Titanium dioxide (TiO2) has been the most intensively investigated binary transition metal oxide in the past four decades as indicated by Figure S1. Furthermore, the annual number of papers published on TiO2 has seen a continuous increase, particularly since the beginning of this century (Figure S2). This is understandable when one considers the wide range of applications of TiO2 from the conventional areas (i.e., pigment, cosmetic, toothpaste, and paint) to the later developed functional areas such as photoelectrochemical cell,(1-3) dye-sensitized solar cells (DSSCs),(4-11) photocatalysis,(12-24) catalysis,(25-31) photovoltaic cell,(32-34) lithium ion batteries,(35-41) sensors,(42-46) electron field emission,(47-51) microwave absorbing material, biomimetic growth, and biomedical treatments.(52-57) Nearly all these functional applications of TiO2 fall in the scope of energy, environment, and health, which are definitely the three most important and challenging themes facing the Human race that need to be addressed in this century. Besides the apparent merits including nontoxicity, elemental abundance, good chemical stability, and easy synthesis, TiO2 has attracted strong research interest worldwide due to its physicochemical properties for realizing various functions.(15, 58, 59) Especially, very encouraging progresses in photocatalysis and DSSCs with the involvement of TiO2 have greatly stimulated the rapid development of TiO2 crystals with controllable phase, size, shape, defect, and heteroatom.(58, 60-68)

Titanium dioxide crystals with tailored facets

One-dimensional TiO2 nanostructured surface heterostructures (1D TiO2NSHs) have been comprehensively studied during the past two decades because of the possible practical applications in various fields, including photocatalysis, dye-sensitized solar cells, sensors, lithium batteries, biomedicine, catalysis, and supercapacitors. Combining extensive advancements in materials science and nanotechnology, a 1D TiO2NSH material with well-controlled size, morphology, and composition has been designed and synthesized. More importantly, its superior properties, including a high aspect ratio structure, chemical stability, large specific surface area, excellent electronic or ionic charge transfer, and a specific interface effect, have attracted a great deal of interest in improving current performance and exploring new applications. In this tutorial review, we introduce the characteristics of 1D TiO2 nanostructures, the design principles for the fabrication of 1D TiO2NSHs, and we also summarize the recent progress in developing synthesis methods and applications of 1D TiO2NSHs in different fields. The relationship between the secondary phase and the 1D TiO2 nanostructure and between the performance in applications and the excellent physical properties of 1D TiO2NSHs are also discussed.

Recent progress in design, synthesis, and applications of one-dimensional TiO2 nanostructured surface heterostructures: a review

Two-dimensional (2D) nanomaterials are ultrathin nanomaterials with a high degree of anisotropy and chemical functionality. Research on 2D nanomaterials is still in its infancy, with the majority of research focusing on elucidating unique material characteristics and few reports focusing on biomedical applications of 2D nanomaterials. Nevertheless, recent rapid advances in 2D nanomaterials have raised important and exciting questions about their interactions with biological moieties. 2D nanoparticles such as carbon-based 2D materials, silicate clays, transition metal dichalcogenides (TMDs), and transition metal oxides (TMOs) provide enhanced physical, chemical, and biological functionality owing to their uniform shapes, high surface-to-volume ratios, and surface charge. Here, we focus on state-of-the-art biomedical applications of 2D nanomaterials as well as recent developments that are shaping this emerging field. Specifically, we describe the unique characteristics that make 2D nanoparticles so valuable, as well as the biocompatibility framework that has been investigated so far. Finally, to both capture the growing trend of 2D nanomaterials for biomedical applications and to identify promising new research directions, we provide a critical evaluation of potential applications of recently developed 2D nanomaterials.

Two‐Dimensional Nanomaterials for Biomedical Applications: Emerging Trends and Future Prospects

Sol-gel based materials for biomedical applications

The fast development of photoactivation for cancer treatment provides an efficient photo-therapeutic strategy for cancer treatment, but traditional photodynamic or photothermal therapy suffers from the critical issue of low in vivo penetration depth of tissues. As a non-invasive therapeutic modality, sonodynamic therapy (SDT) can break the depth barrier of photoactivation because ultrasound has an intrinsically high tissue-penetration performance. Micro/nanoparticles can efficiently augment the SDT efficiency based on nanobiotechnology. The state-of-art of the representative achievements on micro/nanoparticle-enhanced SDT is summarized, and specific functions of micro/nanoparticles for SDT are discussed, from the different viewpoints of ultrasound medicine, material science and nanobiotechnology. Emphasis is put on the relationship of structure/composition-SDT performance of micro/nanoparticle-based sonosensitizers. Three types of micro/nanoparticle-augmented SDT are discussed, including organic and inorganic sonosensitizers and micro/nanoparticle-based but sonosensitizer-free strategies to enhance the SDT outcome. SDT-based synergistic cancer therapy augmented by micro/nanoparticles and their biosafety are also included. Some urgent critical issues and potential developments of micro/nanoparticle-augmented SDT for efficient cancer treatment are addressed. It is highly expected that micro/nanoparticle-augmented SDT will be quickly developed as a new and efficient therapeutic modality which will find practical applications in cancer treatment. At the same time, fundamental disciplines regarding materials science, chemistry, medicine and nanotechnology will be advanced.

Micro/Nanoparticle-Augmented Sonodynamic Therapy (SDT): Breaking the Depth Shallow of Photoactivation.

As one of the most common chemical materials, titanium dioxide (TiO2) has been prepared and widely used for many years. Among all the applications, the biomedical applications of TiO2 have motivated strong interest and intensive experimental and theoretical studies, owing to its unique photocatalytic properties, excellent biocompatibility, high chemical stability, and low toxicity. Advances in nanoscale science suggest that some of the current problems of life science could be resolved or greatly improved through applying TiO2. This paper presents a critical review of recent advances in the biomedical applications of TiO2, which includes the photodynamic therapy for cancer treatment, drug delivery systems, cell imaging, biosensors for biological assay, and genetic engineering. The characterizations and applications of TiO2 nanoparticles, as well as nanocomposites and nanosystems of TiO2, which have been prepared by different modifications to improve the function of TiO2, are also offered in this review. Additionally, some perspectives on the challenges and new directions for future research in this emerging frontier are discussed.

Recent progress in biomedical applications of titanium dioxide

Physical exercise, a common non-drug intervention, is an important strategy in cancer treatment, including hepatocellular carcinoma (HCC). However, the mechanism remains largely unknown. Due to the importance of hypoxia and cancer stemness in the development of HCC, the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer stemness.A physical exercise intervention of swimming (30 min/d, 5 d/week, for 4 weeks) was administered to BALB/c nude mice bearing subcutaneous human HCC tumor. The anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring, hematoxylin and eosin (HE) staining, and immunohistochemistry (IHC) detection of proliferating cell nuclear antigen (PCNA) and Ki67. The expression of stemness transcription factors, including Nanog homeobox (NANOG), octamer-binding transcription factor 4 (OCT-4), v-Myc avian myelocytomatosis viral oncogene homolog (C-MYC) and hypoxia-inducible factor-1α (HIF-1α), was detected using real-time reverse transcription polymerase chain reaction. A hypoxia probe was used to explore the intratumoral hypoxia status. Western blot was used to detect the expression of HIF-1α and proteins related to protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway. The IHC analysis of platelet endothelial cell adhesion molecule-1 (CD31), and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood perfusion. SMMC-7721 cells were treated with nude mice serum. The inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription factors. The hypoxia status was inferred by measuring the protein and mRNA levels of HIF-1α. Further, the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was detected.Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC tumor. HE staining and IHC results showed a lower necrotic area ratio as well as fewer PCNA or Ki67 positive cells in mice receiving the swimming intervention. Swimming potently alleviated the intratumoral hypoxia, attenuated the cancer stemness, and inhibited the Akt/GSK-3β/β-catenin signaling pathway. Additionally, the desmin+/CD31+ ratio, rather than the number of CD31+ vessels, was significantly increased in swimming-treated mice. In vitro experiments showed that treating cells with the serum from the swimming intervention mice significantly reduced the formation of SMMC-7721 cell suspension sphere, as well as the mRNA expression level of stemness transcription factors. Consistent with the in vivo results, HIF-1α and Akt/GSK-3β/β-catenin signaling pathway were also inhibited in cells treated with serum from swimming group.Swimming alleviated hypoxia and attenuated cancer stemness in HCC, through suppression of the Akt/GSK-3β/β-catenin signaling pathway. The alleviation of intratumoral hypoxia was related to the increase in blood perfusion in the tumor. Please cite this article as: Xiao CL, Zhong ZP, Lü C, Guo BJ, Chen JJ, Zhao T, Yin ZF, Li B. Physical exercise suppresses hepatocellular carcinoma progression by alleviating hypoxia and attenuating cancer stemness through the Akt/GSK-3β/β-catenin pathway. J Integr Med. 2023; 21(2): 184-193. 

Physical exercise suppresses hepatocellular carcinoma progression by alleviating hypoxia and attenuating cancer stemness through the Akt/GSK-3β/β-catenin pathway.

Objective Military training-induced fatigue (MIF) often results into non-combat attrition. However, standard evaluation of MIF is unavailable. This study aimed to provide credible suggestions about MIF-evaluation. Methods A 3-round Delphi study was performed. The authority of the experts was assessed by the authority coefficient (Aa). In round 1, categories of indicators were collected via anonymous survey of experts, then potential indicators were selected via literature search. In round 2, experts should evaluate the clinical implication, practical value, and importance of each potential indicators, or recommend new indicators based on feedback of round 1. Indicators with recommendation proportions ≥ 70% and new recommended indicators would be included in round 3 to be rated on a 5-point Likert scale. “Consensus in” was achieved when coefficient of concordance (Kendall's W) of a round was between 0.2 and 0.5 and the coefficient of variation (CV) of each aspect for an indicator was < 0.5. If round 3 could not achieve “consensus in,” more rounds would be conducted iteratively based on round 3. Indicators included in the recommendation set were ultimately classified into grade I (highly recommended) or grade II (recommended) according to the mean score and CV of the aspects. Results Twenty-three experts participated with credible authority coefficient (mean Aa = 0.733). “Consensus in” was achieved in round 3 (Kendall's W = 0.435, p < 0.001; all CV < 0.5). Round 1 recommended 10 categories with 73 indicators identified from 2,971 articles. After 3-round consultation, consensus was reached on 28 indicators focusing on the cardiovascular system (n = 4), oxygen transport system (n = 5), energy metabolism/metabolite level (n = 6), muscle/tissue damage level (n = 3), neurological function (n = 2), neuropsychological/psychological function (n = 3), endocrine function (n = 3), and exercise capacity (n = 2). Among these, 11 indicators were recommended as grade I: basic heart rate, heart-rate recovery time, heart rate variability, hemoglobin, blood lactic acid, urine protein, creatine kinase, reaction time, Borg Rating of Perceived Exertion Scale, testosterone/cortisol, and vertical jump height. Conclusion This study developed a reliable foundation for the comprehensive evaluation of MIF among soldiers.

Comprehensive evaluation of military training-induced fatigue among soldiers in China: A Delphi consensus study

Jiedu Recipe (JR), a Chinese herbal remedy, has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma (HCC). This work investigated the mechanism of JR in HCC treatment. The chemical constituents of JR were detected using liquid chromatography-mass spectrometry. The potential anti-HCC mechanism of JR was screened using network pharmacology and messenger ribonucleic acid (mRNA) microarray chip assay, followed by experimental validation in human HCC cells (SMMC-7721 and Huh7) in vitro and a nude mouse subcutaneous transplantation model of HCC in vivo. HCC cell characteristics of proliferation, migration and invasion under hypoxic setting were investigated using 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, thiazolyl blue tetrazolium bromide, wound healing and Transwell assays, respectively. Image-iT™ Hypoxia Reagent was added to reveal hypoxic conditions. Stem cell sphere formation assay was used to detect the stemness. Epithelial-mesenchymal transition (EMT) markers like E-cadherin, vimentin and α-smooth muscle actin, and pluripotent transcription factors including nanog homeobox, octamer-binding transcription factor 4, and sex-determining region Y box protein 2 were analyzed using Western blotting and real-time polymerase chain reaction. Western blot was performed to ascertain the anti-HCC effect of JR under hypoxia involving the Wnt/β-catenin pathway. According to network pharmacology and mRNA microarray chip analysis, JR may potentially act on hypoxia and inhibit the Wnt/β-catenin pathway. In vitro and in vivo experiments showed that JR significantly decreased hypoxia, and suppressed HCC cell features of proliferation, migration and invasion; furthermore, the hypoxia-induced increases in EMT and stemness marker expression in HCC cells were inhibited by JR. Results based on the co-administration of JR and an agonist (LiCl) or inhibitor (IWR-1-endo) verified that JR suppressed hypoxia-induced cancer stem-like properties in HCC by blocking the Wnt/β-catenin pathway. JR exerts potent anti-HCC effects by inhibiting cancer stemness via abating the Wnt/β-catenin pathway under hypoxic conditions. Please cite this article as: Guo BJ, Ruan Y, Wang YJ, Xiao CL, Zhong ZP, Cheng BB, Du J, Li B, Gu W, Yin ZF. Jiedu Recipe, a compound Chinese herbal medicine, inhibits cancer stemness in hepatocellular carcinoma via Wnt/β-catenin pathway under hypoxia. J Integr Med. 2023; Epub ahead of print. 

Zi Fei Yin

Papers

Recent progress in biomedical applications of titanium dioxide

Physical exercise suppresses hepatocellular carcinoma progression by alleviating hypoxia and attenuating cancer stemness through the Akt/GSK-3β/β-catenin pathway.

Comprehensive evaluation of military training-induced fatigue among soldiers in China: A Delphi consensus study

Jiedu Recipe, a compound Chinese herbal medicine, inhibits cancer stemness in hepatocellular carcinoma via Wnt/β-catenin pathway under hypoxia.