrogenation of Alcohols on TiO2 via Ligand-to-Metal Charge Transfer for Coproduction of H2 and Aldehydes.

Developing visible-light-driven photocatalysts for the catalytic dehydrogenation of organics is of great significance for sustainable solar energy utilization. Here, we first report that aromatic alcohols could be efficiently split into H2 and aldehydes over TiO2 under visible-light irradiation through a ligand-to-metal charge transfer (LMCT) mechanism. A series of TiO2 catalysts with different surface contents of the hydroxyl group (-OH) have been synthesized by controlling the hydrothermal and calcination synthesis methods. An optimal H2 production rate of 18.6 µmol h-1 is obtained on TiO2 synthesized from the hydrothermal method with a high content of surface -OH. Experimental characterizations and comparison studies reveal that the surface -OH markedly influences the formation of LMCT complexes and thus changes the visible-light-driven photocatalytic performance. This work is anticipated to inspire further research endeavors in the design and fabrication of visible-light-driven photocatalyst systems based on the LMCT mechanism to realize the simultaneous synthesis of clean fuel and fine chemicals.

SARS-CoV-2 bivalent mRNA vaccine with broad protection against variants of concern.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has rapidly spread around the globe. With a substantial number of mutations in its Spike protein, the SARS-CoV-2 Omicron variant is prone to immune evasion and led to the reduced efficacy of approved vaccines. Thus, emerging variants have brought new challenges to the prevention of COVID-19 and updated vaccines are urgently needed to provide better protection against the Omicron variant or other highly mutated variants. Materials and methods: Here, we developed a novel bivalent mRNA vaccine, RBMRNA-405, comprising a 1:1 mix of mRNAs encoding both Delta-derived and Omicron-derived Spike proteins. We evaluated the immunogenicity of RBMRNA-405 in BALB/c mice and compared the antibody response and prophylactic efficacy induced by monovalent Delta or Omicron-specific vaccine with the bivalent RBMRNA-405 vaccine in the SARSCoV-2 variant challenge. Results: Results showed that the RBMRNA-405 vaccine could generate broader neutralizing antibody responses against both Wuhan-Hu-1 and other SARS-CoV-2 variants, including Delta, Omicron, Alpha, Beta, and Gamma. RBMRNA-405 efficiently blocked infectious viral replication and lung injury in both Omicron- and Delta-challenged K18-ACE2 mice. Conclusion: Our data suggest that RBMRNA-405 is a promising bivalent SARS-CoV-2 vaccine with broad-spectrum efficacy for further clinical development.

Immunization with a Prefusion SARS-CoV-2 Spike Protein Vaccine (RBMRNA-176) Protects against Viral Challenge in Mice and Nonhuman Primates.

There is an urgent need for a broad-spectrum and protective vaccine due to the emergence and rapid spreading of more contagious SARS-CoV-2 strains. We report the development of RBMRNA-176, a pseudouridine (Ψ) nucleoside-modified mRNA-LNP vaccine encoding pre-fusion stabilized trimeric SARS-CoV-2 spike protein ectodomain, and evaluate its immunogenicity and protection against virus challenge in mice and nonhuman primates. A prime-boost immunization with RBMRNA-176 at intervals of 21 days resulted in high IgG titers (over 1:819,000 endpoint dilution) and a CD4+ Th1-biased immune response in mice. RBMRNA-176 vaccination induced pseudovirus-neutralizing antibodies with IC50 ranging from 1:1020 to 1:2894 against SARS-CoV-2 spike pseudotyped wild-type and variant viruses, including Alpha, Beta, Gamma, and Kappa. Moreover, significant control of viral replication and histopathology in lungs was observed in vaccinated mice. In nonhuman primates, a boost given by RBMRNA-176 on day 21 after the prime induced a persistent and sustained IgG response. RBMRNA-176 vaccination also protected macaques against upper and lower respiratory tract infection, as well as lung injury. Altogether, these findings support RBMRNA-176 as a vaccine candidate for prevention of COVID-19.

Epidemiological characteristics and phylogenic analysis of human respiratory syncytial virus in patients with respiratory infections during 2011-2016 in southern China.

BACKGROUND: Human respiratory syncytial virus (RSV) is one of the most important pathogens that cause acute respiratory infections in children and immunocompromised adults. This work was conducted to understand the epidemiological and phylogenetic features of RSV in southern China during 2011-2016. METHODS: A total of 16 024 nasopharyngeal swabs were collected from patients with respiratory infections in 14 hospitals, and screened for RSV and seven other respiratory viruses using real-time PCR. Six hundred and twenty-three RSV-positive samples from 13 hospitals were further analyzed for subtypes. G gene sequencing and phylogenetic analysis were performed based on 46 RSV-A and 15 RSV-B strains. RESULTS: RSV was detected in 9.5% of the 16 024 specimens, the highest among the eight respiratory viruses screened. Most of these specimens came from inpatients and children under 3 years of age. The incidence of RSV-A (9.4%) was higher than that of RSV-B (4.4%) in children (<15 years), but not in adults (0.64% vs. 0.58%). A 2-year RSV-A dominance followed by a 1-year RSV-B dominance pattern was found. The co-detection rate of RSV was 25.1%. The main prevalent genotypes were NA1, ON1, and BA9. The prevalent RSV-A genotype in 2011-2012 was NA1, close to Chongqing and Brazil, but a new Hong Kong ON1 genotype was introduced and became the prevalent genotype in Guangzhou in 2014-2015. Deduced amino acid sequence analysis confirmed the ongoing evolution and a high selection pressure of RSV-A and B strains, especially in RSV-A ON1 and NA1 genotypes. CONCLUSIONS: This study demonstrated the molecular epidemiological characteristics of RSV in patients with respiratory infections in southern China.

Thyroid imaging reporting and data system combined with Bethesda classification in qualitative thyroid nodule diagnosis.

OBJECTIVE: We aimed to investigate the value of the combined use of high-resolution ultrasound thyroid imaging reporting and data system (TI-RADS) classification and thyroid fine needle aspiration cytology (Bethesda classification) for the qualitative diagnosis of benign and malignant thyroid nodules. METHODS: We enrolled 295 patients with 327 thyroid nodules who were scheduled to undergo thyroid nodule surgery. Before surgery, all the patients underwent ultrasound and scoring with the TI-RADS classification, along with thyroid fine needle biopsy cytology under ultrasound guidance (US-FNAC) and scoring with the Bethesda classification. After surgery, the TI-RADS and Bethesda classification scores, separately and in combination, were compared with the postoperative pathological results in terms of the differential diagnosis of thyroid nodules. RESULTS: TI-RADS classification score 4 exhibited the highest diagnostic value for thyroid cancer; the sensitivity, specificity, and accuracy were 92.7%, 70.7%, and 87.1%, respectively, whereas the Kappa and receiver-operating characteristics (ROC) values were 0.651 and 0.817, respectively. Moreover, Bethesda classification score 3 exhibited the highest diagnostic value for thyroid cancer; the sensitivity, specificity, and accuracy were 90.0%, 94.3%, and 91.1%, respectively, whereas the Kappa and ROC values were 0.78 and 0.914, respectively. With regard to the combined diagnostic method, a score of 7 exhibited the highest diagnostic value for thyroid cancer; the sensitivity, specificity, and accuracy were 97.3%, 92.0%, and 95.9%, respectively, whereas the Kappa and ROC values were 0.893 and 0.946, respectively. CONCLUSION: The combination of high-resolution ultrasonography TI-RADS classification and US-FNAC (Bethesda classification) can improve the accuracy of malignant thyroid nodules diagnosis.

Porcine deltacoronavirus induces TLR3, IL-12, IFN-α, IFN-ß and PKR mRNA expression in infected Peyer's patches in vivo.

Porcine deltacoronavirus (PDCoV) is a newly identified swine enteropathogenic coronavirus that causes watery diarrhea in piglets and results in significant economic losses to the pig industry. Currently there are no effective treatments or vaccines for PDCoV. In particular, the pathogenesis of PDCoV infection is still largely unknown. In this study, we reported that inoculating conventional weaned piglets with 1 × 109 TCID50 of the PDCoV CHN-GD-2016 strain by oral feeding could cause severe diarrhea. Virus RNA was detected in rectal swabs from 1 to 7 days post inoculation. In addition, microscopic lesions in small intestine were observed, and viral antigen also detected in the small intestines with PDCoV immunohistochemical staining. Importantly, PDCoV significantly induced mRNA expression of TLR3, IL-12, IFN-α, IFN-ß, and PKR, the genes involved in modulation of the host immune responses, in infected Peyer's patches at 3 d.p.i., indicating that Peyer's patches play an important role in PDCoV immune responses in vivo. Collectively, our findings suggest that the observed gene expression profile might help explain immunological and pathological changes associated with PDCoV infection.

A Highly Pathogenic Strain of Porcine Deltacoronavirus Caused Watery Diarrhea in Newborn Piglets.

Porcine deltacoronavirus (PDCoV) is a newly identified virus that causes watery diarrhea in newborn piglets and results in significant economic losses to the pig industry. Since first reported in Hong Kong in 2012, PDCoV has been subsequently detected in USA, South Korea, Thailand, and mainland China. Here we isolated a strain of PDCoV, named CHN-GD-2016, from the intestinal content of a diseased newborn piglet with severe diarrhea in a pig farm in Guangdong, China. PDCoV CHN-GD-2016 could be identified by immunofluorescence with PDCoV specific rabbit antisera, and typical crown-shaped particles with spiky surface projections of this PDCoV were observed with electron microscopy. Genomic analysis showed that the PDCoV CHN-GD-2016 was closely related to other Chinese PDCoV strains, with the highest sequence similarity with the strain CHN/Tianjin/2016. Importantly, inoculation of newborn piglets with 1 × 105 TCID50 of CHN-GD-2016 by oral feeding successfully reproduced clear clinical symptoms, including vomiting, dehydration, and severe diarrhea in piglets. In addition, the virus RNA in rectal swabs from 1 to 7 days post inoculation was detected, macroscopic and microscopic lesions in small intestine were observed, and viral antigen was also detected in the small intestines with immunohistochemical staining. Collectively, the data show in this study confirms that PDCoV is present in Guangdong, China and is highly pathogenic in newborn piglets.

Expression of endothelin-1 in laryngocarcinoma tissues and its clinical significance.

In recent years, the incidence of laryngeal carcinoma has been on the increase. The aim of the present study was to examine the expression level of endothelin-1 (ET-1) in laryngeal carcinoma tissues and to establish its clinical significance. A total of 82 cases of laryngeal carcinoma tissues were examined, of which 27 cases were stage I, 34 were stage II, and 21 were stage III. The normal mucosal tissues beyond the surgical incision margin in the 82 laryngeal carcinoma patients were used as the normal control. An additional 80 tissue specimens collected from laryngeal carcinoma outpatients were used as benign lesions. ET-1 expression levels in different tissues were determined using streptavidin-peroxidase (SP) immunohistochemistry. The results showed that the ET-1 expression level was highest in laryngeal carcinoma tissues and was significantly higher than that in the other two groups (P<0.05). The ET-1 expression level was higher in stage III compared to that in stage I and II (P<0.05) and higher than that of the normal control (P<0.05). The ET-1 expression level was higher in stage II compared to that in stage I (P<0.05). In conclusion, ET-1 was strongly expressed in laryngeal carcinoma tissues and may play an important role in the pathogenesis and development of laryngeal carcinoma tissues. ET-1 expression in laryngeal carcinoma tissues was associated with the clinical staging of laryngeal carcinoma.

Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection.

Molecular mechanisms for T-cell immune responses modulated by T cell-inhibitory molecules during tuberculosis (TB) infection remain unclear. Here, we show that active human TB infection up-regulates CD244 and CD244 signaling-associated molecules in CD8(+) T cells and that blockade of CD244 signaling enhances production of IFN-γ and TNF-α. CD244 expression/signaling in TB correlates with high levels of a long noncoding RNA (lncRNA)-BC050410 [named as lncRNA-AS-GSTT1(1-72) or lncRNA-CD244] in the CD244(+)CD8(+) T-cell subpopulation. CD244 signaling drives lncRNA-CD244 expression via sustaining a permissive chromatin state in the lncRNA-CD244 locus. By recruiting polycomb protein enhancer of zeste homolog 2 (EZH2) to infg/tnfa promoters, lncRNA-CD244 mediates H3K27 trimethylation at infg/tnfa loci toward repressive chromatin states and inhibits IFN-γ/TNF-α expression in CD8(+) T cells. Such inhibition can be reversed by knock down of lncRNA-CD244. Interestingly, adoptive transfer of lncRNA-CD244-depressed CD8(+) T cells to Mycobacterium tuberculosis (MTB)-infected mice reduced MTB infection and TB pathology compared with lncRNA-CD244-expressed controls. Thus, this work uncovers previously unidentified mechanisms in which T cell-inhibitory signaling and lncRNAs regulate T-cell responses and host defense against TB infection.

Screening and identification of significant genes related to tumor metastasis and PSMA in prostate cancer using microarray analysis.

Tumor metastasis is one of the causes for the high mortality rate of prostate cancer (PCa) patients, yet the molecular mechanisms of PCa metastasis are not fully understood. In our previous studies, we found that PSMA suppresses the metastasis of PCa, yet the underlying mechanism remains unknown. To identify the genes related to tumor metastasis possibly regulated by PSMA, we performed tumor metastasis PCR array assay to analyze the differentially expressed tumor metastasis-related genes. Eighty-four tumor metastasis related genes were screened in si-PSMA LNCap cells (PSMA silenced by siRNA)/LNCap cells and in PC-3/LNcap cells, respectively. Expression levels of possible related genes were verified by real-time PCR in 4 prostate cancer cell lines (LNCap, 22RV1, PC-3 and DU145) and in 85 clinical samples (12 normal, 26 benign prostatic hypertrophy and 47 prostate cancer tissues). The results showed that 10 genes (including CDH6 and CXCL12) were upregulated and 4 genes (CCL7, ITGB3, MDM2 and MMP2) were downregulated in the si-PSMA LNCap cells. There were 41 genes significantly upregulated and 15 genes downregulated in PC-3 cells when compared with LNCap cells. Eight common genes were found in both the si-PSMA and PSMA(-) groups. CDH6, MMP3, MTSS1 were further identified as PSMA-related genes in the prostate cancer cell lines and clinical samples, and their expression showed a negative correlation with the stage of prostate cancer (P<0.0001) and PSMA level (P<0.05) in clinical samples, indicating their possible involvement in PSMA-related PCa metastasis regulation. These findings may provide insights into the mechanism involved in the suppression of PCa metastasis by PSMA and its possible interacting proteins, and may provide clues for further exploration of the molecular mechanism of PCa metastasis.