Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.

Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8(+) T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intrahepatic myeloid-cell aggregates for T cell population expansion') without causing immunopathology. In the liver, CTL proliferation was restricted to iMATEs that were composed of inflammatory monocyte-derived CD11b(+) cells. Signaling via tumor-necrosis factor (TNF) caused iMATE formation that facilitated costimulation dependent on the receptor OX40 for expansion of the CTL population. The iMATEs arose during acute viral infection but were absent during chronic viral infection, yet they were still induced by TLR signaling. Such hepatic expansion of the CTL population controlled chronic viral infection of the liver after vaccination with DNA. Thus, iMATEs are dynamic structures that overcome regulatory cues that limit the population expansion of CTLs during chronic infection and can be used in new therapeutic vaccination strategies.

Multi-omics analysis reveals mechanism of Schisandra chinensis lignans and acteoside on EMT in hepatoma cells via ERK1/2 pathway.

BACKGROUND: Hepatocellular carcinoma (HCC), a globally common cancer, often presents late and shows high resistance to chemotherapy, resulting in suboptimal treatment efficacy. Components from traditional Chinese medicines have been recognized for their anti-cancer properties. OBJECTIVE: Exploring the mechanism of Schisandra chinensis lignans and acteoside in suppressing Epithelial-Mesenchymal Transition (EMT) in hepatoma cells through the Extracellular signal-Regulated Kinases (ERK)1/2 pathway and identifying biomarkers, molecular subtypes, and targets via multi-omics for precision oncology. METHODS: Proliferation was assessed using cell counting kit-8 (CCK-8) assays, with scratch and transwell assays for evaluating invasion and migration. Flow cytometry quantified apoptosis rates. Expression levels of CCL20, p-ERK1/2, c-Myc, Vimentin, and E-cadherin/N-cadherin were analyzed by real-time PCR and Western blot. Tumor volume was calculated with a specific formula, and growth. RESULTS: The Schisandra chinensis lignans and acteoside combination decreased CCL20 expression, inhibited hepatoma proliferation and migration, and enhanced apoptosis in a dose- and time-dependent manner. Molecular analysis revealed increased E-cadherin and decreased N-cadherin, p-ERK1/2, c-Myc, and Vimentin expression, indicating ERK1/2 pathway modulation. In vivo, treated nude mice showed significantly reduced tumor growth and volume. CONCLUSION: Schisandra chinensis lignans and acteoside potentially counteract CCL20-induced EMT, invasion, and migration in hepatocellular carcinoma cells via the ERK1/2 pathway, enhancing apoptosis. Multi-omics analysis further aids in pinpointing novel biomarkers for precision cancer therapy.

CXCR4-Mediated Codelivery of FLT3 and BCL-2 Inhibitors for Enhanced Targeted Combination Therapy of FLT3-ITD Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is often associated with poor prognosis and survival. Small molecule inhibitors, though widening the treatment landscape, have limited monotherapy efficacy. The combination therapy, however, shows suboptimal clinical outcomes due to low bioavailability, overlapping systemic toxicity and drug resistance. Here, we report that CXCR4-mediated codelivery of the BCL-2 inhibitor venetoclax (VEN) and the FLT3 inhibitor sorafenib (SOR) via T22 peptide-tagged disulfide cross-linked polymeric micelles (TM) achieves synergistic treatment of FLT3-ITD AML. TM-VS with a VEN/SOR weight ratio of 1/4 and T22 peptide density of 20% exhibited an extraordinary inhibitory effect on CXCR4-overexpressing MV4-11 AML cells. TM-VS at a VEN/SOR dosage of 2.5/10 mg/kg remarkably reduced leukemia burden, prolonged mouse survival, and impeded bone loss in orthotopic MV4-11-bearing mice, outperforming the nontargeted M-VS and oral administration of free VEN/SOR. CXCR4-mediated codelivery of BCL-2 and FLT3 inhibitors has emerged as a prospective clinical treatment for FLT3-ITD AML.

Synthesis of Quillaic Acid through Sustainable C-H Bond Activations.

To meet the demand for quillaic acid, a multigram synthesis of quillaic acid was accomplished in 14 steps, starting from oleanolic acid, leading to an overall yield of 3.4%. Key features include C-H activation at C-16 and C-23. Through Pd-catalyzed C-H acetoxylation, the oxidation at C-23 was observed as the major product, as opposed to at C-24. A copper-mediated C-H hydroxylation using O2 successfully afforded the single isomer, 16ß-ol triterpenoid, followed by configuration inversion to the desired 16α-ol compound. In summary, with steps optimized and conducted on a multigram scale, quillaic acid could be feasibly acquired through C-H activation with inexpensive copper catalysts, promoting a more sustainable approach.

Exposures to drinking water disinfection byproducts and kidney function in Chinese women.

BACKGROUND: Disinfection byproducts (DBPs), the ubiquitous contaminants in drinking water, have been shown to impair renal function in experimental studies. However, epidemiological evidence is sparse. OBJECTIVE: To investigate exposures to DBPs in associations with renal function among women. METHODS: A total of 920 women from December 2018 to January 2020 were abstracted from the Tongji Reproductive and Environmental (TREE) Study, an ongoing cohort study in Wuhan, China. Urine samples were gathered at baseline recruitment and analyzed for dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) as biomarkers of DBP exposures. Serum uric acid (UA), creatinine, and estimated glomerular filtration rate (eGFR) were measured as indicators of renal function. Multivariate linear regression and restricted cubic spline (RCS) models were conducted to assess urinary DCAA and TCAA concentrations in associations with renal function indicators. Stratified analyses by age and body mass index (BMI) were also performed. RESULTS: We found null evidence of urinary TCAA in associations with renal function indicators. However, elevated urinary DCAA tertiles were related to decreased eGFR (ß = -1.78%, 95% CI: 3.21%, -0.36%, comparing the upper vs. lower tertile; P for trend = 0.01). This inverse association still existed when urinary DCAA concentration was treated as a continuous variable, and the dose-response relationship was linear based on the RCS model (P for overall association = 0.002 and P for non-linear associations = 0.44). In the stratified analyses, we found an association of urinary DCAA concentration with decreased UA level among women <30 years but an association with increased UA level among women ≥30 years (P for interaction = 0.04). CONCLUSION: Urinary DCAA but not TCAA was associated with impaired renal function among women undergoing assisted reproductive technology.

The Accurate Imaging of Collective Gold Nanorods with a Polarization-Dependent Dark-Field Light Scattering Microscope.

Anisotropic nanomaterials, such as gold nanorods (AuNRs), could be employed as an orientation platform due to their polarization-dependent surface plasmon resonance. However, a variety of factors would affect the dark-field light scattering imaging of anisotropic nanomaterials, resulting in an unstable signal, which is not advantageous to its further application. In this work, the localized surface plasmon resonance properties of a few AuNRs at different angles were excited by polarization with a conventional dark-field microscope, in which it was found that the ratio of AuNRs' light scattering intensity at different polarization angles (I) to that without a polarizer (I0) reflected the orientation information of AuNRs. Furthermore, the light scattering signal ratio between the parallel polarization (Ip) and that without a polarizer (I0) was closely related with the aspect ratio of AuNRs, which could not be affected by external conditions. To verify this concept, a highly sensitive and selective assay of the alkaline phosphatase activity in human serum was successfully developed based on the chemical etching of AuNRs, resulting in a lower aspect ratio and a lesser Ip/I0. This result holds great promise for polarization-dependent colorimetric nanomaterials and single-particle tracers in living cells.

Two-Dimensional Analysis Method for Highly Sensitive Detection of Dual MicroRNAs in Breast Cancer Cells.

Multiple biomarker detection is crucial for early clinical diagnosis, and it is significant to achieve the simultaneous detection of multiple biomarkers with the same nanomaterial. In this work, the hairpin DNA strands were selectively modified on the surface of gold nanorods (AuNRs) to construct two kinds of nanoprobes by rational design. When in the presence of dual microRNAs, AuNRs were assembled to form end-to-end (ETE) and side-by-side (SBS) dimers. Compared with a single AuNR, the dark-field scattering intensity and red color percentage variation of dimers were extremely distinguished, which could be developed for dual microRNA detection by combining the red color percentage and scattering intensity with the data processing method of principal component analysis to construct a two-dimensional analysis method. Especially, the fraction of AuNR dimers presented a linear relationship with the amount of microRNAs. Based on this, microRNA-21 and microRNA Let-7a in breast cancer cells were detected with the detection limits of 1.72 and 0.53 fM, respectively. This method not only achieved the sensitive detection of dual microRNAs in human serum but also realized the high-resolution intracellular imaging, which developed a new way for the oriented assembly of nanomaterials and biological detection in living cells.

Antibody-Mediated Nanodrug of Proteasome Inhibitor Carfilzomib Boosts the Treatment of Multiple Myeloma.

Multiple myeloma (MM) is the second most common hematological malignancy. For relapsed and refractory MM, a proteasome inhibitor, carfilzomib (CFZ), has become one of the few clinical options. CFZ suffers, nevertheless, metabolic instability and poor bioavailability and may induce severe cardiovascular and renal adverse events. Here, we report that daratumumab (Dar)-decorated polypeptide micelles (Dar-PMs) mediate the targeted delivery of CFZ to CD38-positive MM, effectively boosting its anti-MM efficacy. CFZ-loaded Dar-PMs (Dar-PMs-CFZ) exhibited an average diameter of ca. 80 nm and Dar density-dependent cell endocytosis and anti-MM activity, in which over 6-fold greater inhibitory effect to LP-1 and MM.1S MM cells than nontargeted PMs-CFZ control was achieved at a Dar density of 3.2 (Dar3.2-PMs-CFZ). Interestingly, Dar3.2-PMs-CFZ markedly enhanced the growth inhibition of orthotopic LP-1 MM in mice and significantly extended the median survival time compared with PMs-CFZ and free CFZ (95 days vs 60 and 54 days, respectively). In line with its high MM targetability and anti-MM efficacy, Dar3.2-PMs-CFZ revealed little toxic effects and effectively prevented osteolytic lesions. The antibody-targeted nanodelivery of a proteasome inhibitor appears to be an appealing strategy to treat multiple myeloma.

Simple and rapid detection of tyrosinase activity with the adjustable light scattering properties of CoOOH nanoflakes.

Tyrosinase (TYR), as an important biological enzyme, has been widely used in synthetic biology, medical hairdressing, environmental detection, biological sensors, and other fields. In clinical practice, tyrosinase activity is an important indicator for detecting melanoma. Therefore, the detection of tyrosinase activity is of great importance. Based on the polyphenol oxidase activity of tyrosinase, a simple and rapid detection method was proposed based on the adjustable light scattering properties of cobalt hydroxyl oxide nanoflakes (CoOOH NFs). It was found that the amount and size of CoOOH NFs decreased due to the redox reaction mediated by catechol (CC), resulting in a lower light scattering signal of CoOOH NFs. However, in the presence of tyrosinase, catechol was oxidized to a quinone structure, resulting in the reduced decomposition of CoOOH NFs and recovered light scattering signal, which was developed for the quantitative detection of tyrosinase activity. It was found that in the range of 10-400 U/L, the light scattering intensity was correlated linearly with tyrosinase activity, and the limit of detection was 6.71 U/L (3σ/k). To verify the feasibility of the proposed method in clinical samples, the spiked recovery experiments were carried out with human serum samples, which showed recovery rates between 93.0% and 104.6%, suggesting the high accuracy. The proposed assay provides a simple and rapid method for detection of a natural enzyme based on the adjustable light scattering properties of CoOOH nanoflakes, which lays the foundation for the development of various enzyme sensing applications in the future.

New Jersey maternal mortality dashboard: an interactive social-determinants-of-health tool.

OBJECTIVES: The United States maternal mortality (MM) rate is the highest amid developed/industrialized nations, and New Jersey's rate is among the highest. Healthcare professionals, public health officials, and policy makers are working to understand drivers of MM. An interactive data visualization tool for MM and health-related information (New Jersey Maternal Mortality Dashboard [NJMMD]) was recently developed. METHODS: NJMMD is an open-source application that uses data from publicly available state/federal government sources to provide a cross-sectional, high-level depiction of potential relationships between MM and demographic, social, and public health factors. RESULTS: MM rates or ratios (maternal deaths/1,000 women aged 15-49 years or 100,000 live births, respectively) are available by year (2005-2017), age (5-year [15-49] periods), and race/ethnicity (non-Hispanic White, Black, or Asian; Hispanic; or other), and by contextual social determinants of health (percent insured; percent covered by Medicaid; difference in nulliparous, term, singleton, vertex Cesarian birth rate from New Jersey goal; number of obstetrician/gynecologists or midwives per capita; and poverty rate). Bar graphs also can be produced with these variables. CONCLUSIONS: NJMMD is the first publicly available, interactive, state-focused MM tool that takes into account the intersection of social and demographic determinants of health, which play important roles in health outcomes. Trends and patterns in variables associated with MM and health can be identified for New Jersey and each of its 11 counties, and inform areas of focus for further analysis. Outputs may enable researchers, policy makers, and others to develop appropriate interventions and be better positioned to set benchmarks, allocate resources, and evaluate outcomes.

The Role and Mechanism of Hyperoside against Depression-like Behavior in Mice via the NLRP1 Inflammasome.

BACKGROUND AND OBJECTIVES: Hypericum perforatum (HP) is widely used for depressive therapy. Nevertheless, the antidepressant effect and potential mechanism of hyperoside (Hyp), the main active component of HP, have not been determined. MATERIALS AND METHODS: We performed ultra-performance liquid chromatography-quadrupole-time-of-flight-tandem mass spectrometry (UPLC-Q-TOF-MS/MS) technology to analyze the components in HP. Using data mining and network pharmacology methods, combined with Cytoscape v3.7.1 and other software, the active components, drug-disease targets, and key pathways of HP in the treatment of depression were evaluated. Finally, the antidepressant effects of Hyp and the mechanism involved were verified in chronic-stress-induced mice. RESULTS: We identified 12 compounds from HP. Hyp, isoquercetin, and quercetin are the main active components of HP. The Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), the Analysis Platform, DrugBank, and other databases were analyzed using data mining, and the results show that the active components of HP and depression are linked to targets such as TNF-, IL-2, TLR4, and so on. A potential signaling pathway that was most relevant to the antidepressant effects of Hyp is the C-type lectin receptor signaling pathway. Furthermore, the antidepressant effects of Hyp were examined, and it is verified for the first time that Hyp significantly alleviated depressive-like behaviors in chronic-stress-induced mice, which may be mediated by inhibiting the NLRP1 inflammasome through the CXCL1/CXCR2/BDNF signaling pathway. CONCLUSION: Hyp is one of the main active components of HP, and Hyp has antidepressant effects through the NLRP1 inflammasome, which may be connected with the CXCL1/CXCR2/BDNF signaling pathway.

[Bifidobacterium bifidum TMC3115 Promotes Early Life Intestinal Microbiota Building to Alleviate Symptoms of Inflammatory Bowel Disease].

Objective: To investigate the effects of using Bifidobacterium bifidum TMC3115 in early life on intestinal microbiota and immune functions and the long-term impact on inflammatory bowel disease. Methods: Fourteen pregnant BALB/c mice were purchased and 84 newborn BALB/c mice were subsequently obtained. Then, the newborn mice were randomly assigned to a normal saline (NS) group and a TMC3115 group, given via oral gavage normal saline and TMC3115, respectively, at a daily volume of 0.2 mL for each mouse. About 42 mice were assigned to each group. The gavage was stopped after 3 weeks. At this point, half of the mice in each group were sacrificed, and then the remaining mice in each group were randomly divided into NS-water group, NS-DSS group, TMC3115-water group, and TMC3115-DSS group, with about 10 mice in each group. The mice were given regular feed until the end of week 6 when they were given 3% dextran sulphate sodium (DSS) ad libitum for 4 days to establish the enteritis model, while the non-modeling groups were given pure water ad libitum. The experiment ended after 6 weeks and 4 days. The weekly body mass changes of the mice were documented. The intestinal tissue at the end of the experiment and the fecal samples, spleen and serum of the mice at 3 weeks and at the end of the experiment were collected to determine the pathology scores of colonic inflammation, the composition of fecal gut microbiota, spleen organ index and the mass concentration of serum cytokines. Results: 1) At the end of the experiment, the inflammatory pathology score was significantly lower in the TMC3115-DSS group compared with that of the Saline-DSS group ( P<0.05), with less disruption of colonic crypt structures and other structures, less inflammatory infiltration, and more intact epithelial structures. 2) At 3 weeks, in comparison with those of the NS group, the relative abundance of Bifidobacteriumwas significantly higher in the feces of the TMC3115 ( P<0.05), the relative abundance of both Enterococcusand Staphylococcuswas lower ( P<0.05), the splenic organ index was significantly higher ( P<0.05), and interleukin (IL)-10 was significantly decreased ( P<0.05), while there was no significant change in IL-6 or TNF-α ( P>0.05). At the end of the experiment, in comparison with those of the NS-DSS group that undergone DSS induction, the TMC3115-DSS group had reduced relative abundance of Staphylococcus, Staphylococcus tumefaciens and Escherichia/ Shigellain the feces ( P<0.05), while the splenic organ index was significantly higher ( P<0.05), and there were no significant changes in IL-6 or TNF-α ( P>0.05). Conclusion: The use of TMC3115 in early life promotes the construction of gut microbiota in neonatal mice, thereby producing a long-term effect that alleviates colitis in mice, but the mechanisms involved are still not fully understood.

Molecular Identification of Cryptosporidium spp., Enterocytozoon bieneusi, and Giardia duodenalis in Captive Pet Birds in Henan Province, Central China.

Cryptosporidium spp., Enterocytozoon bieneusi, and Giardia duodenalis are common enteric pathogens that are capable of infecting humans and animals. Total of 1,005 fecal samples from captive pet birds were collected from seven locations in Henan Province, China. The results demonstrated that 9.9% (99/1,005) of the captive birds were infected with one of these three pathogens. Enterocytozoon bieneusi was the most prevalent species among the birds (45/1,005, 4.5%) followed by G. duodenalis (33/1,005, 3.3%) and Cryptosporidium spp. (21/1,005, 2.1%). Five Cryptosporidium species were identified, namely, C. baileyi (10), C. galli (5), C. meleagridis (4), C. andersoni (1), and C. parvum (1). Two known E. bieneusi genotypes were identified: Peru 6 (44) was identified in pigeons (34) and European turtle doves (10); whereas, the genotype PtEb I (1) was only identified in a pigeon. Only G. duodenalis assemblage E (33) was identified in some pet birds. To the best of our knowledge, this study is the first to undertake the molecular identification of G. duodenalis in birds in China. The identification of potentially zoonotic species/genotypes of the pathogens suggests that exposure to the excreta of these birds, either directly or via food and water, may pose a threat to human health.

Interaction between antibiotic use and MS4A2 gene polymorphism on childhood eczema: a prospective birth cohort study.

BACKGROUND: Eczema is usually the first allergic manifestation to appear in life attributed to gene-environment interactions. IL13, IL4, MS4A2 and ILR4A are four key inflammatory genes associated with atopy. This study aimed to explore gene-environment interactions on eczema in early life among the above four genes and environmental factors in Chinese Han children. METHODS: Five hundred ninety-seven children from a birth cohort who completed two-year follow-up were enrolled and their cord blood was collected. Subjects were genotyped for six polymorphisms in the aforementioned four genes. The children were followed at 6, 12 and 24 months, with epidemiologic information and medical history of eczema collected by questionnaire and eczema assessed by dermatologists. RESULTS: Among the 597 children, 168 were diagnosed with eczema and the others were not after 2 years of follow-up. MS4A2 rs569108 GG genotype (P = 1.68E-02, odds ratio (OR) = 4.66) and antibiotic use (P = 3.75E-4, OR = 2.02) were found independently associated with development of childhood eczema. Children with both antibiotic use and MS4A2 rs569108 GG genotype were more likely to develop eczema than those with only antibiotic use or GG homozygote (OR = 6.24 VS. 2.04 or 4.68). CONCLUSIONS: MS4A2 rs569108 polymorphism and antibiotic use were solely associated with eczema, and they interacted with each other to increase the risk of developing the disease in Chinese Han toddlers. Long-term follow-up along with functional and replication studies are still needed.

Size-dependent light scattering of CoOOH nanoflakes for convenient and sensitive detection of alkaline phosphatase in human serum.

As a natural enzyme, alkaline phosphatase (ALP) plays an essential role in clinicopathological examinations and biomedical research, and is capable of hydrolyzing the phosphate group of l-ascorbic acid-2-phosphate (AAP) to yield l-ascorbic acid (L-AA). L-AA reduced cobalt oxyhydroxide (CoOOH) nanoflakes to Co2+ , leading to a smaller size and weaker light scattering, which could be monitored by electron microscopic images and optical spectra. The indirect detection of ALP was achieved by the reduced light scattering signal of CoOOH nanoflakes. Under optimal conditions, the decrease in scattering intensity was proportional to the ALP concentration over the range 0.1-160 U/L and the detection limit was 0.034 U/L (3σ/k). Compared with other assays, this proposed light scattering method was more convenient and economic for ALP sensing. The method was successfully applied to ALP analysis in human serum samples, and was similar to the results obtained by commercial kits.

Bottom-metal-printed thermo-optic waveguide switches based on low-loss fluorinated polycarbonate materials.

In this work, thermo-optic (TO) waveguide switches are designed and fabricated based on the bottom-metal-printed technique. Low-loss fluorinated polycarbonate (AF-Z-PC MA) and polymethyl methacrylate (PMMA) are used as core and cladding materials, respectively. The thermal stability and optical absorption characteristics of AF-Z-PC MA are analyzed. The optical and thermal field distributions of the TO switch are simulated. The insertion loss and extinction ratio of the device are found to be 4.5 dB and 19.8 dB, respectively, at a wavelength of 1550 nm. The on-off time of the switching chip is 80 µs. The electrical power consumption is approximately 8.8 mW. The proposed low-loss fluorinated polymer TO waveguide switch realized by bottom-metal-printed fabrication technology is suitable for large-scale integrated photonic circuit systems.

Systemic Delivery of NAC-1 siRNA by Neuropilin-Targeted Polymersomes Sensitizes Antiangiogenic Therapy of Metastatic Triple-Negative Breast Cancer.

Antiangiogenic therapy with bevacizumab while being interesting for metastatic triple-negative breast cancer (mTNBC) is restrained by tumor hypoxia elevation and cancer stem cell enrichment. Here, we find that neuropilin-1 (NRP-1)-targeted delivery of nucleus accumbens-associated protein-1 (NAC-1) siRNA mediated by tLyP-1 peptide-functionalized chimaeric polymersomes (tLyP-1-Ps) effectively sensitizes antiangiogenic therapy of mTNBC in vivo. tLyP-1-Ps showed good encapsulation (up to 14.4 wt. %) of siNAC-1, giving robust tLyP-1-Ps-siNAC-1 nanoformulation with a defined size of 48.5 nm (PDI = 0.13) and a surface charge of -9.2 mV, and mediated efficient cytoplasmic transportation of siNAC-1 in MDA-MB-231 TNBC cells, resulting in significant silencing of NAC-1 mRNA and the corresponding oncoprotein. Transwell invasion and wound healing assays revealed that tLyP-1-Ps-siNAC-1 potently inhibited MDA-MB-231 cell invasion and migration. Intriguingly, tLyP-1-Ps-siNAC-1 was shown to markedly improve the bevacizumab therapy of mTNBC, significantly curbing lung metastasis and prolonging the survival time of the MDA-MB-231 metastatic model. The combination of targeted NAC-1 gene silencing and antiangiogenic therapy appears to be an innovative treatment for mTNBC.

A6 Peptide-Tagged Core-Disulfide-Cross-Linked Micelles for Targeted Delivery of Proteasome Inhibitor Carfilzomib to Multiple Myeloma In Vivo.

Carfilzomib (CFZ) is a second-generation proteasome inhibitor approved for treating relapsed/refractory multiple myeloma (MM). The clinical formulation utilizing sulfobutylether-ß-cyclodextrin to solubilize CFZ (Captisol, CFZ-CD) shows, however, short circulation time, lack of cell selectivity, and unmet antitumor efficacy. Here, we designed and prepared A6 peptide (sequence: KPSSPPEE)-tagged core-disulfide-cross-linked biodegradable micelles (A6-PMs) for targeted CFZ therapy of CD44-overexpressing LP-1 human MM in vivo. A6-PMs had a small size of about 40 nm and stable CFZ encapsulation. CFZ-loaded micelles (CFZ-A6-PMs) showed a glutathione-triggered drug release profile with negligible drug leakage under physiological conditions. CFZ-A6-PMs displayed good proteasome activity inhibition and more potent apoptotic activity than CFZ-CD and nontargeted CFZ-PMs toward LP-1 MM cells in vitro. The in vivo fluorescence images revealed that Cy5-labeled A6-PMs induced much higher tumor accumulation than the nontargeted Cy5-labeled PMs control. The systemic administration of CFZ-A6-PMs to subcutaneous LP-1 xenografts in mice brought about notably more potent tumor suppression, higher survival rate and lower systemic toxicities than clinically used CFZ-CD formulation. These A6-tagged core-disulfide-cross-linked micelles appear interesting for targeted delivery of proteasome inhibitors to CD44+ MM.

CD44-Targeted Multifunctional Nanomedicines Based on a Single-Component Hyaluronic Acid Conjugate with All-Natural Precursors: Construction and Treatment of Metastatic Breast Tumors in Vivo.

Metastasis is responsible for >90% of the deaths of breast cancer patients in the clinic. Here, we report on cross-linked multifunctional hyaluronic acid nanoparticles carrying docetaxel (DTX-CMHN) for enhanced suppression of highly metastatic 4T1 breast tumors in vivo. DTX-CMHN was formed from a single and all-natural hyaluronic acid-g-polytyrosine-lipoic acid conjugate (HA-g-PTyr-LA; HA, 20 kDa; PTyr, 2.2 kDa), and the size of DTX-CMHN increased from 69 to 78 to 96 nm as the increasing degree of substitution (DS) of PTyr increased from 4 to 11 to 15, respectively. Robust encapsulation of DTX was obtained when DS ≥ 11. DTX-CMHN while steady in a nonreducing environment was destabilized under 10 mM glutathione releasing ∼90% of the DTX within 24 h. It is noteworthy that DTX-CMHN exhibited better antitumor, antimigration, and anti-invasion activity in CD44-overexpressed 4T1-Luc breast cancer cells than free DTX. Interestingly, DTX-CMHN displayed a long elimination half-life of 5.75 h, in contrast to half-lives of 2.11 and 0.75 h for its non-cross-linked counterpart (DTX-MHN) and free DTX, respectively. In vivo therapeutic studies showed significantly better inhibition of primary 4T1-Luc tumor growth and lung metastasis and lower toxicity of DTX-CMHN compared with that of free DTX. These multifunctional nanoformulations based on a single and all-natural hyaluronic acid conjugate emerge as a potential nanoplatform for targeted treatment of CD44-positive metastatic tumors.

Genetic Susceptibility and Protein Expression of Extracellular Matrix Turnover-Related Genes in Oral Submucous Fibrosis.

Betel quid (BQ) chewing increased the risk of oral cancer and oral submucous fibrosis (OSMF), an oral premalignant disorder (OPMD) with malignant transformation potential. BQ components such as areca nut (AN), trauma by coarse AN fiber, catechin, copper, alkaloids, stimulated reactive oxygen species (ROS), inflammation and cytotoxicity are suggested to be the contributing factors. They may induce tissue inflammation, proliferation of fibroblasts and collagen deposition, myofibroblast differentiation and contraction, collagen cross-links and inhibit collagen phagocytosis, finally leading to the development of OSMF and oral cancer. These events are mediated by BQ components-induced changes of extracellular matrix (ECM) turnover via regulation of TGF-ß1, plasminogen activator inhibitor-1 (PAI-1), cystatin, lysyl oxidase (LOX) and tissue inhibitors of metalloproteinases (TIMPs) and metalloproteinases (MMPs). Genetic susceptibility is also involved in these disease processes. Further understanding the molecular mechanisms of BQ-induced OSMF and oral cancer can be helpful for future disease prevention and treatment.