Ultrasound imaging guided targeted sonodynamic therapy enhanced by magnetophoretically controlled magnetic microbubbles.

Sonodynamic therapy (SDT) utilizes ultrasonic excitation of a sensitizer to generate reactive oxygen species (ROS) to destroy tumor. Two dimensional (2D) black phosphorus (BP) is an emerging sonosensitizer that can promote ROS production to be used in SDT but it alone lacks active targeting effect and showed low therapy efficiency. In this study, a stable dispersion of integrated micro-nanoplatform consisting of BP nanosheets loaded and Fe3O4 nanoparticles (NPs) connected microbubbles was introduced for ultrasound imaging guided and magnetic field directed precision SDT of breast cancer. The targeted ultrasound imaging at 18 MHz and efficient SDT effects at 1 MHz were demonstrated both in-vitro and in-vivo on the breast cancer. The magnetic microbubbles targeted deliver BP nanosheets to the tumor site under magnetic navigation and increased the uptake of BP nanosheets by inducing cavitation effect for increased cell membrane permeability via ultrasound targeted microbubble destruction (UTMD). The mechanism of SDT by magnetic black phosphorus microbubbles was proposed to be originated from the ROS triggered mitochondria mediated apoptosis by up-regulating the pro-apoptotic proteins while down-regulating the anti-apoptotic proteins. In conclusion, the ultrasound theranostic was realized via the magnetic black phosphorus microbubbles, which could realize targeting and catalytic sonodynamic therapy.

Effects of active vitamin D analogues on muscle strength and falls in elderly people: an updated meta-analysis.

Background: Elderly people are at high risk of falls due to decreased muscle strength. So far, there is currently no officially approved medication for treating muscle strength loss. The active vitamin D analogues are promising but inconsistent results have been reported in previous studies. The present study was to meta-analyze the effect of active vitamin D analogues on muscle strength and falls in elderly people. Methods: The protocol was registered with PROSPERO (record number: CRD42021266978). We searched two databases including PubMed and Cochrane Library up until August 2023. Risk ratio (RR) and standardized mean difference (SMD) with 95% confidence intervals (95% CI) were used to assess the effects of active vitamin D analogues on muscle strength or falls. Results: Regarding the effects of calcitriol (n= 1), alfacalcidol (n= 1) and eldecalcitol (n= 1) on falls, all included randomized controlled trials (RCT) recruited 771 participants. Regarding the effects of the effects of calcitriol (n= 4), alfacalcidol (n= 3) and eldecalcitol (n= 3) on muscle strength, all included RCTs recruited 2431 participants. The results showed that in the pooled analysis of three active vitamin D analogues, active vitamin D analogues reduced the risk of fall by 19%. Due to a lack of sufficient data, no separate subgroup analysis was conducted on the effect of each active vitamin D analogue on falls. In the pooled and separate analysis of active vitamin D analogues, no significant effects were found on global muscle, hand grip, and back extensor strength. However, a significant enhancement of quadriceps strength was observed in the pooled analysis and separate analysis of alfacalcidol and eldecalcitol. The separate subgroup analysis on the impact of calcitriol on the quadriceps strength was not performed due to the lack to sufficient data. The results of pooled and separate subgroup analysis of active vitamin D analogues with or without calcium supplementation showed that calcium supplementation did not affect the effect of vitamin D on muscle strength. Conclusions: The use of active vitamin D analogues does not improve global muscle, hand grip, and back extensor strength but improves quadriceps strength and reduces risk of falls in elderly population.

Glioma diagnosis and therapy: Current challenges and nanomaterial-based solutions.

Glioma is often referred to as one of the most dreadful central nervous system (CNS)-specific tumors with rapidly-proliferating cancerous glial cells, accounting for nearly half of the brain tumors at an annual incidence rate of 30-80 per a million population. Although glioma treatment remains a significant challenge for researchers and clinicians, the rapid development of nanomedicine provides tremendous opportunities for long-term glioma therapy. However, several obstacles impede the development of novel therapeutics, such as the very tight blood-brain barrier (BBB), undesirable hypoxia, and complex tumor microenvironment (TME). Several efforts have been dedicated to exploring various nanoformulations for improving BBB permeation and precise tumor ablation to address these challenges. Initially, this article briefly introduces glioma classification and various pathogenic factors. Further, currently available therapeutic approaches are illustrated in detail, including traditional chemotherapy, radiotherapy, and surgical practices. Then, different innovative treatment strategies, such as tumor-treating fields, gene therapy, immunotherapy, and phototherapy, are emphasized. In conclusion, we summarize the article with interesting perspectives, providing suggestions for future glioma diagnosis and therapy improvement.

Vitamin D supplementation reduces the risk of fall in the vitamin D deficient elderly: An updated meta-analysis.

INTRODUCTION: Vitamin D supplementation has been widely recommended to prevent falls. However, considerable controversy exists regarding the association of such supplementation and fall risk. Previous meta-analyses yielded inconsistent results because of differences in the baseline of 25-hydroxyvitamin D [25(OH)D] and dose of vitamin D and use of vitamin D or in combination with calcium in different studies. Furthermore, some studies published recently were not included in the previous meta-analyses. Therefore, an updated and comprehensive meta-analysis is warranted. METHODS: We systematically searched several literature databases including PubMed and the Embase from inception to September 2020. The protocol for this meta-analysis was registered with PROSPERO (CRD42021226380). Randomized clinical trials (RCTs) reporting the effect of vitamin D supplementation alone or with calcium on fall incidence were selected from studies. Qualitative and quantitative information was extracted; the random-effects model was conducted to pool the data for fall; statistical heterogeneity was assessed using the I2 test and potential for publication bias was assessed qualitatively by a visual estimate of the funnel plot and quantitatively by calculation of the Begg's test and the Egger's test. RESULTS: Of the citations retrieved, 31 eligible studies involving 57 867 participants met inclusion criteria, reporting 17 623 falls. A total of 21 RCTs of vitamin D alone and 10 RCTs of vitamin D plus calcium were included in the meta-analysis. The meta-analysis of 21 RCTs (51 984 participants) of vitamin D supplementation alone (daily or intermittent doses of 400-60 000 IU) did not show a reduced risk of falls (The risk ratio [RR] 1.00, 95% confidence intervals [CI] 0.95 to 1.05) compared to placebo or no treatment. Subgroup analyses showed that the baseline of serum 25(OH)D concentration less than 50 nmol/L resulted in a reduction of fall risk (RR 0.77, 95% CI 0.61 to 0.98). In contrast, the meta-analysis of 10 RCTs (5883 participants) of combined supplementation of vitamin D (daily doses of 700-1000 IU) and calcium (daily doses of 1000-1200 mg) showed a 12% reduction in the risk of fall (RR 0.88, 95% CI 0.80 to 0.97). CONCLUSIONS: The combination of vitamin D and calcium have beneficial effects on prevention falls in old adults. Although vitamin D supplementation alone has no effect on fall risk in old adults with 25(OH)D levels higher than 50 nmol/L, vitamin D supplementation alone does have a benefit on prevention of falls in old adults with 25(OH)D levels lower than 50 nmol/L.

pH-responsive black phosphorus quantum dots for tumor-targeted photodynamic therapy.

Black phosphorus quantum dots(BPQDs) have shown a good application prospect in the field of tumor therapy due to their photoelectric effect and good biodegradability. Due to the active endocytosis and fast metabolic efficiency of tumor cells, BPQDs are easy to be absorbed by tumor cells. However, this does not guarantee that BPQDs will be completely targeted to tumor cells, and normal cells will also absorb BPQDs. Because the cell membrane is negatively charged, BPQDs are also negatively charged and are not easily absorbed by cells under the action of electrostatic repulsion. Surface pegylation is the most common modification method of black phosphorus at present. However, surface pegylation can reduce the uptake of BPQDs by tumor cells. Positive PEG is also easy to be recognized and swallowed by the reticuloendothelial system. The inherent instability and poor tumor targeting of BPQDs under physiological conditions limit further research and clinical application. For this purpose, we selected cationic polymer polyethylenimine (PEI) to modify BPQDs and then added RGD peptides targeting tumor cells. An outer layer of negatively charged PEG+DMMA makes the nanosystem more stable . In the acidic environment of the tumor, the PEG layer has a charge reversal, and the positively charged PEI and the RGD polypeptide BPQDs targeted by the tumor cells are released into the tumor cells. It provides a new method for efficiently and accurately transporting BPQDs, a novel photosensitive nanomaterial, into tumor cells for photodynamic therapy.

Liquid-phase exfoliation of black sesame to create a nanoplatform for in vitro photoluminescence and photothermal therapy.

Aim: The present study aims to apply the facile liquid-phase exfoliation (LPE) strategy to fabricate 2D organic materials and thus to broaden the family of biocompatible and multifunctional 2D materials. Materials & methods: 2D material-organic melanin and cellulose nanosheets were synthesized from black sesame hull using LPE. Photoluminescence and photothermal properties of the nanosheets were assessed, as well as stability and cell killing ability. Results: The prepared 2D nanoplatform exhibited broad and multiple photoluminescent emission bands. It also demonstrated efficient photothermal cancer therapy with excellent biocompatibility. Conclusion: The present study could open an avenue in exfoliating organic materials using the LPE strategy. This could make the fabrication of multifunctional 2D organic materials more efficient and broaden the family of biocompatible 2D nanomaterials.

Brain-targeted delivery shuttled by black phosphorus nanostructure to treat Parkinson's disease.

The treatment of Parkinson's disease (PD) is hampered by the blood-brain barrier (BBB). As such, there is an urgent need for the development of a novel nanoplatform capable of penetrating the BBB in order to effectively treat PD. In the present study, we utilized black phosphorus nanosheets (BP) containing the brain-targeting ligand lactoferrin (Lf) and loaded with Paeoniflorin (Pae) to obtain Lf-BP-Pae. Through an effective photo-thermal effect, these Lf-BP-Pae particles were capable of traversing the BBB and effectively treating PD in a targeted manner. Importantly, this BP-based nanoplatform was capable of achieving satisfactory biocompatibility and biosafety with excellent anti-Parkinsonian efficacy, making it ideal for clinical applications.

Progress in the therapeutic applications of polymer-decorated black phosphorus and black phosphorus analog nanomaterials in biomedicine.

Wonderful black phosphorus (BP) and some BP analogs (BPAs) have been increasingly studied for their biomedical applications owing to their fascinating properties and biodegradability, but opportunities and challenges have always coexisted in their study. Poor stability upon exposure to the natural environment is the major obstacle hampering their in vivo applications. BP/polymer and BPAs/polymer nanocomposites can not only efficiently prevent their oxidation and aggregation but also exhibit "biological activity" due to synergistic effects. In this review, we briefly describe the synthesis methods and stability strategies of BP/polymer and BPAs/polymer. Then, advances pertaining to their exciting therapeutic applications in various fields are systematically introduced, such as cancer therapy (phototherapy, drug delivery, and synergistic immunotherapy), bone regeneration, and neurogenesis. Some challenges for future clinical trials and possible directions for further study are finally discussed.

Emerging combination strategies with phototherapy in cancer nanomedicine.

Optical techniques using developed laser and optical devices have made a profound impact on modern medicine, with "biomedical optics" becoming an emerging field. Sophisticated technologies have been developed in cancer nanomedicine, such as photothermal therapy and photodynamic therapy, among others. However, single-mode phototherapy cannot completely treat persistent tumors, with the challenges of relapse or metastasis remaining; therefore, combinatorial strategies are being developed. In this review, the role of light in cancer therapy and the challenges of phototherapy are discussed. The development of combinatorial strategies with other therapeutic methods, including chemotherapy, immunotherapy, gene therapy, and radiotherapy, is presented and future directions are further discussed. This review aims to highlight the significance of light in cancer therapy and discuss the combinatorial strategies that show promise in addressing the challenges of phototherapy.

Photothermal cancer immunotherapy by erythrocyte membrane-coated black phosphorus formulation.

Basal-like breast cancer exhibits a triple-negative phenotype and has a poor prognosis, even with traditional chemical and anti-human epidermal growth factor receptor (HER) treatments. However, the high mutation rate of this obstinate cancer type renders it suitable for immunotherapy. Photothermal therapy (PTT) is a high-efficiency method for inducing tumor neoantigen release in situ, which has great potential for use in cancer immunotherapy. Here, we prepared a biomimetic black phosphorus quantum dot (BPQDs) formulation to induce breast cancer cell apoptosis in situ by near-infrared (NIR) laser irradiation to mobilize the immune system to eliminate the residual and metastatic cancer cells. Erythrocyte membranes (RMs) were used to coat the BPQDs, forming a BPQD-RM nanovesicle (BPQD-RMNV) biomimetic formulation that exhibited a long circulation time and tumor accumulation in vivo. The basal-like 4T1 breast tumor underwent apoptosis and necrosis with the irradiation and recruited dendritic cells (DCs) to capture the tumor antigens in vivo. Furthermore, programmed cell death protein 1 (PD-1) antibody (aPD-1) was employed to prevent the CD8+ T cells from exhaustion. Notably, BPQD-RMNV-mediated PTT combined with aPD-1 treatment significantly delayed residual and metastatic tumor growth in vivo. Hence, BPQD-RMNV-mediated PTT combined with immune checkpoint blockade antibody increased the infiltration and activity of CD8+ T cells in the tumor, which directly restrained basal-like breast tumor growth in vivo.

Conceptually Novel Black Phosphorus/Cellulose Hydrogels as Promising Photothermal Agents for Effective Cancer Therapy.

Black phosphorus (BP) has recently emerged as an intriguing photothermal agent in photothermal therapy (PTT) against cancer by virtue of its high photothermal efficiency, biocompatibility, and biodegradability. However, naked BP is intrinsically characterized by easy oxidation (or natural degradation) and sedimentation inside the tumor microenvironment, leading to a short-term therapeutic and inhomogeneous photothermal effect. Development of BP-based nanocomposites for PTT against cancer therefore remains challenging. The present work demonstrates that green and injectable composite hydrogels based on cellulose and BP nanosheets (BPNSs) are of great efficiency for PTT against cancer. The resultant cellulose/BPNS-based hydrogel possesses 3D networks with irregular micrometer-sized pores and thin, strong cellulose-formed walls and exhibits an excellent photothermal response, enhanced stability, and good flexibility. Importantly, this hydrogel nanoplatform is totally harmless and biocompatible both in vivo and in vitro. This work may facilitate the development of BP-polymer-based photothermal agents in the form of hydrogels for biomedical-related clinic applications.

p120-Catenin Is Required for Dietary Calcium Suppression of Oral Carcinogenesis in Mice.

Previous studies have shown that dietary calcium suppresses oral carcinogenesis, but the mechanism is unclear. p120-catenin (p120) is a cytoplasmic protein closely associated with E-cadherin to form the E-cadherin-ß-catenin complex and may function as a tumor suppressor in the oral epithelium. To determine whether p120 is involved in the mechanism by which dietary calcium suppresses oral carcinogenesis, The normal, low, or high calcium diet was fed control mice (designated as floxed p120 mice) or mice in which p120 was specifically deleted in the oral squamous epithelium during the adult stage (designated as p120cKO mice). All mice were exposed to a low dose of oral cancer carcinogen 4-nitroquinoline 1-oxide and rates of oral squamous cell carcinoma (OSCC) and proliferation and differentiation in the cancerous and non-cancerous oral epithelium of these mice were examined. The results showed that the low calcium diet increased rates of OSCC and proliferation of the non-cancerous oral epithelium and decreased differentiation of the non-cancerous oral epithelium, but had no effect on cancerous oral epithelium. In contrast, the high calcium diet had opposite effects. However, the effect of the dietary calcium on the rates of OSCC, proliferation, and differentiation of the non-cancerous epithelium were not seen in p120cKO mice. Based on these results, we conclude that p120 is required for dietary calcium suppression of oral carcinogenesis and oral epithelial proliferation and dietary calcium induction of oral epithelial differentiation. J. Cell. Physiol. 232: 1360-1367, 2017. © 2016 Wiley Periodicals, Inc.

Performance evaluation of two immunoassays for 25-hydroxyvitamin D.

Although immunoassays in measuring 25-hydroxyvitamin D [25(OH)D] have been improved recently, relatively large differences are still seen between results of 25(OH)D measured by immunoassays and by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the present studies, we compared two immunoassays with LC-MS/MS for measuring 25(OH)D concentrations. Concentrations of 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] in serum samples from 59 healthy subjects were measured by two immunoassays including Siemens ADVIA Centaur Vitamin D Total (Centaur) and Roche Elecsys Vitamin D Total (Elecsys) and LC-MS/MS. To determine the cross reactivity of Elecsys and Centaur toward 25(OH)D2, a dosage of 200,000 IU vitamin D2 was given after first sampling. Serum samples were obtained 30 days later and concentrations of 25(OH)D2 and 25(OH)D3 were measured again. The results showed poor agreement between the immunoassays and LC-MS/MS in 25(OH)D2 and 25(OH)D3 measurements. The percentage of 25(OH)D2 cross-reactivity was 45.3% for Centaur and 41.2% for Elecsys and there was no significant difference between Centaur and Elecsys. In conclusion, Centaur and Elecsys perform unsatisfactorily in measuring 25(OH)D levels, especially for 25(OH)D2 cross-reactivity. Therefore, clinicians need to be aware of the underestimation of vitamin D status when using these immunoassays for measuring individuals supplemented with vitamin D2.

Inhibition of 4NQO-Induced Oral Carcinogenesis by Dietary Oyster Shell Calcium.

Oyster has gained much attention recently for its anticancer activity but it is unclear whether calcium, the major antitumor ingredient in oyster shell, is responsible for the anticarcinogenic role of the oyster. To address this issue, C57BL/6 mice were fed with the carcinogen 4-nitroquinoline-1-oxide (4NQO, 50 µg/mL) and normal diet or a diet containing oyster powder, oyster calcium, or calcium depleted oyster powder. The tongue tissue specimens isolated from these mice were histologically evaluated for hyperplasia, dysplasia, and papillary lesions, and then analyzed for proliferation and differentiation markers by immunohistochemistry. The results showed that mice on the diet containing oyster calcium significantly reduced rates of tumors in the tongue and proliferation and enhanced differentiation in the oral epithelium compared with the diet containing calcium depleted oyster powder. These results suggest that calcium in oyster plays a critical role in suppressing formation of oral squamous cell carcinoma and proliferation and promoting differentiation of the oral epithelium.

Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human epidermal keratinocytes.

Extracellular Ca(2+) (Ca(2+)(o)) is a critical regulator that promotes differentiation in epidermal keratinocytes. The calcium sensing receptor (CaR) is essential for mediating Ca(2+) signaling during Ca(2+)(o)-induced differentiation. Inactivation of the endogenous CaR-encoding gene CASR by adenoviral expression of a CaR antisense cDNA inhibited the Ca(2+)(o)-induced increase in intracellular free calcium (Ca(2+)(i)) and expression of terminal differentiation genes, while promoting apoptosis. Ca(2+)(o) also instigates E-cadherin-mediated cell-cell adhesion, which plays a critical role in orchestrating cellular signals mediating cell survival and differentiation. Raising Ca(2+)(o) concentration ([Ca(2+)](o)) from 0.03 to 2 mm rapidly induced the co-localization of alpha-, beta-, and p120-catenin with E-cadherin in the intercellular adherens junctions (AJs). To assess whether CaR is required for the Ca(2+)(o)-induced activation of E-cadherin signaling, we examined the impact of CaR inactivation on AJ formation. Decreased CaR expression suppressed the Ca(2+)(o)-induced AJ formation, membrane translocation, and the complex formation of E-cadherin, catenins, and the phosphatidylinositol 3-kinase (PI3K), although the expression of these proteins was not affected. The assembly of the E-cadherin-catenin-PI3K complex was sensitive to the pharmacologic inhibition of Src family tyrosine kinases but was not affected by inhibition of Ca(2+)(o)-induced rise in Ca(2+)(i). Inhibition of CaR expression blocked the Ca(2+)(o)-induced tyrosine phosphorylation of beta-, gamma-, and p120-catenin, PI3K, and the tyrosine kinase Fyn and the association of Fyn with E-cadherin and PI3K. Our results indicate that the CaR regulates cell survival and Ca(2+)(o)-induced differentiation in keratinocytes at least in part by activating the E-cadherin/PI3K pathway through a Src family tyrosine kinase-mediated signaling.