Customized Intranasal Hydrogel Delivering Methylene Blue Ameliorates Cognitive Dysfunction against Alzheimer's Disease.

The accumulation of hyperphosphorylated tau protein aggregates is a key pathogenic event in Alzheimer's disease (AD) and induces mitochondrial dysfunction and reactive oxygen species overproduction. However, the treatment of AD remains challenging owning to the hindrance caused by the blood-brain barrier (BBB) and the complex pathology of AD. Nasal delivery represents an effective means of circumventing the BBB and delivering drugs to the brain. In this study, black phosphorus (BP) is used as a drug carrier, as well as an antioxidant, and loaded with a tau aggregation inhibitor, methylene blue (MB), to obtain BP-MB. For intranasal (IN) delivery, a thermosensitive hydrogel is fabricated by cross-linking carboxymethyl chitosan and aldehyde Pluronic F127 (F127-CHO) micelles. The BP-MB nanocomposite is incorporated into the hydrogel to obtain BP-MB@Gel. BP-MB@Gel could be injected intranasally, providing high nasal mucosal retention and controlled drug release. After IN administration, BP-MB is continuously released and delivered to the brain, exerting synergistic therapeutic effects by suppressing tau neuropathology, restoring mitochondrial function, and alleviating neuroinflammation, thus inducing cognitive improvements in mouse models of AD. These findings highlight a potential strategy for brain-targeted drug delivery in the management of the complex pathologies of AD.

Synergistic and Long-Lasting Wound Dressings Promote Multidrug-Resistant Staphylococcus Aureus-Infected Wound Healing.

Background: Multidrug-resistant staphylococcus aureus infected wounds can lead to nonhealing, systemic infections, and even death. Although advanced dressings are effective in protecting, disinfecting, and maintaining moist microenvironments, they often have limitations such as single functionality, inadequate drug release, poor biosafety, or high rates of drug resistance. Methods: Here, a novel wound dressing comprising glycyrrhizic acid (GA) and tryptophan-sorbitol carbon quantum dots (WS-CQDs) was developed, which exhibit synergistic and long-lasting antibacterial and anti-inflammatory effects. We investigated the characterization, mechanical properties, synergistic antibacterial effects, sustained-release properties, and cytotoxicity of GA/WS-CQDs hydrogels in vitro. Additionally, we performed transcriptome sequence analysis to elucidate the antibacterial mechanism. Furthermore, we evaluated the biosafety, anti-inflammatory effects, and wound healing ability of GA/WS-CQDs dressings using an in vivo mouse model of methicillin-resistant staphylococcus aureus (MRSA)-infected wounds. Results: The prepared GA/WS-CQDs hydrogels demonstrated superior anti-MRSA effects compared to common antibiotics in vitro. Furthermore, the sustained release of WS-CQDs from GA/WS-CQDs hydrogels lasted for up to 60 h, with a cumulative release of exceeding 90%. The sustained-released WS-CQDs exhibited excellent anti-MRSA effects, with low drug resistance attributed to DNA damage and inhibition of bacterial biofilm formation. Notably, in vivo experiments showed that GA/WS-CQDs dressings reduced the expression of inflammatory factors (TNF-α, IL-1ß, and IL-6) and significantly promoted the healing of MRSA-infected wounds with almost no systemic toxicity. Importantly, the dressings did not require replacement during the treatment process. Conclusion: These findings emphasize the high suitability of GA/WS-CQDs dressings for MRSA-infected wound healing and their potential for clinical translation.

Clinical features of multifocal papillary thyroid carcinoma and risk factors of cervical metastatic lymph nodes.

OBJECTIVE: To analyze the clinical features of multifocal papillary thyroid carcinoma (PTC) and the risk factors of cervical metastatic lymph nodes. METHODS: A total of 1524 patients with papillary thyroid carcinoma admitted in Gansu Provincial Cancer Hospital from January 2020 to August 2021 were enrolled, including 492 cases of multifocal PTC and 1032 cases of unifocal PTC. The clinicopathologic features of multifocal PTC and unifocal PTC were analyzed by comparing their differences in gender, ethnicity, age, body mass index, accompanying diabetes mellitus, accompanying hypertension, preoperative thyroid stimulating hormone and thyroglobulin levels, location of lesions, maximum diameter of lesions, sum of lesion diameters, central metastatic lymph nodes, lateral cervical metastatic lymph nodes, presence of Hashimoto's thyroiditis, and thyroid capsule invasion. Patients were also assessed according to the presence or absence of central metastatic lymph nodes and lateral cervical metastatic lymph nodes to understand clinicopathological parameter differences, and multivariate logistic regression analysis was used to explore the risk factors. RESULTS: Compared with unifocal PTC group, multifocal PTC group had significantly higher proportion of patients aged over 55 years, accompanying hypertension, central metastatic lymph nodes or cervical metastatic lymph nodes, Hashimoto's thyroiditis and capsule invasion (all P<0.05); 55.1% of patients with multifocal PTC had lesions distributed bilaterally, and the maximum diameter and diameter sum of the lesions were greater than those in unifocal PTC group (all P<0.01). Multivariate logistic regression analysis showed that male, maximum diameter of lesion more than 7 mm, capsular invasion were independent risk factors for central metastatic lymph nodes (all P<0.05); while male, maximum diameter of lesion more than 7 mm, preoperative thyroglobulin more than 55 ng/mL, and central metastatic lymph nodes were risk factors for lateral cervical metastatic lymph nodes in patients with multifocal PTC (all P<0.05). CONCLUSION: Patients with multifocal PTC have significantly higher central and lateral cervical metastatic lymph nodes, particularly for male patients with a maximum diameter of lesion more than 7 mm, invasion of capsule, and preoperative thyroglobulin more than 55 ng/mL.

Self-assembly hydrogels of therapeutic agents for local drug delivery.

Advanced drug delivery systems are of vital importance to enhance therapeutic efficacy. Among various recently developed formulations, self-assembling hydrogels composed of therapeutic agents have shown promising potential for local drug delivery owing to their excellent biocompatibility, high drug-loading efficiency, low systemic toxicity, and sustained drug release behavior. In particular, therapeutic agents self-assembling hydrogels with well-defined nanostructures are beneficial for direct delivery to the target site via injection, not only improving drug availability, but also extending their retention time and promoting cellular uptake. In brief, the self-assembly approach offers better opportunities to improve the precision of pharmaceutical treatment and achieve superior treatment efficacies. In this review, we intend to cover the recent developments in therapeutic agent self-assembling hydrogels. First, the molecular structures, self-assembly mechanisms, and application of self-assembling hydrogels are systematically outlined. Then, we summarize the various self-assembly strategies, including the single therapeutic agent, metal-coordination, enzyme-instruction, and co-assembly of multiple therapeutic agents. Finally, the potential challenges and future perspectives are discussed. We hope that this review will provide useful insights into the design and preparation of therapeutic agent self-assembling hydrogels.

Self-healing, injectable hydrogel based on dual dynamic covalent cross-linking against postoperative abdominal cavity adhesion.

Clinically, increasing the peritoneal barrier is an effective adjunct to reducing postoperative peritoneal adhesion. This study presents a facile template for preparing a supramolecular hybrid hydrogel through dynamic covalent cross-linking between carboxymethyl chitosan (CMCS), 2-formylphenylboronic acid (2-FPBA), and quercetin (Que). The as-prepared complex CMCS/2-FPBA/Que (CFQ) hydrogel exhibited favorable antibacterial, anti-inflammatory, and antioxidant effects. A L929 cytotoxicity evaluation confirmed the favorable cytocompatibility of the CFQ hydrogel. The postoperative anti-adhesion ability of the CFQ hydrogel was further evaluated in rats with lateral wall defects and cecal abrasions. Compared with control groups, the tissue adhesion rate was significantly reduced by increasing the Que concentration in all the hydrogel-treated groups. Additionally, the sustained-release time of the C3F0.8Q0.08 hydrogel can exceed 14 days, which is highly desirable for clinical wound treatment. STATEMENT OF SIGNIFICANCE: Postoperative adhesions are a very common postoperative complication that seriously affects the quality of life of patients. The currently commonly used methods for preventing adhesion mainly use degradable barrier materials for physical separation. In this study, we prepared a dual dynamic covalently cross-linked CFQ hydrogel, which is not only degradable and injectable, but also has multiple properties such as antibacterial, antioxidant and anti-inflammatory, which can effectively prevent postoperative adhesion and promote wound healing.

Potential metal-related strategies for prevention and treatment of COVID-19.

Abstract: The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed severe threats to human health, public safety, and the global economy. Metal nutrient elements can directly or indirectly take part in human immune responses, and metal-related drugs have served as antiviral drugs and/or enzyme inhibitors for many years, providing potential solutions to the prevention and treatment of COVID-19. Metal-based drugs are currently under a variety of chemical structures and exhibit wide-range bioactivities, demonstrating irreplaceable advantages in pharmacology. This review is an intention to summarize recent progress in the prevention and treatment strategies against COVID-19 from the perspective of metal pharmacology. The current and potential utilization of metal-based drugs is briefly introduced. Specifically, metallohydrogels that have been shown to present superior antiviral activities are stressed in the paper as potential drugs for the treatment of COVID-19.

Facile Preparation of Drug-Releasing Supramolecular Hydrogel for Preventing Postoperative Peritoneal Adhesion.

Hydrogels have attracted widespread attention for breaking the bottlenecks faced during facile drug delivery. To date, the preparation of jelly carriers for hydrophobic drugs remains challenging. In this study, by evaporating ethanol to drive the formation of hydrogen bonds, hydrophilic poly(vinyl alcohol) (PVA) and certain hydrophobic compounds [luteolin (LUT), quercetin (QUE), and myricetin (MYR)] were rapidly prepared into supramolecular hydrogel within 10 min. The gelation performance of these three hydrogels changed regularly with the changing sequence of LUT, QUE, and MYR. An investigation of the gelation pathway of these hybrid gels reveals that the formation of this type of gel follows a simple supramolecular self-assembly process, called "hydrophobe-hydrophile crosslinked gelation". Because the hydrogen bond between PVA and the drug is noncovalent and reversible, the hydrogel has good plasticity and self-healing properties, while the drugs can be controllably released by tuning the output stimuli. Using a rat sidewall-cecum abrasion adhesion model, the as-prepared hydrogel was highly efficient and safe in preventing postsurgical adhesion. This work provides a useful archetypical template for researchers interested in the efficient delivery and controllable release of hydrophobic drugs.

[Clinical epidemiological analysis of 3602 cases of primary liver cancer in Xinjiang].

OBJECTIVE: To investigate the clinical epidemiological characteristics and the major causes of primary liver cancer (PLC) in Xinjiang region. METHODS: The clinical epidemiological information on the first page of case history of 3602 PLC patients, which were diagnosed in our hospital from January 2002 to December 2010, were retrospectively reviewed and analyzed. RESULTS: Among the 3602 cases, the men/women gender ratio was 3.72:1; The proportion of Han, Uighur, Kazakh, and other nationality (Hui, Mongolian, Manchu, Xibo nationality) was 81.95%, 9.30%, 4.14%, 2.89%, and 1.72%, respectively. The comparative difference between Uighur and Han nationalities was significant (P < 0.05). The hepatitis virus detection results showed that HBs-Ag was positive in 1680 cases (59.57%), HCV-Ab was positive in 229 cases (9.41%). Virus detection was negative in 888 patients (24.65%). The hepatitis B virus positive rate in Uygur patients was 36.13% and in Kazakh patients was 40.37%, both significantly lower than that in patients of Han nationality (63.18%, P < 0.05). CONCLUSIONS: In Xinjiang region, the infection rate of hepatitis B virus in Uygur and Kazak people is significantly lower than that in Han people. The distribution of gender and age does not differ significantly among different nationalities, compared with those in other regions. The prevalence of primary liver cancer in Xinjiang region has certain regional characteristics and features.

Curative effect of radiotherapy at various doses on subcutaneous alveolar echinococcosis in rats.

BACKGROUND: Alveolar echinococcosis (AE) is a disease in human and animals, and the cure rate is unsatisfactory. This study aimed to investigate the curative efficacy of different doses of locally applied radiotherapy on alveolar echinococcosis in rats. METHODS: Rats infected with Echinococcus multilocularis were randomly divided into 4 groups of 15 rats each: low-, middle-, and high-irradiation groups and a control group. Rats in the control group underwent no treatment, while rats in the irradiation groups received 6-MeV radiotherapy at 20 Gy/8 f, 40 Gy/8 f, and 60 Gy/8 f respectively, once every 3 days for a total of 8 times. One month after radiotherapy, wet weight and AE vesicle inhibitory rate were detected in rats of each group. Histopathologic and ultrastructural observations of tissues with AE lesions were performed. RESULTS: In the treatment groups, an obvious inhibitory effect was found in AE rats; the inhibitory rates were 50%, 72%, and 82%, respectively. There were also statistical differences in pathological changes and average wet weight of the lesions compared with the control group (P < 0.05). In the treatment groups, injuries of various degrees were found in the ultrastructure of the laminated and germinal layers in the capsular wall of AE, and injury was most severe in the high-dose group. CONCLUSION: Radiotherapy has a dose-dependent inhibitory effect on the growth of AE.

[X-ray irradiation against Echinococcus multilocularis protoscoleces in vitro].

OBJECTIVE: To explore the effect of X-ray irradiation on Echinococcus multilocularis protoscoleces in vitro. METHODS: Echinococcus multilocularis protoscoleces were collected from cysts of infected Meriones meridianus and then cultured in RPMI 1640 medium. Protoscoleces were subpackaged into culture flasks at a density of about 10(4) per flask after culture for 3 days. Each group has 10 culture flasks. There were seven groups named as blank control group, low dose group (15 Gy and 30 Gy), medium dose group (45 Gy and 60 Gy), high dose group (75 Gy and 90 Gy), albendazole group (2 500 ng/ml), 45 Gy X-ray + 2 500 ng/ml albendazole group, and 75 Gy X-ray + 2 500 ng/ml albendazole group. Protoscoleces received three radiations on every other day with a source-skin distance of 100 cm and at a dose rate of 200 cGy/min after 3 days in culture. At each day after irradiation, protoscoleces were counted by light microscope with 0.1% eosin staining, and calculated mortality rate (per 100 protoscoleces) until all the parasites in experimental groups died. At the same time, the morphological changes of protoscoleces were observed. RESULTS: There were significant differences in protoscolex mortality between X-ray groups and blank control group (P < 0.05), between X-ray + albendazole groups and albendazole group (P < 0.05). Protoscolex mortality in albendazole group were higher than that of blank control group (P < 0.05). Significant difference were also found in protoscolex mortality between albendazole combined with radiation and radiation only (P < 0.05). Before radiation, protoscoleces was normal with complete structure. After radiation, the parasites were mostly valgus type protoscoleces with disordered rostellar hooks and deformed acetabulum, and finally died. CONCLUSION: X-ray can kill Echinococcus multilocularis protoscoleces in vitro.

[Effect of 6 MeV radiotherapy on secondary Echinococcus multilocularis infection in rats].

OBJECTIVE: To explore the effect of 6-MeV X-ray radiotherapy on secondary Echinococcus multilocularis infection in rats. METHODS: Female SD rats were used to develop a secondary infection model, and then randomly divided into experimental group and control group (5/group). Rats in experimental group received two irradiations at 7-day intervals with the same dose (20 Gy) which applied with 6-MeV ray. The rats in control group did not receive any treatment. At one month after the second irradiation, the pathomorphological changes of E. multilocularis cysts were observed. RESULTS: Cysts in experimental group showed different degrees of damage, including that the laminated layer and germinal layer became swollen and separated from each other, brood capsules and protoscoleces were rare. The structure of cysts was normal in control group, laminated layer and germinal layer were clear, and there were many protoscoleces in the brood capsule. CONCLUSION: 6 MeV radiotherapy can inhibit the growth of E. multilocularis.