Imaging the intracellular refractive index distribution (IRID) for dynamic label-free living colon cancer cells via circularly depolarization decay model (CDDM).

Label-free detection of intracellular substances for living cancer cells remains a significant hurdle in cancer pathogenesis research. Although the sensitivity of light polarization to intracellular substances has been validated, current studies are predominantly focused on tissue lesions, thus label-free detection of substances within individual living cancer cells is still a challenge. The main difficulty is to find specific detection methods along with corresponding characteristic parameters. With refractive index as an endogenous marker of substances, this study proposes a detection method of intracellular refractive index distribution (IRID) for label-free living colon cancer (LoVo) cells. Utilizing the circular depolarization decay model (CDDM) to calculate the degree of circular polarization (DOCP) modulated by the cell allows for the derivation of the IRID on the focal plane. Experiments on LoVo cells demonstrated the refractive index of single cell can be accurately and precisely measured, with precision of 10-3 refractive index units (RIU). Additionally, chromatin content during the interphases (G1, S, G2) of cell cycle was recorded at 56.5%, 64.4%, and 71.5%, respectively. A significantly finer IRID can be obtained compared to the phase measurement method. This method is promising in providing a dynamic label-free intracellular substances detection method in cancer pathogenesis studies.

Revisiting the Role of Valeric Acid in Manipulating Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is characterized by a complicated interaction between mucosal inflammation, epithelial dysfunction, abnormal activation of innate immune responses, and gut microbiota dysbiosis. Though valeric acid (VA), one type of short-chain fatty acids (SCFAs), has been identified in other inflammatory disorders and cancer development, the pathological role of VA and underlying mechanism of VA in UC remain under further investigation. METHODS: Studies of human clinical specimens and experimental colitis models were conducted to confirm the pathological manifestations of the level of SCFAs from human fecal samples and murine colonic homogenates. Valeric acid-intervened murine colitis and a macrophage adoptive transfer were applied to identify the underlying mechanisms. RESULTS: In line with gut microbiota dysfunction in UC, alteration of SCFAs from gut microbes were identified in human UC patients and dextran sodium sulfate -induced murine colitis models. Notably, VA was consistently negatively related to the disease severity of UC, the population of monocytes, and the level of interluekin-6. Moreover, VA treatment showed direct suppressive effects on lipopolysaccharides (LPS)-activated human peripheral blood mononuclear cells and murine macrophages in the dependent manner of upregulation of GPR41 and GPR43. Therapeutically, replenishment of VA or adoptive transfer with VA-modulated macrophages showed resistance to dextran sodium sulfate-driven murine colitis though modulating the production of inflammatory cytokine interleukin-6. CONCLUSIONS: In summary, the research uncovered the pathological role of VA in modulating the activation of macrophages in UC and suggested that VA might be a potential effective agent for UC patients.

The study collectively indicated that valeric acid (VA) was consistently negatively related to the disease severity of UC, and hypofunction of macrophage driven by VA impeded the progression of UC.

Hydrogel dressings with intrinsic antibiofilm and antioxidative dual functionalities accelerate infected diabetic wound healing.

Chronic wounds are often infected with biofilm bacteria and characterized by high oxidative stress. Current dressings that promote chronic wound healing either require additional processes such as photothermal irradiation or leave behind gross amounts of undesirable residues. We report a dual-functionality hydrogel dressing with intrinsic antibiofilm and antioxidative properties that are synergistic and low-leaching. The hydrogel is a crosslinked network with tethered antibacterial cationic polyimidazolium and antioxidative N-acetylcysteine. In a murine diabetic wound model, the hydrogel accelerates the closure of wounds infected with methicillin-resistant Staphylococcus aureus or carbapenem-resistant Pseudomonas aeruginosa biofilm. Furthermore, a three-dimensional ex vivo human skin equivalent model shows that N-acetylcysteine promotes the keratinocyte differentiation and accelerates the re-epithelialization process. Our hydrogel dressing can be made into different formats for the healing of both flat and deep infected chronic wounds without contamination of the wound or needing other modalities such as photothermal irradiation.

Diagnostic efficacy of combining diffusion-weighted magnetic resonance imaging with serum Mucin 1, Mucin 13, and Mucin 16 in distinguishing borderline from malignant epithelial ovarian tumors.

AIMS: To enhance ovarian tumor diagnosis beyond conventional methods, this study explored combining diffusion-weighted magnetic resonance imaging (DWI-MRI) and serum biomarkers (Mucin 1 [MUC1], MUC13, and MUC16) for distinguishing borderline from malignant epithelial ovarian tumors. METHODS: A total of 126 patients, including 71 diagnosed with borderline (BEOTs) and 55 with malignant epithelial ovarian tumors (MEOTs), underwent preoperative DWI-MRI. Region of interest (ROI) was manually drawn along the solid component's boundary of the largest tumor, focusing on areas with potentially the lowest apparent diffusion coefficient (ADC). For entirely cystic tumors, a free-form ROI enclosed the maximum number of septa while targeting the lowest ADC. Serum biomarkers were determined using enzyme-linked immunosorbent assay. RESULTS: Basic morphological traits proved inadequate for malignancy diagnosis, warranting this investigation. BEOTs had an ADC mean of (1.670 ± 0.250) × 103 mm2 /s, while MEOTs had a lower ADC mean of (1.332 ± 0.481) × 103 mm2 /s, with a sensitivity of 63.6% and specificity of 90.1%. Median MUC1 (167.0 U/mL vs. 87.3 U/mL), MUC13 (12.44 ng/mL vs. 7.77 ng/mL), and MUC16 (180.6 U/mL vs. 36.1 U/mL) levels were higher in MEOTs patients. The biomarker performance was: MUC1, sensitivity 50.9%, specificity 100%; MUC13, sensitivity 56.4%, specificity 78.9%; MUC16, sensitivity 83.64%, specificity 100%. Combining serum biomarkers and ADC mean resulted in a sensitivity of 96.4% and specificity of 100%. CONCLUSION: The integration of DWI-MRI with serum biomarkers (MUC1, MUC13, and MUC16) achieves exceptional diagnostic accuracy, offering a powerful tool for the precise differentiation between borderline and malignant epithelial ovarian tumors.

Ochratoxin A Induces Renal Cell Ferroptosis by Disrupting Iron Homeostasis and Increasing ROS.

Mycotoxin ochratoxin A (OTA) is a critical food safety concern due to its nephron-toxic effects and is detected in a wide range of food and feedstuffs. OTA nephrotoxicity is related to oxidative stress and damage. However, the mediator(s) of the excessive oxidative stress is unclear. The current study used human kidney cell lines to investigate whether and how intracellular iron contributed to OTA-induced ROS accumulation and how OTA-induced iron-dependent ferroptotic cell death. Our results showed that OTA treatment affected the cell viability and induced the typical characteristics of cell ferroptosis. Furthermore, gene and protein expression results indicated that OTA disrupted iron homeostasis by upregulating the expression levels of iron importer TFR1 and FTH, while downregulating the expression level of iron exporter FPN and dramatically increasing its negative regulator Hepcidin. The changes were consistent with the induction of intracellular iron accumulation and elevated levels of oxidative stress and lipid peroxidation. Additionally, co-treatment with OTA and an iron chelator significantly improved cell viability, reduced cellular total iron and ROS, and reversed OTA-induced changes in iron metabolism gene expression levels. Interestingly, the addition of a ROS scavenger also reversed cell death and changes in mRNA and protein expression levels of iron metabolism genes but to a lesser degree than that of the iron-chelating agent. Our results revealed that OTA induced ferroptosis in renal cells by disrupting iron homeostasis and increasing ROS.

The Safety and Efficacy of Hepatic Arterial Infusion Chemotherapy Combined with PD-(L)1 Inhibitors and Molecular Targeted Therapies for the Treatment of Intermediate and Advanced Hepatocellular Carcinoma Unsuitable for Transarterial Chemoembolization.

Objective: To investigate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with PD-(L)1 inhibitors and molecular targeted therapies (MTT) for intermediate and advanced HCC that are unsuitable for transarterial chemoembolization (TACE). Methods: We conducted a retrospective analysis of data from patients with TACE-unsuitable HCC who were receiving triple therapy from January 2020 to December 2021 at two medical centers. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), objective response rates (ORR), disease control rates (DCR), and incidence of adverse events (AEs). Results: A total of 55 patients were enrolled in the study with median treatment periods of 4 and 6 for HAIC and PD-(L)1 inhibitors, respectively. The median OS and PFS were 15.0 and 10.0 months, respectively, with a median follow-up of 11.0 months (range: 4.0-27.5 months). According to the mRECIST criteria, the optimal ORR was 43.6% (24/55) and the DCR was 61.8% (34/55). The incidence of AEs was 58.2%, with grade 3 and above accounting for 20.0%; elevated AST (18.2%), hyperbilirubinemia (16.4%), and thrombocytopenia (16.4%) were most common. There were no treatment-related fatalities and all AEs were effectively managed. Multifactorial analysis showed that NLR > 3.82 (HR 2.380, 95% CI 1.116-2-5.079, P = 0.025), ECOG 1 (HR 2.906, 95% CI 1.373-6.154, P = 0.005), and extrahepatic metastases (HR 8.373, 95% CI 3.492-20.078, P < 0.001) were associated with the median OS. Conclusion: Triple therapy with HAIC, PD-(L)1 inhibitors, and MTT was safe and effective for patients with intermediate and advanced HCC for TACE-unsuitability.

Structural Characteristics and Antioxidant Mechanism of Donkey-Hide Gelatin Peptides by Molecular Dynamics Simulation.

This study aimed to explore the structural characteristics and antioxidant mechanism of donkey-hide gelatin peptides. After hydrolysis and ultrafiltration treatment, five gelatin peptides with different molecular weights (MWs) were obtained. Amino acid analysis showed that gelatin peptides with different MWs contained a large number of amino acids, including G, P, E, N, A, and R, and differences were noted in the content of various amino acids. Fourier transform infrared spectroscopy and circular dichroism revealed that these gelatin peptides differed in terms of the peak strength of functional groups and number of secondary structures. Moreover, 26 pentapeptides/hexapeptides were identified. Among them, we investigated by molecular docking how PGPAP, which has the best antioxidant activity, may interact with the Keap1 protein. The results showed that the PGPAP-Keap1 complex had a stable conformation, and Arg415, Gly462, Phe478, and Tyr572 were the key residues involved in the binding of the peptide PGPAP to Keap1. Our results demonstrated that PGPAP could serve as a bioactive peptide with antioxidant activity.

TrkA-mediated sensory innervation of injured mouse tendon supports tendon sheath progenitor cell expansion and tendon repair.

Peripheral neurons terminate at the surface of tendons partly to relay nociceptive pain signals; however, the role of peripheral nerves in tendon injury and repair remains unclear. Here, we show that after Achilles tendon injury in mice, there is new nerve growth near tendon cells that express nerve growth factor (NGF). Conditional deletion of the Ngf gene in either myeloid or mesenchymal mouse cells limited both innervation and tendon repair. Similarly, inhibition of the NGF receptor tropomyosin receptor kinase A (TrkA) abrogated tendon healing in mouse tendon injury. Sural nerve transection blocked the postinjury increase in tendon sensory innervation and the expansion of tendon sheath progenitor cells (TSPCs) expressing tubulin polymerization promoting protein family member 3. Single cell and spatial transcriptomics revealed that disruption of sensory innervation resulted in dysregulated inflammatory signaling and transforming growth factor-ß (TGFß) signaling in injured mouse tendon. Culture of mouse TSPCs with conditioned medium from dorsal root ganglia neuron further supported a role for neuronal mediators and TGFß signaling in TSPC proliferation. Transcriptomic and histologic analyses of injured human tendon biopsy samples supported a role for innervation and TGFß signaling in human tendon regeneration. Last, treating mice after tendon injury systemically with a small-molecule partial agonist of TrkA increased neurovascular response, TGFß signaling, TSPC expansion, and tendon tissue repair. Although further studies should investigate the potential effects of denervation on mechanical loading of tendon, our results suggest that peripheral innervation is critical for the regenerative response after acute tendon injury.

Flexible dynamic quantitative phase imaging based on division of focal plane polarization imaging technique.

This paper proposes a flexible and accurate dynamic quantitative phase imaging (QPI) method using single-shot transport of intensity equation (TIE) phase retrieval achieved by division of focal plane (DoFP) polarization imaging technique. By exploiting the polarization property of the liquid crystal spatial light modulator (LC-SLM), two intensity images of different defocus distances contained in orthogonal polarization directions can be generated simultaneously. Then, with the help of the DoFP polarization imaging, these images can be captured with single exposure, enabling accurate dynamic QPI by solving the TIE. In addition, our approach gains great flexibility in defocus distance adjustment by adjusting the pattern loaded on the LC-SLM. Experiments on microlens array, phase plate, and living human gastric cancer cells demonstrate the accuracy, flexibility, and dynamic measurement performance for various objects. The proposed method provides a simple, flexible, and accurate approach for real-time QPI without sacrificing the field of view.

Construction of NiFe(CN)5NO/Ni3S2 hierarchical submicro-rods on nickel foam as advanced oxygen evolution electrocatalysts.

The development of cheap, abundant, and highly efficient electrocatalysts for the oxygen evolution reaction (OER) is urgently needed for hydrogen production from water splitting. Herein, we demonstrate a novel OER electrocatalyst (NiFe(CN)5NO/Ni3S2) prepared by coupling Ni3S2 and a bimetallic metal-organic framework (MOF) of NiFe(CN)5NO on nickel foam (NF) via a simple two-step route. The NiFe(CN)5NO/Ni3S2 electrocatalyst displays an interesting rod-like hierarchical architecture assembled by ultrathin nanosheets. The combination of NiFe(CN)5NO and Ni3S2 optimizes the electronic structure of the metal active sites and increases the electron transfer capability. Benefitting from the synergistic effect between Ni3S2 and the NiFe-MOF as well as the unique hierarchical architecture, the NiFe(CN)5NO/Ni3S2/NF electrode exhibits excellent electrocatalytic OER activity with ultralow overpotentials of 162/197 mV at 10/100 mA cm-2 and an ultrasmall Tafel slope of 26 mV dec-1 in 1.0 M KOH, which are far superior to those of the individual NiFe(CN)5NO, Ni3S2 and commercial IrO2 catalysts. In particular, unlike common metal sulfide-based electrocatalysts, the composition, morphology and microstructure of the NiFe-MOF/Ni3S2 composite electrocatalyst can be well retained after the OER, which endows it with fantastic long-term durability. This work offers a new strategy for the construction of novel and high-efficiency MOF-based composite electrocatalysts for energy applications.

Endogenous HMGB1 regulates GSDME-mediated pyroptosis via ROS/ERK1/2/caspase-3/GSDME signaling in neuroblastoma.

Pyroptosis, a newly discovered mode of programmed cell death (PCD), is important in the regulation of cancer development. High mobility group box 1 (HMGB1) is a non-histone nuclear protein that is closely related to tumor development and chemotherapy resistance. However, whether endogenous HMGB1 regulates pyroptosis in neuroblastoma remains unknown. Here, we showed that HMGB1 showed ubiquitous higher expression in SH-SY5Y cells and clinical tumors, and was positively correlated with the risk factors of patients with neuroblastoma. Knockdown of GSDME or pharmacological inhibition of caspase-3 blocked pyroptosis and cytosolic translocation of HMGB1. Moreover, knockdown of HMGB1 inhibited cisplatin (DDP) or etoposide (VP16)-induced pyroptosis by decreasing GSDME-NT and cleaved caspase-3 expression, resulting in cell blebbing and LDH release. Knockdown of HMGB1 expression increased the sensitivity of SH-SY5Y cells to chemotherapy and switched pyroptosis to apoptosis. Furthermore, the ROS/ERK1/2/caspase-3/GSDME pathway was found to be functionally connected with DDP or VP16-induced pyroptosis. Hydrogen peroxide (H2O2, a ROS agonist) and EGF (an ERK agonist) promoted the cleavage of GSDME and caspase-3 in DDP or VP16 treatment cells, both of which were inhibited by HMGB1 knockdown. Importantly, these data were further supported by the in vivo experiment. Our study suggests that HMGB1 is a novel regulator of pyroptosis via the ROS/ERK1/2/caspase-3/GSDME pathway and a potential drug target for therapeutic interventions in neuroblastoma.

Construction of a prognostic risk assessment model for HER2 + breast cancer based on autophagy-related genes.

Although breast cancer (BC) has a low mortality rate relative to other cancers, it prominently affects the survival of patients with human epidermal growth factor receptor-2 (HER2 +) BC due to its high recurrence rate. By far, it has been found that autophagy can affect various tumor occurrence and development, as well as patients' prognosis. HER2 + BC patient samples and autophagy-related genes (ARGs) were acquired from a public database, least absolute shrinkage and selection operator (LASSO) and Cox analyses (including univariate and multivariate analyses) were utilized to construct a 9-ARGs model, which was verified by using HER2 + BC patient samples in The Cancer Genome Atlas (TCGA) dataset. Sample risk score was worked out based on characteristic genes, and prominent differences in overall survival were tracked down between high- and low-risk groups. Predictive ability of the model was validated by drawing receiver operating characteristic (ROC) curves and then calculating the area under the curves (AUC) value. Results showed good accuracy and prediction ability of the model in both validation set and training set. For the purpose of facilitating model application in clinical practice, we constructed a nomogram combing clinical factors and risk scores to evaluate 1-year, 3-year and 5-year survival of HER2 + BC patients. In addition, we assessed the correlation of risk score with tumor mutational burden and tumor immune infiltration. Results exhibited that in a high-risk group, tumor mutation was relatively high, while tumor immune infiltration was relatively poor. Overall, based on ARGs, the prognostic signature in this study can tellingly evaluate prognoses of HER2 + BC patients and provide a reference for clinicians.

Silicate Ions Derived from Calcium Silicate Extract Decelerate Ang II-Induced Cardiac Remodeling.

BACKGROUND: Pathological cardiac hypertrophy is one of the main activators of heart failure. Currently, no drug can completely reverse or inhibit the development of pathological cardiac hypertrophy. To this end, we proposed a silicate ion therapy based on extract derived from calcium silicate (CS) bioceramics for the treatment of angiotensin II (Ang II) induced cardiac hypertrophy. METHODS: In this study, the Ang II induced cardiac hypertrophy mouse model was established, and the silicate ion extract was injected to mice intravenously. The cardiac function was evaluated by using a high-resolution Vevo 3100 small animal ultrasound imaging system. Wheat germ Agglutinin, Fluo4-AM staining and immunofluorescent staining was conducted to assess the cardiac hypertrophy, intracellular calcium and angiogenesis of heart tissue, respectively. RESULTS: The in vitro results showed that silicate ions could inhibit the cell size of cardiomyocytes, reduce cardiac hypertrophic gene expression, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ß-myosin heavy chain (ß-MHC), decrease the content of intracellular calcium induced by Ang II. In vivo experiments in mice confirmed that intravenous injection of silicate ions could remarkably inhibit the cardiac hypertrophy and promote the formation of capillaries, further alleviating Ang II-induced cardiac function disorder. CONCLUSION: This study demonstrated that the released silicate ions from CS possessed potential value as a novel therapeutic strategy of pathological cardiac hypertrophy, which provided a new insight for clinical trials.

Transdermal delivery of Protocatechuic aldehyde using hyaluronic acid/gelatin-based microneedles for the prevention and treatment of hypertrophic scars.

The formation of hypertrophic scar (HS) involves many pathological processes, such as reduced apoptosis in fibroblasts, excessive collagen deposition by fibroblasts, over-abundant angiogenesis, etc. The therapeutic effects of current treatments targeting one single pathological process are limited. Due to their diverse biological activities, natural products offer a potential solution to this issue. In this study reported herein, we investigated the effects of Protocatechuic aldehyde (PA) on both hypertrophic scar-derived fibroblasts (HSF) and vascular endothelial growth factor (VEGF)-stimulated human umbilical vein endothelial cells (HUVECs). Microneedles (MN) containing PA and hyaluronic acid (HA) or containing PA, HA, and gelatin were prepared by mixing PA stock solution with HA or HA/gelatin at a ratio of 1:10. The HS prevention and treatment outcomes of these HA-PA-MN and HA/gelatin-PA-MN were tested using a rabbit ear HS model. Our data indicate that PA induces apoptosis and reduces collagen deposition in HSF. In addition, PA attenuates VEGF-stimulated angiogenesis of HUVECs. Furthermore, HA-PA-MN or HA/gelatin-PA-MN are able to effectively penetrate the epidermis of the HS tissues and then quickly dissolve, enabling the fast release of PA directly into the dermis of the HS tissues. HA-PA-MN or HA/Gelatin-PA-MN have also been found to effectively prevent or alleviate HS in a rabbit ear HS model. In conclusion, this study demonstrates that PA can be used to prevent and treat HS by simultaneously regulating HSF and HUVECs, which offers a potential novel reagent for HS management.

Ball-and-Chain Inactivation in Potassium Channels.

Carefully orchestrated opening and closing of ion channels control the diffusion of ions across cell membranes, generating the electrical signals required for fast transmission of information throughout the nervous system. Inactivation is a parsimonious means for channels to restrict ion conduction without the need to remove the activating stimulus. Voltage-gated channel inactivation plays crucial physiological roles, such as controlling action potential duration and firing frequency in neurons. The ball-and-chain moniker applies to a type of inactivation proposed first for sodium channels and later shown to be a universal mechanism. Still, structural evidence for this mechanism remained elusive until recently. We review the ball-and-chain inactivation research starting from its introduction as a crucial component of sodium conductance during electrical signaling in the classical Hodgkin and Huxley studies, through the discovery of its simple intuitive mechanism in potassium channels during the molecular cloning era, to the eventual elucidation of a potassium channel structure in a ball-and-chain inactivated state.

Hemin protects UVB-induced skin damage through inhibiting keratinocytes apoptosis and reducing neutrophil infiltration.

Ultraviolet-B (UVB) exposure on the skin triggers apoptosis, oxidative stress and acute inflammatory responses, which eventually increases the risk of various skin disorders. Hemin, an iron-binding porphyrin, has been clinically used for porphyria treatment. However, whether hemin contributes to the skin protection against UVB injury remains to be elucidated. Here, we found that hemin treatment (10 and 20 mg/kg) by intraperitoneal administration could dramatically relieve UVB irradiation-induced skin damage featured by erythema, edema, epidermal hyperplasia and collagen loss in C57BL/6 J mice. Importantly, hemin treatment attenuated UVB irradiation-triggered cell apoptosis in skin epidermis. Consistently, hemin (10, 20 µM) treatment decreased Caspase-3 activation and protected against UVB-induced apoptosis in HaCaT cells. Besides, hemin treatment reduced the infiltration of neutrophils in skin under UVB irradiation, thus restrained neutrophil extracellular traps (NET) formation and myeloperoxidase (MPO) release. We further revealed that hemin inhibited the expression of inflammation associated cytokines and chemokines in UVB-induced HaCaT cells and blocked the chemotaxis of dHL-60 cells to preconditioned media from HaCaT culture upon UVB irradiation. Furthermore, hemin inhibited the excessive maturation and mobilization of bone marrow neutrophils and rectified the proportion of abnormally elevated neutrophils in the blood under UVB irradiation. In conclusion, our study showed that hemin treatment protects against UVB-induced skin damage through inhibiting keratinocytes apoptosis, and suppressing neutrophils infiltration in the skin via externally restraining the keratinocyte attraction and internally regulating bone marrow neutrophil maturation and mobilization, suggesting that hemin is an effective drug candidate for the therapy of UVB damage.

Discovery of the novel Benzo[b]thiophene 1,1-dioxide derivatives as a potent STAT3 inhibitor against idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease of unknown aetiology with limited treatment options. Currently, only two drugs, nintedanib and pirfenidone, are approved for the clinical treatment of IPF, but their efficacies are not satisfactory. Previous studies have shown that STAT3 might be a promising therapeutic target for IPF. Here, we designed several series of compounds and finally synthesized a total of 48 novel compounds as potential STAT3 inhibitors. Notably, compound 10K was the most promising compound with excellent inhibitory activity against STAT3 phosphorylation. Subsequently, the anti-pulmonary fibrosis effect of 10K was further investigated by TGF-ß1-stimulated in vitro cell assay and bleomycin (BLM)-induced pulmonary fibrosis animal models. Specifically, compound 10K inhibited the TGF-ß1 induced fibrotic response and blocked the epithelial-mesenchymal transition (EMT) of A549 cells, and its inhibitory effect was significantly better than that of Stattic. In addition, after oral administration of 10K, the symptoms of IPF in the lung tissue in the prevention and treatment mouse models were significantly reversed, and the efficacy was comparable to that of nintedanib. Moreover, 10K improved BLM-induced imbalance of immune microenvironment in lung tissue. Taken together, these results suggest that 10K could be a potential STAT3 inhibitor for the treatment of IPF.

Vascular and Collagen Target: A Rational Approach to Hypertrophic Scar Management.

Significance: Hypertrophic scarring is a challenging issue for patients and clinicians. The prevalence of hypertrophic scarring can be up to 70% after burns, and patients suffer from pain, itching, and loss of joint mobility. To date, the exact mechanisms underlying hypertrophic scar formation are unclear, and clinical options remain limited. Recent Advances: Several studies have demonstrated that pathological scars are a type of hyperactive vascular response to wounding. Scar regression has been found to be accompanied by microvessel occlusion, which causes severe hypoxia, malnutrition, and endothelial dysfunction, suggesting the essential roles of microvessels in scar regression. Therefore, interventions that target the vasculature, such as intense pulsed light, pulsed dye lasers, vascular endothelial growth factor antibodies, and Endostar, represent potential treatments. In addition, the mass of scar-associated collagen is usually not considered by current treatments. However, collagen-targeted therapies such as fractional CO2 laser and collagenase have shown promising outcomes in scar treatment. Critical Issues: Traditional modalities used in current clinical practice only partially target scar-associated microvessels or collagen. As a result, the effectiveness of current treatments is limited and is too often accompanied by undesirable side effects. The formation of scars in the early stage is mainly affected by microvessels, whereas the scars in later stages are mostly composed of residual collagen. Traditional therapies do not utilize specific targets for scars at different stages. Therefore, more precise treatment strategies are needed. Future Directions: Scars should be classified as either "vascular-dominant" or "collagen-dominant" before selecting a treatment. In this way, strategies that are vascular-targeted, collagen-targeted, or a combination thereof could be recommended to treat scars at different stages.

Gating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel.

Understanding how ion channels gate is important for elucidating their physiological roles and targeting them in pathophysiological states. Here, we used SthK, a cyclic nucleotide-modulated channel from Spirochaeta thermophila, to define a ligand-gating trajectory that includes multiple on-pathway intermediates. cAMP is a poor partial agonist for SthK and depolarization increases SthK activity. Tuning the energy landscape by gain-of-function mutations in the voltage sensor domain (VSD) allowed us to capture multiple intermediates along the ligand-activation pathway, highlighting the allosteric linkage between VSD, cyclic nucleotide-binding (CNBD) and pore domains. Small, lateral displacements of the VSD S4 segment were necessary to open the intracellular gate, pointing to an inhibitory VSD at rest. We propose that in wild-type SthK, depolarization leads to such VSD displacements resulting in release of inhibition. In summary, we report conformational transitions along the activation pathway that reveal allosteric couplings between key sites integrating to open the intracellular gate.

Extracellular fluid viscosity enhances cell migration and cancer dissemination.

Cells respond to physical stimuli, such as stiffness1, fluid shear stress2 and hydraulic pressure3,4. Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer5. However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na+/H+ exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.