NLRP3 inflammasomes are involved in the progression of postoperative cognitive dysfunction: from mechanism to treatment.

Postoperative cognitive dysfunction (POCD) involves patient memory and learning decline after surgery. POCD not only presents challenges for postoperative nursing and recovery but may also cause permanent brain damage for patients, including children and the aged, with vulnerable central nervous systems. Its occurrence is mainly influenced by surgical trauma, anesthetics, and the health condition of the patient. There is a lack of imaging and experimental diagnosis; therefore, patients can only be diagnosed by clinical observation, which may underestimate the morbidity, resulting in decreased treatment efficacy. Except for symptomatic support therapy, there is a relative lack of effective drugs specific for the treatment of POCD, because the precise mechanism of POCD remains to be determined. One current hypothesis is that postoperative inflammation promotes the progression of POCD. Accumulating research has indicated that overactivation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes contribute to the POCD progression, suggesting that targeting NLRP3 inflammasomes may be an effective therapy to treat POCD. In this review, we summarize recent studies and systematically describe the pathogenesis, treatment progression, and potential treatment options of targeting NLRP3 inflammasomes in POCD patients.

Emerging peptide-based nanovaccines: From design synthesis to defense against cancer and infection.

Peptide-based vaccines, which form one of the most potent vaccine platforms, offer exclusive advantages over classical vaccines that use whole organisms or proteins. However, peptides alone are still poor stability and weak immunogenicity, thus need a delivery system that can overcome these shortcomings. Currently, nanotechnology has been extensively utilized to address this issue. Nanovaccines, as new formulations of vaccines using nanoparticles (NPs) as carriers or adjuvants, are undergoing development instead of conventional vaccines. Indeed, peptide-based nanovaccine is a rapidly developing field of research that is emerging out of the confluence of antigenic peptides with the nano-delivery system. In this review, we shed light on the rational design and preparation strategies based on various nanomaterials of peptide-based nanovaccines, and we spotlight progress in the development of peptide-based nanovaccines against cancer and infectious diseases. Finally, the future prospects for development of peptide-based nanovaccines are presented.

Melanoma stem cell vaccine induces effective tumor immunity against melanoma.

Melanoma stem cells (MSCs)-based vaccine strategies have been a potent immunotherapeutic approach for melanoma treatment, which aimed at inducing specific anti-tumor immunity and targeting cancer stem-like cells. As the main cancer-fighting immune cells, CD8+T cells play an important role in vaccine-induced antitumor immunity. Here, we developed a novel MSC vaccine that induces CD8+T cells to target melanoma stem cells specifically. The MSC vaccine was prepared for our study in order to determine the effectiveness of antitumor immunity. The proportion and activity of CD8+T cells were examined in the spleen after immunization, in particular, the expression and cytotoxicity of the immune checkpoint of spleen lymphocytes were detected by flow cytometry and ELISA, moreover, tumor size and the number of lung metastasis nodules were observed and the specific killing effect of the vaccine was evaluated in immunized mice. We found that the MSC vaccine could promote DCs maturation, activate CD8+T cells, suppress the expression of CTLA-4, PD-1, and Tim-3, and increase the expression of IFN-γ and GzmB of CD8+T cells. Melanoma growth and metastasis were inhibited by the vaccine's specific targeted killing effect. The vaccines based on melanoma stem cells (MSCs) delay the progression of melanoma by inducing anti-tumor immune responses in CD8+T cells.

Nanovaccines: Merits, and diverse roles in boosting antitumor immune responses.

An attractive type of cancer immunotherapy is cancer therapeutic vaccines that induce antitumor immunity effectively. Although supportive results in the recent vaccine studies, there are still numerous drawbacks, such as poor stability, weak immunogenicity and strong toxicity, to be tackled for promoting the potency and durability of antitumor efficacy. NPs (Nanoparticles)-based vaccines offer unique opportunities to breakthrough the current bottleneck. As a rule, nanovaccines are new the generations of vaccines that use NPs as carriers and/or adjuvants. Several advantages of nanovaccines are constantly explored, including optimal nanometer size, high stability, plenty of antigen loading, enhanced immunogenicity, tunable antigen presentation, more retention in lymph nodes and promote patient compliance by a lower frequency of dosing. Here, we summarized the merits and highlight the diverse role nanovaccines play in improving antitumor responses.

Effect of melanoma stem cells on melanoma metastasis.

Cancer stem cells (CSCs) are involved in the metastatic process, the resistance of many types of cancer to therapeutic treatments and consequently the onset of recurrences. The CSC concept therefore significantly extends our understanding of melanoma biology. More recently, melanoma stem cells (MSCs) have been described in melanoma as expressing specific biomarkers. These primitive melanoma cells are not only capable of self-renewal and differentiation plasticity, but may also confer virulence via immune evasion and multidrug resistance, and potentially, via vasculogenic mimicry and transition to migratory and metastasizing derivatives. This review will present the specific biomarkers of MSCs, including CD133, ATP binding cassette subfamily B member 5, CD271, CD20 and aldehyde dehydrogenase, which can regulate the transduction of tumor-related signals. These signal molecules can reversely act on tumor cells and regulate tumor angiogenesis, leading to the occurrence of melanoma metastasis. Targeting these specific biomarkers could inhibit the progression of melanoma and may help the development of novel therapeutic strategies for melanoma.

Prospective study of clinical characteristics of melanoma patients with retinopathy caused by a high-dose interferon α-2b.

Retinopathy is a rare side effect of interferon α-2b treatment. The goal of this study was to prospectively investigate the clinical characteristics of Chinese patients with melanomas who developed retinopathy following high doses of interferon α-2b (HD-IFN) therapy. The study included 56 melanoma stage I-III patients that were treated with HD-IFN. Fourty-three patients developed HD-IFN-induced retinopathies. Forty-three melanoma patients (76%) developed retinopathy after being treated with HD-IFN. Among these patients, 49% had cotton-wool spots, 19% had retinal hemorrhage, and 30% had retinal hemorrhage. The median time of occurrence of retinopathy was 4 weeks after treatment, and the median time of duration was 4 weeks. No patient showed other symptoms except one who had blurred vision. A comparison of clinical characteristics (age, gender, primary site, stage, and ulceration) and laboratory examinations (white blood cell and platelet counts, hemoglobin, serum lactate dehydrogenase, alanine transaminase, aspartate aminotransferase, triiodothyronine, thyroxine, thyroid-stimulating hormone, and lipid) between the HD-IFN-induced retinopathy patients and nonretinopathy patients did not show any significant differences (P > 0.05). Although all patients that developed retinopathy had diabetes or hypertension, an equal percentage of patients were without retinopathy had diabetes or hypertension. HD-IFN therapy in patients with melanomas may induce mild retinopathy. Our results; however, do not necessarily suggest to discontinue the HD-IFN treatment because retinopathy is a reversible disorder.

Reactive Oxygen Species Interact With NLRP3 Inflammasomes and Are Involved in the Inflammation of Sepsis: From Mechanism to Treatment of Progression.

Over the past 10 years, the crisis of sepsis has remained a great challenge. According to data from 2016, the sepsis-related mortality rate remains high. In addition, sepsis consumes extensive medical resources in intensive care units, and anti-inflammatory agents fail to improve sepsis-associated hyperinflammation and symptoms of immunosuppression. The specific immune mechanism of sepsis remains to be elucidated. Reactive oxygen species (ROS) are triggered by energy metabolism and respiratory dysfunction in sepsis, which not only cause oxidative damage to tissues and organelles, but also directly and indirectly promote NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. NLRP3 inflammasomes enlarge the inflammatory response and trigger apoptosis of immune cells to exacerbate sepsis progression. Inhibiting the negative effects of ROS and NLRP3 inflammasomes therefore provides the possibility of reversing the excessive inflammation during sepsis. In this review, we describe the interaction of ROS and NLRP3 inflammasomes during sepsis, provide prevention strategies, and identify fields that need further study.

Critical role of toll-like receptor 4 (TLR4) in ricin toxin-induced inflammatory responses in macrophages.

Ricin toxin (RT) is a natural plant-derived protein toxin from the seed of castor beans that belongs to a family of type II ribosome-inactivating proteins (RIPs). In addition to its main toxic mechanism of inhibiting the synthesis of cellular proteins, RT can induce the production of inflammatory cytokines and cause inflammatory injury. Macrophages play a crucial role in innate immunity and the adaptive immune response as the first line of host defense against bacterial infections and various types of invading pathogens. Upon activation, macrophages release types of cytokines to remove pathogens. However, the effect of RT on the immune response and its mechanism are not well characterized. In the current study, we investigated the activation of the TLR4-mediated signaling pathway by low-dose RT treatment and its interaction with signaling molecules in the transduction pathway. We found that low-dose RT can activate MyD88- and TRIF-dependent signaling pathways, revealing a possible mechanism by which low-dose RT-activates TLR4-mediated signaling pathways. We also confirmed that the TLR4-induced activation of the inflammatory signaling pathways was produced via its binding to RT. This study may help to identify the most important target molecules and clarify the mechanism of inflammatory injury of ricin.

Comparison of senescence-related changes between three- and two-dimensional cultured adipose-derived mesenchymal stem cells.

BACKGROUND: Adipose-derived mesenchymal stem cells (ADMSCs) have attracted widespread interest as cell-based tissue repair systems. To obtain adequate quantities of ADMSCs for therapeutic applications, extensive in vitro expansion is required. However, under current two-dimensional (2D) approaches, ADMSCs rapidly undergo replicative senescence, and cell growth is impeded and stem cell properties are eliminated by mechanisms that are poorly understood. These issues limit the extensive applications of ADMSCs. In this study, we investigated senescence-related changes in mesenchymal stem cells (MSCs) isolated from human adipose tissue in 2D and three-dimensional (3D) cultures. METHODS: We studied cell growth over a given period (21 days) to determine if modes of culture were associated with ADMSC senescence. ADMSCs were isolated from healthy females by liposuction surgery and then were grown in 2D and 3D cultures. The cell morphology was observed during cell culture. Every other time of culture, senescence-associated ß-galactosidase (SA-ß-gal) expression, cell viability, proliferation, and differentiation potential of ADMSCs from 2D and 3D cultures were detected. Also, senescence- and stemness-related gene expression, telomere length, telomerase activity, and energy metabolism of ADMSCs for different culture times were evaluated. RESULTS: With long-term propagation, we observed significant changes in cell morphology, proliferation, differentiation abilities, and energy metabolism, which were associated with increases in SA-ß-gal activity and decreases in telomere length and telomerase activity. Notably, when cultured in 3D, these changes were improved. CONCLUSIONS: Our results indicate that 3D culture is able to ameliorate senescence-related changes in ADMSCs.

Antitumor potential of a novel camptothecin derivative, ZBH-ZM-06.

Camptothecin (CPT) is a cytotoxic quinoline alkaloid that is used clinically as an anticancer drug. However, the clinical application of CPT is limited due to its low solubility as well as serious and unfathomable side-effects. In the present study, we created a novel 10-hydroxy CPT prodrug, ZBH-ZM­06. Its cellular cytotoxic activity was analyzed in terms of cellular viability, acetylcholinesterase (AchE) inhibition, DNA relaxation, cellular cycling and apoptosis properties. Our results showed that the AchE inhibition rate of 10 µmol/l ZBH-ZM-06 was 12.5%, compared to 96.5% for carbonyl-oxycamptothecin (CPT-11). In a chemical stability assay, only 4.9% of ZBH-ZM-06 remained after 4 h at pH 7.4. In addition, 10 µmol/l ZBH-ZM-06 significantly inhibited the tumor cell viability of nine tumor cell lines, compared to CPT-11 and the CPT active ingredient, 7-ethyl-10-hydroxy-camptothecin (SN38) (p<0.01-0.05). In the apoptosis assay, ZBH-ZM-06 increased the ratio of annexin V+/propidium iodide (PI)-/+ cells by flow cytometric analysis (p<0.05). Moreover, ZBH-ZM-06 activated caspase-3 and poly(ADP-ribose)polymerase (PARP) expression by immunoblotting. Furthermore, ZBH-ZM-06 induced a greater G2/M phase arrest ratio, compared to CPT-11 and SN38. These results indicated that ZBH-ZM-06 had higher antitumor activity than CPT-11 and SN38, which was shown by its: i) release of the effective ingredient; ii) growth inhibition of a broad spectrum of tumor cells; iii) inhibition of DNA topoisomerase (Topo-1); and iv) promotion of apoptosis through an intrinsic signaling pathway. Thus, ZBH-ZM-06 may be applied in the preclinic study for cancer treatment.