Anti-tumor activity of niclosamide-mediated oxidative stress against acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a heterogeneous clonal disease originated from B- or T-cell lymphoid precursor cells. ALL is often refractory or relapses after treatment. Novel treatments are anxiously needed in order to achieve a better response and prolonged overall survival in ALL patients. In the present study, we aimed at examining the anti-tumor effect of niclosamide on ALL. We investigated the effects of niclosamide on the proliferation and apoptosis in vitro, the growth of ALL cells in xenografted NCG mice. The results showed that niclosamide treatment potently inhibited the growth of ALL cells and induced apoptosis via elevating the levels of reactive oxygen species (ROS) and activating TP53. These findings suggest that niclosamide may be a promisingly potential agent for ALL therapy.

Supramolecular Chiral Binding Affinity-Achieved Efficient Synergistic Cancer Therapy.

Supramolecular chirality-mediated selective interaction among native assemblies is essential for precise disease diagnosis and treatment. Herein, to fully understand the supramolecular chiral binding affinity-achieved therapeutic efficiency, supramolecular chiral nanoparticles (WP5⊃D/L-Arg+DOX+ICG) with the chirality transfer from chiral arginine (D/L-Arg) to water-soluble pillar[5]arene (WP5) are developed through non-covalent interactions, in which an anticancer drug (DOX, doxorubicin hydrochloride) and a photothermal agent (ICG, indocyanine green) are successfully loaded. Interestingly, the WP5⊃D-Arg nanoparticles show 107 folds stronger binding capability toward phospholipid-composed liposomes compared with WP5⊃L-Arg. The enantioselective interaction further triggers the supramolecular chirality-specific drug accumulation in cancer cells. As a consequence, WP5⊃D-Arg+DOX+ICG exhibits extremely enhanced chemo-photothermal synergistic therapeutic efficacy (tumor inhibition rate of 99.4%) than that of WP5⊃L-Arg+DOX+ICG (tumor inhibition rate of 56.4%) under the same condition. This work reveals the breakthrough that supramolecular chiral assemblies can induce surprisingly large difference in cancer therapy, providing strong support for the significance of supramolecular chirality in bio-application.

Chiral cysteine-copper ion-based assemblies for improved phototherapy.

Phototherapy, encompassing photothermal therapy and photodynamic therapy, is gaining attention as an appealing cancer treatment modality. To enhance its clinical implementation, a comprehensive exploration of the pivotal factors influencing phototherapy is warranted. In this study, the L/d-cysteine (Cys)-copper ion (Cu2+) chiral nanoparticles, through the assembly of L/d-Cys-Cu2+ coordination complexes, were constructed. We found that these nanoparticles interacted with chiral liposomes in a chirality-dependent manner, with d-Cys-Cu2+ nanoparticles exhibiting more than three times stronger binding affinity than l-Cys-Cu2+ nanoparticles. Furthermore, we demonstrated that the d-Cys-Cu2+ nanoparticles were more efficiently internalized by Hela cells in contrast with l-Cys-Cu2+. On this basis, indocyanine green (ICG), acting as both photothermal and photodynamic agent, was encapsulated into L/d-Cys-Cu2+ nanoparticles. Experimental results showed that the l-Cys-Cu2+-ICG and d-Cys-Cu2+-ICG nanoparticles displayed almost identical photothermal performance and singlet oxygen (1O2) generation capability in aqueous solution. However, upon laser irradiation, the d-Cys-Cu2+-ICG nanoparticles achieved enhanced anti-tumor effects compared to l-Cys-Cu2+-ICG due to their chirality-promoted higher cellular uptake efficiency. These findings highlight the crucial role of chirality in phototherapy and provide new perspectives for engineering cancer therapeutic agents.

Efficacy and safety of combined Chinese and Western medicine in the treatment of knee osteoarthritis: a prospective, multicenter cohort study.

Purpose: To conduct a real-world evaluation of the efficacy and safety of combined Chinese and Western medicine in treating knee osteoarthritis (KOA). Methods: A multicenter, prospective cohort study design was employed, enrolling 450 KOA patients (Kellgren-Lawrence score of 3 or less). The patients were divided into a Western medicine treatment group (WM group) and a combined Western and traditional Chinese medicine treatment group (WM-CM group). A 6-week treatment plan was administered, and follow-up visits occurred at 2 weeks, 4 weeks, and 6 weeks after initiating treatment. The primary outcome indicator was the total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score after 6 weeks of treatment. Secondary outcome indicators included WOMAC subscales for pain, stiffness, and joint function, visual analogue scale (VAS) score, physical component summary (PCS), mental component summary (MCS), and clinical effectiveness. The incidence of drug-related adverse events was used as a safety evaluation indicator. Results: A total of 419 patients were included in the final analysis: 98 in the WM group and 321 in the WM-CM group. The baseline characteristics of the two groups were comparable, except for the incidence of stiffness symptoms and stiffness scores. After 6 weeks of treatment, the WM-CM group exhibited superior results to the WM group in improving the total WOMAC score (24.71 ± 1.38 vs. 16.36 ± 0.62, p < 0.001). The WM-CM group also outperformed the WM group in WOMAC pain and joint function scores, VAS score, PCS score, MCS score, and clinical effectiveness (p < 0.05), which was consistent with the findings of the main evaluation index. Subgroup analysis indicated that the combined Chinese and Western medicine treatment showed more pronounced benefits in patients under 65 years of age and in those with a Kellgren-Lawrence (K-L) classification of 0-I. Throughout the study, no adverse effects were observed in either group. Conclusion: The combination of Chinese and Western medicine demonstrated superiority over Western medicine alone in relieving knee pain symptoms, improving knee function, and enhancing the quality of life for KOA patients with a K-L score of 3 or less. Moreover, the treatment exhibited a good safety profile. Clinical Trial Registration: (https://www.chictr.org.cn/), identifier (ChiCTR1900027175).

Discrimination and Quantification of Glutathione by Cu+-Based Nanozymes.

Glutathione (GSH) is the most abundant low-molecular-weight biological thiol in vivo and has been linked to several diseases. The accurate quantification of GSH is therefore crucial for disease diagnosis and monitoring. In this study, we prepared self-assembled Cu(I)-Cys (cysteine) nanozymes through a two-step procedure. The Cu(I)-Cys nanoparticles exhibited peroxidase-mimicking activity. Upon the addition of H2O2, they were able to oxidize 3,3,5,5-tetramethylbenzidine (TMB) into oxTMB, resulting in a measurable increase in UV-Vis absorption at 655 nm. However, in the presence of GSH, oxTMB was reduced back to TMB, leading to a decrease in UV-Vis absorption at 655 nm. By utilizing these changes in the absorption intensity, we achieved the sensitive detection of GSH with a detection limit of 2.13 µM. Moreover, taking advantage of the different peroxidase-mimicking activities of Cu(I)-Cys nanoparticles at various pH values, a sensor array with Cu(I)-Cys nanoparticles at pH 4 and pH 5 was constructed. The discrimination of GSH among Cys and ascorbic acid was achieved and the practicability of the sensor array in human serum was validated. This novel approach holds significant promise for the precise discrimination and quantification of GSH and its potential applications in disease diagnosis and therapeutics.

Ferroptosis induced by DCPS depletion diminishes hepatic metastasis in uveal melanoma.

Hepatic metastasis develops in ∼50% of uveal melanoma (UM) patients with scarcely effective treatment resulting in lethality. The underlying mechanism of liver metastasis remains elusive. Ferroptosis, a cell death form characterized by lipid peroxide, in cancer cells may decrease metastatic colonization. In the present study, we hypothesized that decapping scavenger enzymes (DCPS) impact ferroptosis by regulating mRNA decay during the metastatic colonization of UM cells to liver. We found that inhibition of DCPS by shRNA or RG3039 induced gene transcript alteration and ferroptosis through reducing the mRNA turnover of GLRX. Ferroptosis induced by DCPS inhibition eliminates cancer stem-like cells in UM. Inhibition of DCPS hampered the growth and proliferation both in vitro and in vivo. Furthermore, targeting DCPS diminished hepatic metastasis of UM cells. These findings may shed light on the understanding of DCPS-mediated pre-mRNA metabolic pathway in UM by which disseminated cells gain enhanced malignant features to promote hepatic metastasis, providing a rational target for metastatic colonization in UM.

A mechanistic review of chinese medicine polyphenols on bone formation and resorption.

Bone reconstruction includes a steady state system of bone formation and bone absorption. This tight coupling requires subtle coordination between osteoblasts and osteoclasts. If this balance is broken, it will lead to bone mass loss, bone density reduction, and bone metabolic diseases, such as osteoporosis. Polyphenols in Chinese herbal medicines are active ingredients in plant extracts with high safety and few side effects, and they can play a role in affecting bone formation and bone resorption. Some of these have estrogen-like effects and can better target bone health in postmenopausal women. The purpose of this review is to provide comprehensive information on the mechanisms underlying the relationship between traditional Chinese medicine polyphenols and bone formation or bone resorption.

Glycine Acts Through Estrogen Receptor Alpha to Mediate Estrogen Receptor Signaling, Stimulating Osteogenesis and Attenuating Adipogenesis in Ovariectomized Rats.

SCOPE: Glycine is commonly used as an additive in bone health supplements, the activity and differentiation of bone mesenchymal stem cells (BMSCs) are essential to bone metabolism, but the effect of Glycine on bone metabolism and specific mechanism are not fully clarified. METHODS AND RESULTS: The ovariectomized rats to evaluate the effects of Glycine on bone quality and quantity is constructed; then used an ER signaling inhibitor (ICI182780) and an ERα deficient BMSCs to explore how Glycine mediated ERα regulating the osteogenic and adipogenic differentiation of BMSCs; furthermore, an autodock analysis is used to assess the affinity of Glycine and ERα. The results show that Glycine significantly moderated bone mass and bone microstructure in ovariectomized rats; Glycine stimulates the osteogenic differentiation and attenuates the adipogenic differentiation in OVX rats and BMSCs, and these effects could be abolished by ICI 182780; further docking experiment showes that Glycine and ERα have a stronger affinity, and finally proves that the impact of Glycine could be blocked by ERα. CONCLUSION: Glycine stimulates osteogenesis and attenuates adipogenesis in ovariectomized rats, which process may involve in ERα mediated ER signaling pathway.

Fluorescent Sensing of Glutathione and Related Bio-Applications.

Glutathione (GSH), as the most abundant low-molecular-weight biological thiol, plays significant roles in vivo. Abnormal GSH levels have been demonstrated to be related to the dysfunction of specific physiological activities and certain kinds of diseases. Therefore, the sensing of GSH is emerging as a critical issue. Cancer, with typical high morbidity and mortality, remains one of the most serious diseases to threaten public health. As it is clear that much more concentrated GSH is present at tumor sites than at normal sites, the in vivo sensing of GSH offers an option for the early diagnosis of cancer. Moreover, by monitoring the amounts of GSH in specific microenvironments, effective diagnosis of ROS levels, neurological diseases, or even stroke has been developed as well. In this review, we focus on the fluorescent methodologies for GSH detection, since they can be conveniently applied in living systems. First, the fluorescent sensing methods are introduced. Then, the principles for fluorescent sensing of GSH are discussed. In addition, the GSH-sensing-related biological applications are reviewed. Finally, the future opportunities in in the areas of fluorescent GSH sensing-in particular, fluorescent GSH-sensing-prompted disease diagnosis-are addressed.

Transcriptional inhibition by CDK7/9 inhibitor SNS-032 abrogates oncogene addiction and reduces liver metastasis in uveal melanoma.

BACKGROUND: Life of patients with uveal melanoma (UM) is largely threatened by liver metastasis. Little is known about the drivers of liver organotropic metastasis in UM. The elevated activity of transcription of oncogenes is presumably to drive aspects of tumors. We hypothesized that inhibition of transcription by cyclin-dependent kinase 7/9 (CDK7/9) inhibitor SNS-032 diminished liver metastasis by abrogating the putative oncogenes in charge of colonization, stemness, cell motility of UM cells in host liver microenvironment. METHODS: The effects of SNS-032 on the expression of the relevant oncogenes were examined by qRT-PCR and Western blotting analysis. Proliferative activity, frequency of CSCs and liver metastasis were evaluated by using NOD-SCID mouse xenograft model and NOG mouse model, respectively. RESULTS: The results showed that CDK7/9 were highly expressed in UM cells, and SNS-032 significantly suppressed the cellular proliferation, induced apoptosis, and inhibited the outgrowth of xenografted UM cells and PDX tumors in NOD-SCID mice, repressed the cancer stem-like cell (CSC) properties through transcriptional inhibition of stemness-related protein Krüppel-like factor 4 (KLF4), inhibited the invasive phonotypes of UM cells through matrix metalloproteinase 9 (MMP9). Mechanistically, SNS-032 repressed the c-Myc-dependent transcription of RhoA gene, and thereby lowered the RhoA GTPase activity and actin polymerization, and subsequently inhibited cell motility and liver metastasis. CONCLUSIONS: In conclusion, we validate a set of transcription factors which confer metastatic traits (e.g., KLF4 for CSCs, c-Myc for cell motility) in UM cells. Our results identify SNS-032 as a promising therapeutic agent, and warrant a clinical trial in patients with metastatic UM.