When the production of reactive oxygen species (ROS) is overloaded surpassing the capacity of the reductive rheostat, mammalian cells undergo a series of oxidative damage termed oxidative stress ...(OS). This phenomenon is ubiquitously detected in many human pathological conditions. Wound healing program implicates continuous neovascularization, cell proliferation, and wound remodeling. Increasing evidence indicates that reactive oxygen species (ROS) have profound impacts on the wound healing process through regulating a series of the physiological and pathological program including inflammatory response, cell proliferation, angiogenesis, granulation as well as extracellular matrix formation. In most pathological wound healing processes, excessive ROS exerts a negative role on the wound healing process. Interestingly, the moderate increase of ROS levels is beneficial in killing bacteria at the wound site, which creates a sterile niche for revascularization. In this review, we discussed the physiological rhythms of wound healing and the role of ROS in this progress, aim to explore the potential manipulation of OS as a promising therapeutic avenue.
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•ROS regulates the wound healing process by affecting inflammation, cell proliferation, angiogenesis, granulation formation, and extracellular matrix formation.•Excess ROS negatively affects the healing process in most pathological wounds.•Moderate elevation of ROS facilitates the re-establishment of a sterile ecological niche at the wound site.•Targeting oxidative stress therapy prompts clinical wound healing treatment.
Methylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis of diabetic vascular complications, including endothelial cell apoptosis induced by oxidative ...stress. Metformin (MET), a widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation and limit cell apoptosis. However, the molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Protein expression and protein phosphorylation were investigated using western blotting, ELISA, and immunohistochemical staining, respectively. Cell viability and apoptosis were assessed by the MTT assay, TUNEL staining, and Annexin V-FITC and propidium iodide double staining. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results revealed that MET prevented MGO-induced HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3, and attenuated MGO-induced mitochondrial morphological alterations in a dose-dependent manner. MET pretreatment also significantly suppressed MGO-stimulated ROS production, increased signaling through the ROS-mediated PI3K/Akt and Nrf2/HO-1 pathways, and markedly elevated the levels of its downstream antioxidants. Finally, similar results were obtained in vivo, and we demonstrated that MET prevented MGO-induced oxidative damage, apoptosis, and inflammation. As expected, MET reversed MGO-induced downregulation of Nrf2 and p-Akt. In addition, a PI3K inhibitor (LY-294002) and a Nrf2 inhibitor (ML385) observably attenuated the protective effects of MET on MGO-induced apoptosis and ROS generation by inhibiting the Nrf2/HO-1 pathways, while a ROS scavenger (NAC) and a permeability transition pores inhibitor (CsA) completely reversed these effects. Collectively, these findings broaden our understanding of the mechanism by which MET regulates apoptosis induced by MGO under oxidative stress conditions, with important implications regarding the potential application of MET for the treatment of diabetic vascular complications.
Objectives
To evaluate the prediction performance of deep convolutional neural network (DCNN) based on ultrasound (US) images for the assessment of breast cancer molecular subtypes.
Methods
A dataset ...of 4828 US images from 1275 patients with primary breast cancer were used as the training samples. DCNN models were constructed primarily to predict the four St. Gallen molecular subtypes and secondarily to identify luminal disease from non-luminal disease based on the ground truth from immunohistochemical of whole tumor surgical specimen. US images from two other institutions were retained as independent test sets to validate the system. The models’ performance was analyzed using per-class accuracy, positive predictive value (PPV), and Matthews correlation coefficient (MCC).
Results
The model achieved good performance in identifying the four breast cancer molecular subtypes in the two test sets, with accuracy ranging from 80.07% (95% CI, 76.49–83.23%) to 97.02% (95% CI, 95.22–98.16%) and 87.94% (95% CI, 85.08–90.31%) to 98.83% (95% CI, 97.60–99.43) for the two test cohorts for each sub-category, respectively. In terms of 4-class weighted average MCC, the model achieved 0.59 for test cohort A and 0.79 for test cohort B. Specifically, the DCNN also yielded good diagnostic performance in discriminating luminal disease from non-luminal disease, with a PPV of 93.29% (95% CI, 90.63–95.23%) and 88.21% (95% CI, 85.12–90.73%) for the two test cohorts, respectively.
Conclusion
Using pretreatment US images of the breast cancer, deep learning model enables the assessment of molecular subtypes with high diagnostic accuracy.
Trial registration
Clinical trial number: ChiCTR1900027676
Key Points
• Deep convolutional neural network (DCNN) helps clinicians assess tumor features with accuracy.
• Multicenter retrospective study shows that DCNN derived from pretreatment ultrasound imagine improves the prediction of breast cancer molecular subtypes.
• Management of patients becomes more precise based on the DCNN model.
Trace fossils represent records of the activity of both epifaunal and infaunal animals, providing significant information for a deeper understanding of Earth's past environments and ecosystems. ...Increasingly, more and more ichno-metrics (quantitative ichnological indicators) have been proposed and applied to critical geological intervals as a methodology to assess the mechanisms and timing of biotic recoveries following mass extinctions. However, detailed assessment of the robustness and the scope of their applications is needed before we place them on more solid theoretical grounds. This paper presents a critical review of a range of popularly used ichnological parameters, including ichnodiversity, bioturbation index, ichnofabric index, bedding plane bioturbation index, burrow size, complexity, tiering, key ichnotaxa and some new parameters (e.g., ichnodisparity) with respect to their applicability and relative robustness as proxies for assessing the pacing of marine ecosystem recovery following major biotic perturbations, with a particular reference to the end-Permian mass extinction event. A detailed summary of the significance and caveats of each parameter is also provided. We suggest that bedding plane bioturbation index remains to be explored to indicate recovery while ichnodisparity holds potential to assess biotic recovery in future studies. Key ichnotaxa (e.g., Rhizocorallium and Thalassinoides) that are produced by malacostracan crustaceans, among other organisms, can be reliable indicators of environmental stability and ecosystem recovery. Further, we propose that the overall low bioturbation intensities may have substantially influenced marine elemental cycling during the Permian–Triassic transition that led to a possible drawdown of sulfate concentration in the Early Triassic oceans through enhanced pyrite burial.
•Discussion on significance and caveats of ichno-parameters for assessing recovery;•Ichnodisparity is a new promising parameter to assess infaunal biotic recovery;•Malacostracan crustacean traces are suggested as reliable indicators of ecosystem recovery;•Global data suggest a reduction of burrow sizes of trace makers in the Early Triassic;•Early Triassic low sulfate concentration may be linked to low bioturbation intensities.
Detection of the pulse signal at low signal-to-noise ratio (SNR) is difficult but meaningful. Some documents have already used coupled Duffing oscillators to detect non-periodic pulse signal, but ...those oscillators have a few defects. This Letter presents a type of strong coupled Duffing oscillators system, and by using the generalised time scale transformation, the system can detect signal with any sampling frequency. The system is coupled by damping force and restoring force of the oscillators and has characteristics of high synchronisation speed and high coupling degree. The simulation results show that the system can detect large amplitude signal, large time-width pulse, and plus–minus signal, and the detection SNR is lower than −27 dB.
Coronavirus disease 2019 (COVID-19), which has high incidence rates with rapid rate of transmission, is a pandemic that spread across the world, resulting in more than 3,000,000 deaths globally. ...Currently, several drugs have been used for the clinical treatment of COVID-19, such as antivirals (radecivir, baritinib), monoclonal antibodies (tocilizumab), and glucocorticoids (dexamethasone). Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are essential regulators of virus infections and antiviral immune responses including biological processes that are involved in the regulation of COVID-19 and subsequent disease states. Upon viral infections, cellular lncRNAs directly regulate viral genes and influence viral replication and pathology through virus-mediated changes in the host transcriptome. Additionally, several host lncRNAs could help the occurrence of viral immune escape by inhibiting type I interferons (IFN-1), while others could up-regulate IFN-1 production to play an antiviral role. Consequently, understanding the expression and function of lncRNAs during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection will provide insights into the development of lncRNA-based methods. In this review, we summarized the current findings of lncRNAs in the regulation of the strong inflammatory response, immune dysfunction and thrombosis induced by SARS-CoV-2 infection, discussed the underlying mechanisms, and highlighted the therapeutic challenges of COVID-19 treatment and its future research directions.
Aims
MicroRNA-103 (miR-103) family plays important roles in regulating glucose homeostasis in type 2 diabetes mellitus (DM2). However, the underlying mechanisms remain poorly characterized. The ...objective of this study was to test the hypothesis that circulating miR-103a and miR-103b, which regulate CAV-1 and SFRP4, respectively, are novel biomarkers for diagnosis of DM2.
Methods
We determined the predictive potential of circulating miR-103a and miR-103b in pre-DM subjects (pre-DM), noncomplicated diabetic subjects, and normal glucose-tolerance individuals (control) using bioinformatic analysis, qRT-PCR, luciferase assays, and ELISA assays.
Results
We found that both miR-103a and miR-103b had high complementarity and conservation, modulated reporter gene expression through seed sequences in the 3′UTRs of CAV-1 and SFRP4 mRNA, and negatively regulated their mRNA and protein levels, respectively. We also found that increased miR-103a and decreased miR-103a in plasma were significantly and negatively correlated with reduced CAV-1 levels and elevated SFRP4 levels in pre-DM and DM2, respectively, and were significantly associated with glucose metabolism, HbA1c levels, and other DM2 risk factors for progression from a normal individual to one with pre-DM. Furthermore, we demonstrated that the reciprocal changes in circulating miR-103a and miR-103b not only provided high sensitivity and specificity to differentiate the pre-DM population but also acted as biomarkers for predicting DM2 with high diagnostic value.
Conclusions
These findings suggest that circulating miR-103a and miR-103b may serve as novel biomarkers for diagnosis of DM2, providing novel insight into the mechanisms underlying pre-DM.
Alterations in the vascular smooth muscle cells (VSMC) phenotype play a critical role in the pathogenesis of several cardiovascular diseases, including hypertension, atherosclerosis, and restenosis ...after angioplasty. MicroRNAs (miRNAs) are a class of endogenous noncoding RNAs (approximately 19–25 nucleotides in length) that function as regulators in various physiological and pathophysiological events. Recent studies have suggested that aberrant miRNAs’ expression might underlie VSMC phenotypic transformation, appearing to regulate the phenotypic transformations of VSMCs by targeting specific genes that either participate in the maintenance of the contractile phenotype or contribute to the transformation to alternate phenotypes, and affecting atherosclerosis, hypertension, and coronary artery disease by altering VSMC proliferation, migration, differentiation, inflammation, calcification, oxidative stress, and apoptosis, suggesting an important regulatory role in vascular remodeling for maintaining vascular homeostasis. This review outlines recent progress in the discovery of miRNAs and elucidation of their mechanisms of action and functions in VSMC phenotypic regulation. Importantly, as the literature supports roles for miRNAs in modulating vascular remodeling and for maintaining vascular homeostasis, this area of research will likely provide new insights into clinical diagnosis and prognosis and ultimately facilitate the identification of novel therapeutic targets.
A biomimetic mineralization method was used in the facile and rapid preparation of nanoflowers for immobilizing alcohol dehydrogenase (ADH). The method mainly uses ADH as an organic component and ...zinc phosphate as an inorganic component to prepare flower-like ADH/Zn
(PO
)
organic-inorganic hybrid nanoflowers (HNFs) with the high specific surface area through a self-assembly process. The synthesis conditions of the ADH HNFs were optimized and its morphology was characterized. Under the optimum enzymatic reaction conditions, the Michaelis-Menten constant (
) of ADH HNFs (β-NAD
as substrate) was measured to be 3.54 mM, and the half-maximal inhibitory concentration (IC
) of the positive control ranitidine (0.2-0.8 mM) was determined to be 0.49 mM. Subsequently, the inhibitory activity of natural medicine
Pursh and nine small-molecule compounds on ADH was evaluated using ADH HNFs. The inhibition percentage of the aqueous extract of
is 57.9%. The vanillic acid, protocatechuic acid, gallic acid, and naringenin have obvious inhibitory effects on ADH, and their percentages of inhibition are 55.1%, 68.3%, 61.9%, and 75.5%, respectively. Moreover, molecular docking analysis was applied to explore the binding modes and sites of the four most active small-molecule compounds to ADH. The results of this study can broaden the application of immobilized enzymes through biomimetic mineralization, and provide a reference for the discovery of ADH inhibitors from natural products.
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