Global burden of head and neck cancers from 1990 to 2019.

Head and neck cancer (HNC) exerts a significant healthcare burden worldwide. Insufficient data impedes a comprehensive understanding of its global impact. Through analysis of the 2019 Global Burden of Disease (GBD) database, our secondary investigation unveiled a surging global incidence of HNC, yet a decline in associated mortality and disability-adjusted life years (DALYs) owing to enhanced prognosis. Particularly noteworthy is the higher incidence of escalation among females compared to males. Effective resource allocation, meticulous control of risk factors, and tailored interventions are imperative to curtail mortality rates among young individuals afflicted with HNC in underprivileged regions, as well as in elderly individuals grappling with thyroid cancer.

Emerging roles of circular RNAs in regulating the hallmarks of thyroid cancer.

Thyroid cancer is a prevalent endocrine malignancy with increasing incidence in recent years. Although most thyroid cancers grow slowly, they can become refractory, leading to a high mortality rate once they exhibit recurrence, metastasis, resistance to radioiodine therapy, or a lack of differentiation. However, the mechanisms underlying these malignant characteristics remain unclear. Circular RNAs, a type of closed-loop non-coding RNAs, play multiple roles in cancer. Several studies have demonstrated that circular RNAs significantly influence the development of thyroid cancers. In this review, we summarize the circular RNAs identified in thyroid cancers over the past decade according to the hallmarks of cancer. We found that eight of the 14 hallmarks of thyroid cancers are regulated by circular RNAs, whereas the other six have not been reported to be correlated with circular RNAs. This review is expected to help us better understand the roles of circular RNAs in thyroid cancers and accelerate research on the mechanisms and cure strategies for thyroid cancers.

Association between multiple sleep dimensions in obstructive sleep apnea and the early sign of atherosclerosis.

STUDY OBJECTIVES: We investigated the associations between multiple sleep dimensions in obstructive sleep apnea (OSA) and carotid intima-media thickness (CIMT), an early sign of atherosclerosis, in subjects from the Shanghai Sleep Health Study (SSHS). METHODS: We performed secondary analysis of SSHS in a group of subjects performed the ultrasound evaluation from 2018 to 2022. Multiple sleep dimensions were measured using standard polysomnography. CIMT was measured from ultrasound images as an early sign of atherosclerosis. Multivariable-adjusted linear regression and logistic regression analyses were performed to detect associations between sleep traits in OSA and CIMT. RESULTS: CIMT was found to increase with increasing severity of OSA (P < 0.001). When adjusted for conventional risk factors, microarousal index (MAI) and hypoxic burden (HB) were positively correlated with CIMT while slow wave sleep (SWS) and mean apnea-hypopnea event duration (MAHD) showed negative correlation with CIMT (all P < 0.01). In binary logistic regression analysis, participants with high MAI, less SWS, higher HB and shorter MAHD showed a higher prevalence of thick CIMT with no evidence of interaction by age, sex, or body mass index (P-interaction > 0.05). CONCLUSIONS: Subjects with more severe sleep fragmentation, more severe hypoxemia and increased arousability were more likely to have increased CIMT after adjusting for potential confounders. It is important to evaluate novel indices of sleep fragmentation, hypoxemia and arousability in OSA for early detection and prevention of cardiovascular disease, including stroke. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry; URL: http://www.chictr.org.cn/showproj.aspx?proj=43057; No. ChiCTR1900025714.

Vicious Cycle-Breaking Lipid Nanoparticles Remodeling Multicellular Crosstalk to Reverse Liver Fibrosis.

During liver fibrogenesis, the reciprocal crosstalk among capillarized liver sinusoidal endothelial cells (LSECs), activated hepatic stellate cells (HSCs), and dysfunctional hepatocytes constructs a self-amplifying vicious cycle, greatly exacerbating the disease condition and weakening therapeutic effect. Limited by the malignant cellular interactions, the previous single-cell centric treatment approaches show unsatisfactory efficacy and fail to meet clinical demand. Herein, a vicious cycle-breaking strategy is proposed to target and repair pathological cells separately to terminate the malignant progression of liver fibrosis. Chondroitin sulfate-modified and vismodegib-loaded nanoparticles (CS-NPs/VDG) are designed to efficiently normalize the fenestrae phenotype of LSECs and restore HSCs to quiescent state by inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid-modified and silybin-loaded nanoparticles (GA-NPs/SIB) are prepared to restore hepatocytes function by relieving oxidative stress. The results show successful interruption of vicious cycle as well as distinct fibrosis resolution in two animal models through multiregulation of the pathological cells. This work not only highlights the significance of modulating cellular crosstalk but also provides a promising avenue for developing antifibrotic regimens.

Differences in Physiological Endotypes Between Nonpositional and Positional OSA: Results From the Shanghai Sleep Health Study Cohort.

BACKGROUND: Positional OSA (POSA) is a recognized subtype of OSA that exhibits distinct endotypic characteristics when compared with nonpositional OSA (NPOSA). The basis for the disparity in endotypes between these subtypes remains poorly understood. RESEARCH QUESTION: (1) Do individuals with NPOSA and POSA have different underlying OSA endotypes? (2) Which endotypic characteristics are critical in determining NPOSA and POSA severity?. STUDY DESIGN AND METHODS: Within the Shanghai Sleep Health Study cohort, individuals with OSA were recruited and classified as having POSA or NPOSA. Endotypes were calculated using polysomnography. RESULTS: Endotype analysis was conducted in 1,036 individuals with OSA. Compared with individuals with NPOSA, those with POSA had lower loop gain in all sleep stages and all sleep positions (LGAll) (0.55; 95% CI, 0.46-0.66 vs 0.68, 95% CI, 0.52-0.90; P < .001), lower arousal threshold in all sleep stages and all sleep positions (138.67; 95% CI, 118.94-180.87 %Veupnea vs 189.00; 95% CI, 129.71-257.76 %Veupnea; P < .001), higher pharyngeal collapsibility in all sleep stages and all sleep positions (VpassiveAll) (91.85; 95% CI, 83.13-95.15 %Veupnea vs 76.38; 95% CI, 23.77-92.08 %Veupnea; P < .001), and higher muscle compensation in all sleep stages and all sleep positions (6.50; 95% CI, -6.77 to 16.39 %Veupnea vs 3.65; 95% CI, -10.47 to 12.14 %Veupnea; P = .003). Logistic regression analyses indicated that higher VpassiveAll was associated with increased odds of POSA vs NPOSA. In NPOSA, fully adjusted linear regression analyses indicated that VpassiveAll (ß = -0.55; 95% CI, -0.68 to -0.42; P < .001) and LGAll (ß = 0.19; 95% CI, 0.08-0.30; P < .001) were significant independent predictors of the apnea hypopnea index, with VpassiveAll being the most critical factor. In contrast, in POSA, collapsibility appeared to be less influential (ß = -0.09; 95% CI, -0.21 to 0.03; P = .138). Nonanatomic endotypic characteristics (LGAll: ß = 0.29; 95% CI, 0.18-0.41; P < .001; arousal threshold in all sleep stages and all sleep positions: ß = 0.15; 95% CI, 0.01-0.28; P = .031; muscle compensation in all sleep stages and all sleep positions: ß = -0.21; 95% CI, -0.29 to -0.12; P < .001) were significant in determining the severity of POSA, with loop gain being the most crucial factor. INTERPRETATION: This study highlights the differences in endotypes between NPOSA and POSA. In Chinese individuals, anatomic factors were more significant in determining the severity of NPOSA, whereas nonanatomic traits were more likely to determine the severity of POSA. Future research should focus on developing personalized management strategies for individuals with NPOSA and POSA based on their endotypes. TRIAL REGISTRATION: Chinese Clinical Trial Registry; No.: ChiCTR1900025714; URL: https://www.chictr.org.cn/indexEN.html.

Engineered stem cell-based strategy: A new paradigm of next-generation stem cell product in regenerative medicine.

Stem cells have garnered significant attention in regenerative medicine owing to their abilities of multi-directional differentiation and self-renewal. Despite these encouraging results, the market for stem cell products yields limited, which is largely due to the challenges faced to the safety and viability of stem cells in vivo. Besides, the fate of cells re-infusion into the body unknown is also a major obstacle to stem cell therapy. Actually, both the functional protection and the fate tracking of stem cells are essential in tissue homeostasis, repair, and regeneration. Recent studies have utilized cell engineering techniques to modify stem cells for enhancing their treatment efficiency or imparting them with novel biological capabilities, in which advances demonstrate the immense potential of engineered cell therapy. In this review, we proposed that the "engineered stem cells" are expected to represent the next generation of stem cell therapies and reviewed recent progress in this area. We also discussed potential applications of engineered stem cells and highlighted the most common challenges that must be addressed. Overall, this review has important guiding significance for the future design of new paradigms of stem cell products to improve their therapeutic efficacy.

Glutathione depletion and dihydroorotate dehydrogenase inhibition actuated ferroptosis-augment to surmount triple-negative breast cancer.

Ferroptosis is a promising therapeutic approach for combating malignant cancers, but its effectiveness is limited in clinical due to the adaptability and self-repair abilities of cancer cells. Mitochondria, as the pivotal player in ferroptosis, exhibit tremendous therapeutic potential by targeting the intramitochondrial anti-ferroptotic pathway mediated by dihydroorotate dehydrogenase (DHODH). In this study, an albumin-based nanomedicine was developed to induce augmented ferroptosis in triple-negative breast cancer (TNBC) by depleting glutathione (GSH) and inhibiting DHODH activity. The nanomedicine (ATO/SRF@BSA) was developed by loading sorafenib (SRF) and atovaquone (ATO) into bovine serum albumin (BSA). SRF is an FDA-approved ferroptosis inducer and ATO is the only drug used in clinical that targets mitochondria. By combining the effects of SRF and ATO, ATO/SRF@BSA promoted the accumulation of lipid peroxides within mitochondria by inhibiting the glutathione peroxidase 4 (GPX4)-GSH pathway and downregulating the DHODH-coenzyme Q (CoQH2) defense mechanism, triggers a burst of lipid peroxides. Simultaneously, ATO/SRF@BSA suppressed cancer cell self-repair and enhanced cell death by inhibiting the synthesis of adenosine triphosphate (ATP) and pyrimidine nucleotides. Furthermore, the anti-cancer results showed that ATO/SRF@BSA exhibited tumor-specific killing efficacy, significantly improved the tumor hypoxic microenvironment, and lessened the toxic side effects of SRF. This work presents an efficient and easily achievable strategy for TNBC treatment, which may hold promise for clinical applications.

COL, a pipeline for identifying putatively functional back-splicing.

Circular RNAs (circRNAs) are a class of generally non-coding RNAs produced by back-splicing. Although the vast majority of circRNAs are likely to be products of splicing error and thereby confer no benefits to organisms, a small number of circRNAs have been found to be functional. Identifying other functional circRNAs from the sea of mostly non-functional circRNAs is an important but difficult task. Because available experimental methods for this purpose are of low throughput or versality and existing computational methods have limited reliability or applicability, new methods are needed. We hypothesize that functional back-splicing events that generate functional circRNAs (i) exhibit substantially higher back-splicing rates than expected from the total splicing amounts, (ii) have conserved splicing motifs, and (iii) show unusually high back-splicing levels. We confirm these features in back-splicing shared among human, macaque, and mouse, which should enrich functional back-splicing. Integrating the three features, we design a computational pipeline named COL for identifying putatively functional back-splicing. Using experimentally verified functional back-splicing as a benchmark, we find COL to outperform a commonly used computational method with a similar data requirement. We conclude that COL is an efficient and versatile method for rapid identification of putatively functional back-splicing and circRNAs that can be experimentally validated.

A Pro-Metastatic Derivatives Eliminator for In Vivo Dual-Removal of Circulating Tumor Cells and Tumor-Derived Exosomes Impedes their Biodistribution into Distant Organs.

Circulating tumor cells (CTCs) and tumor-derived exosomes (TDEs) play an irreplaceable role in the metastatic cascade and preventing them from reaching distant organs via blood circulation helps to reduce the probability of cancer recurrence and metastasis. However, technologies that can simultaneously prevent CTCs and TDEs from reaching distant organs have not been thoroughly developed until now. Here, inspired by hemoperfusion, a pro-metastatic derivative eliminator (PMDE) is developed for the removal of both CTCs and TDEs from the peripheral blood, which also inhibits their biodistribution in distant organs. This device is designed with a dual antibody-modified immunosorbent filled into a capture column that draws peripheral blood out of the body to flow through the column to specifically capture CTCs and TDEs, followed by retransfusing the purified blood into the body. The PMDE can efficiently remove CTCs and TDEs from the peripheral blood and has excellent biocompatibility. Interestingly, the PMDE device can significantly inhibit the biodistribution of CTCs and TDEs in the lung and liver by scavenging them. This work provides a new perspective on anti-metastatic therapy and has broad prospects in clinical applications to prevent metastasis and recurrence.

Tirapazamine combined with photodynamic therapy improves the efficacy of ABZSO nanoparticles on Echinococcosis granulosus via further enhancing "breaking-then-curing".

BACKGROUND: Photodynamic therapy (PDT) has a promising application prospect in Echinococcus granulosus (Egs), however, the hypoxic environment of Egs and the hypoxia associated with PDT will greatly limit its effects. As a hypoxic-activated pre-chemotherapeutic drug, tirapazamine (TPZ) can be only activated and produce cytotoxicity under hypoxia environment. Albendazole sulfoxide (ABZSO) is the first choice for the treatment of Egs. This study aimed to explore the effects of ABZSO nanoparticles (ABZSO NPs), TPZ combined with PDT on the activity of Egs in vitro and in vivo. METHODS: The Egs were divided into control, ABZSO NPs, ABZSO NPs + PDT, and ABZSO NPs + TPZ + PDT groups, and the viability of Egs was determined using methylene blue staining. Then, the ROS, LDH and ATP levels were measured using their corresponding assay kit, and H2AX and TopoI protein expression was detected by western blot. The morphology of Egs with different treatments was observed using hematoxylin eosin (HE) staining and scanning electron microscopy (SEM). After that, the in vivo efficacy of ABZSO NPs, TPZ and PDT on Egs was determined in a Egs infected mouse model. RESULTS: In vitro experiments showed that the combined treatment of TPZ, ABZSO NPs and PDT significantly inhibited Egs viability; and significantly increased ROS levels and LDH contents, while decreased ATP contents in Egs; as well as up-regulated H2AX and down-regulated TopoI protein expression. HE staining and SEM results showed that breaking-then-curing treatment seriously damaged the Egs wall. Additionally, in vivo experiments found that the combination of ABZSO NPs, PDT and TPZ had more serious calcification and damage of the wall structure of cysts. CONCLUSIONS: ABZSO NPs combined with TPZ and PDT has a better inhibitory effect on the growth of Egs in vitro and in vivo based on the strategy of "breaking-then-curing".

Progress on the pathological tissue microenvironment barrier-modulated nanomedicine.

Imbalance in the tissue microenvironment is the main obstacle to drug delivery and distribution in the human body. Before penetrating the pathological tissue microenvironment to the target site, therapeutic agents are usually accompanied by three consumption steps: the first step is tissue physical barriers for prevention of their penetration, the second step is inactivation of them by biological molecules, and the third step is a cytoprotective mechanism for preventing them from functioning on specific subcellular organelles. However, recent studies in drug-hindering mainly focus on normal physiological rather than pathological microenvironment, and the repair of damaged physiological barriers is also rarely discussed. Actually, both the modulation of pathological barriers and the repair of damaged physiological barriers are essential in the disease treatment and the homeostasis maintenance. In this review, we present an overview describing the latest advances in the generality of these pathological barriers and barrier-modulated nanomedicine. Overall, this review holds considerable significance for guiding the design of nanomedicine to increase drug efficacy in the future.

Association between TSH suppression therapy and type 2 deiodinase gene polymorphism in differentiated thyroid carcinoma.

INTRODUCTION: Oral levothyroxine (L-T4) suppression of thyroid-stimulating hormone (TSH) levels is the most commonly used clinical approach to manage and treat patients after thyroid cancer surgery. This study aimed to investigate the association between TSH suppression therapy and type 2 deiodinase gene (DIO2) polymorphism in differentiated thyroid carcinoma (DTC). MATERIAL AND METHODS: A total of 240 patients with DTC who received total thyroidectomy (TT; 120) and hemithyroidectomy (HT; 120) were enrolled in this study. The serum TSH, free triiodothyronine (FT3), and free thyroxine (FT4) levels were detected using an automatic serum immune analyser and electrochemiluminescence immunoassay. Based on the results of DIO2 gene detection, 3 genotypes of Thr92Ala were detected. RESULTS: The serum TSH levels were inhibited after oral L-T4 treatment, but the proportion of patients who reached the TSH suppression standard in the hemithyroidectomy group was higher than in the total thyroidectomy group. After TSH suppression treatment, serum FT4 levels were increased in both total thyroidectomy and hemithyroidectomy. The difference in serum TSH, FT3, and FT4 levels was associated with different genotypes, and patients with high cytosine cytosine (CC) genotypes may have difficulty meeting the TSH suppression criteria. CONCLUSIONS: Patients who underwent total thyroidectomy exhibited higher postoperative serum FT4 levels than patients in the hemithyroidectomy group after TSH suppression therapy. The Thr92Ala polymorphism of type 2 deiodinase (D2) was associated with TSH suppression therapy.

Tumor microenvironment-initiated lipid redox cycling for efficient triple-negative breast cancer therapy.

The use of overwhelming reactive oxygen species (ROS) attack has shown great potential for treating aggressive malignancies; however, targeting this process for further applications is greatly hindered by inefficiency and low selectivity. Here, a novel strategy for ROS explosion induced by tumor microenvironment-initiated lipid redox cycling was proposed, which was developed by using soybean phosphatidylcholine (SPC) to encapsulate lactate oxidase (LOX) and sorafenib (SRF) self-assembled nanoparticles (NPs), named LOX/SRF@Lip. SPC is not only the delivery carrier but an unsaturated lipid supplement for ROS explosion. And LOX catalyzes excessive intratumoral lactate to promote the accumulation of large amounts of H2O2. Then, H2O2 reacts with excessive endogenous iron ions to generate amounts of hydroxyl radical for the initiation of SPC peroxidation. Once started, the reaction will proceed via propagation to form new lipid peroxides (LPO), resulting to devastating LPO explosion and widespread oxidative damage in tumor cells. Furthermore, SRF makes contribution to mass LPO accumulation by inhibiting LPO elimination. Compared to normal tissue, tumor tissue has higher levels of lactate and iron ions. Therefore, LOX/SRF@Lip shows low toxicity in normal tissues, but generates efficient inhibition on tumor proliferation and metastasis, enabling excellent and safe tumor-specific therapy. This work offers new ideas on how to magnify anticancer effect of ROS through rational nanosystem design and tumor-specific microenvironment utilization.

Effects of obstructive sleep apnea during rapid eye movement sleep on cardiac autonomic dysfunction: Results from the Shanghai sleep health study cohort.

In our large-scale study, the correlation between obstructive sleep apnea (OSA) related to rapid eye movement (REM) sleep and cardiac autonomic dysfunction was assessed by standard polysomnography (PSG). Cardiac autonomic dysfunction was evaluated by the measurement of heart rate variability (HRV). The cardiovascular disease (CVD) risk was determined using the cross-sectional prevalence of CVD and its overall 10 year risk according to the Framingham risk score (FRS). 4152 individuals were included in the study. A higher apnea-hypopnea index during REM sleep (AHIREM ) was correlated with increased CVD risk. The adjusted odds ratios (95% CIs) for CVD prevalence and its high 10 year risk in participants having severe OSA during REM sleep (AHIREM ≥30 events/h) were 1.452 (1.012-2.084) and 1.904 (1.470-2.466) in the demographic adjusted model and 1.175 (0.810-1.704) and 1.716 (1.213-2.427) in the multivariate adjusted model, respectively, compared with the group with a AHIREM of <5 events/h. Fully adjusted multivariate linear regression models showed the independent association between AHIREM and a more elevated ratio of low-frequency and high-frequency (LF/HF) and LF in normalised units [LF (n.u.)] (P = 0.042, P = 0.027 in all participants and P = 0.033, P = 0.029 in participants with AHI during non-REM sleep <5 events/h, respectively). Mediation analysis demonstrated that OSA during REM sleep and CVD risk was significantly mediated by LF/HF and LF (n.u.). OSA during REM sleep may be a marker behind CVD risk because it promotes cardiac autonomic dysfunction.

Hypoxia Inhibitor Combined with Chemotherapeutic Agents for Antitumor and Antimetastatic Efficacy against Osteosarcoma.

Chemotherapy is the main treatment method for osteosarcoma in the clinic. However, drug resistance and its poor antimetastatic effects greatly limit its clinical application. In this work, dual-drug nanoparticles (NPs) containing albendazole (ABZ) and doxorubicin (DOX), named AD@PLGA-PEG NPs, were prepared to solve the problems of chemotherapeutic drug resistance and poor antimetastasis effects. Compared with free DOX, ABZ combined with DOX can increase intracellular reactive oxygen species (ROS) and induce more tumor cell apoptosis; therefore, AD@PLGA-PEG NPs produced more mitochondria-mediated oxidative stress and better apoptosis efficiency. Importantly, ABZ can also effectively inhibit the expression of hypoxia inducible factor-1α (HIF-1α) and then reduce the expression of its downstream vascular endothelial growth factor (VEGF); thus, the AD@PLGA-PEG NPs effectively inhibited tumor metastasis in vivo. Collectively, the dual-drug AD@PLGA-PEG NPs delivery system provided prominent antitumor and antimetastatic efficacy and might be a promising treatment for osteosarcoma.

A novel whole blood purifier for efficient capture and separation of circulating tumor cells.

Circulating tumor cells (CTCs) as important biomarkers for noninvasive clinical diagnosis and prognostic evaluation are significant in predicting the overall survival and progression-free survival of cancer patients. However, the current typical CTCs separation and enrichment techniques were limited to a single collection of small-volume blood samples, which was inadequate to comprehensively profile the distribution of CTCs in the systemic blood. In addition, those techniques cannot reduce metastasis of CTCs unless adjuvant chemotherapy. Herein, inspired by hemodialysis, we designed a whole blood purifier (WBP) composed of a functionalized special spiral-like glass tube modified by anti-epithelial cell adhesion molecule (anti-EpCAM). The WBP allowed real-time capture, enrichment and removal of CTCs from systemic blood circulation, and the purified blood was immediately returned to the body. Furthermore, the WBP did not cause any organic damages in vivo. This approach achieves the high accuracy of liquid biopsy technology and is expected to become an effective clinical adjuvant therapy for tumor metastasis.

Injectable rhein-assisted crosslinked hydrogel for efficient local osteosarcoma chemotherapy.

Osteosarcoma (OS) is the most common malignant tumor of the bone that affects children and adolescents, and its treatment usually involves doxorubicin hydrochloride (DOX). However, the drug resistance and side effects caused by high-dose DOX infusion greatly hinder its therapeutic effects. To achieve efficient OS treatment with low toxicity, an injectable rhein (RH)-assisted crosslinked hydrogel (PVA@RH@DOX hydrogel, PRDH) was designed, which was prepared by loading DOX and RH into a polyvinyl alcohol (PVA) solution. The cytotoxicity assay and live/dead staining results showed that the combination of RH and DOX more effectively killed OS cells, producing excellent effects at low concentrations of DOX. The wound healing and transwell test results proved that PRDH could significantly inhibit the metastasis and invasion of OS cells. PRDH showed a long-lasting antitumor effect after injection of a single dose, significantly suppressing the proliferation and metastasis of OS and achieving the strategy of a single administration for long-term treatment. Excitingly, RH facilitated hydrogel formation by assisting with PVA crosslinking. This system provides an alternative regimen and broadens the horizon for the clinical treatment of OS.

Pathological collagen targeting and penetrating liposomes for idiopathic pulmonary fibrosis therapy.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease in which collagen progressively deposits in the supporting framework of the lungs. The pathological collagen creates a recalcitrant barrier in mesenchyme for drug penetration, thus greatly restricting the therapeutical efficacy. On the other hand, this overloaded collagen is gradually exposed to the bloodstream at fibrotic sites because of the vascular hyperpermeability, thus serving as a potential target. Herein, pathological collagen targeting and penetrating liposomes (DP-CC) were constructed to deliver anti-fibrotic dual drugs including pirfenidone (PFD) and dexamethasone (DEX) deep into injured alveoli. The liposomes were co-decorated with collagen binding peptide (CBP) and collagenase (COL). CBP could help vehicle recognize the pathological collagen and target the fibrotic lungs efficiently because of its high affinity to collagen, and COL assisted in breaking through the collagen barrier and delivering vehicle to the center of injured sites. Then, the released dual drugs developed a synergistic anti-fibrotic effect to repair the damaged epithelium and remodel the extracellular matrix (ECM), thus rebuilding the lung architecture. This study provides a promising strategy to deliver drugs deep into pathological collagen accumulated sites for the enhanced treatment of IPF.

Timosaponin AIII Suppresses RAP1 Signaling Pathway to Enhance the Inhibitory Effect of Paclitaxel on Nasopharyngeal Carcinoma.

Although PTX has been identified as an effective drug for nasopharyngeal carcinoma (NPC) therapy, it has serious side effects in the human body. Previous studies have shown that timosaponin AIII (TSAIII) can inhibit the malignant progression of NPC cells. This study investigated the active mechanism of the combination of TSAIII and paclitaxel (PTX) on NPC. Cellular viability, apoptosis, apoptotic factors, and RAP1 signaling regulators were detected in the PNC cells (CNE-1 and HNE-2) and the subcutaneous CNE-1 transplanted nude mice treated with PTX or/and TSAIII. The results showed that TSAIII notably strengthened the inhibitory effect of PTX on the proliferation of NPC cells CNE-1 and HNE-2; upregulated the expression of Bax B-cell lymphoma 2 (Bcl-2)/Bcl-xL-associated death promoter (Bad), and Ras-associated protein1 (RAP1) GTPase activating protein (Rap1GAP); inhibited the level of Bcl-2, RAP1, and Ras guanine nucleotide releasing protein (RasGRP2); and significantly enhanced the promoting effect of PTX on apoptosis in the CNE-1 and HNE-2 cells. Besides, TSAIII strengthened the inhibitory effect of PTX on xenograft tumor in nude mice without adverse reactions. In conclusion, the combination administration of TSAIII and PTX had a significantly therapeutic effect on NPC and avoided the PTX's side effects, which may have acted as a new direction for the study of therapeutic approaches for NPC clinically.