A facile and scalable method to synthesize PEGylated PDMAEMA for gene delivery.

In recent years, cationic polymer vectors have been viewed as a promising method for delivering nucleic acids. With the advancement of synthetic polymer chemistry, we can control chemical structures and properties to enhance the efficacy of gene delivery. Herein, a facile, cost-effective, and scalable method was developed to synthesize PEGylated PDMAEMA polymers (PEO-PDMAEMA-PEO), where PEGylation could enable prolonged polyplexes circulation time in the blood stream. Two polymers of different molecular weights were synthesized, and polymer/eGFP polyplexes were prepared and characterized. The correlation between polymers' molecular weight and physicochemical properties (size and zeta potential) of polyplexes was investigated. Lipofectamine 2000, a commercial non-viral transfection reagent, was used as a standard control. PEO-PDMAEMA-PEO with higher molecular weight exhibited slightly better transfection efficiency than Lipofectamine 2000, and the cytotoxicity study proved that it could function as a safe gene vector. We believe that PEO-PDMAEMA-PEO could serve as a model to investigate more potential in the gene delivery area.

Clinical Value of the Diagonal Earlobe Crease in Patients with Chest Pain for Diagnosing Coronary Heart Disease.

Purpose: To investigate the clinical application value of diagonal earlobe crease (DELC) in patients with chest pain for the diagnosis of coronary heart disease (CHD) and to construct a risk model by multivariate logistic regression. Patients and Methods: Our trial enrolled prospectively and consecutively 706 chest pain patients with suspected CHD between January 2021 to June 2023 from Chengde Central Hospital. According to coronary angiography results, they were categorized into the CHD (n=457) and non-CHD groups (n=249). Results: The trial demonstrated a significant positive relationship between DELC and CHD. Independent risk factors were sex, age, hypertension, diabetes mellitus, LP (a), Cys C, and DELC, whilst HDL-C was a protective factor, for CHD. Patients with-DELC were older than those in the without-DELC arm (P<0.001) and had a higher proportion of males than females (61.6% vs 50.0%, P=0.026). After multifactorial correction, independent risk factors for CHD included DELC (OR=1.660, 95% CI:1.153 to 2.388, P=0.006), age (OR=1.024, 95% CI:1.002 to 1.045, P=0.030), gender (OR=1.702, 95% CI:1.141 to 2.539, P=0.009), hypertension (OR=1.744, 95% CI:1.226 to 2.482, P=0.002), diabetes mellitus (OR=2.113, 95% CI:1.404 to 3.179, P<0.001), LP(a) (OR=1.010, 95% CI:1.003 to 1.017, P=0.005), Cys C (OR=3.549, 95% CI:1.605 to 7.846, P=0.002). The Hosmer and Lemeshow (H-L) test (P=0.818) suggests a high goodness of fit, and the area under the ROC curve was calculated to be 0.721 (95% CI:0.682 to 0.760, P<0.001), which demonstrates that the model has a superior diagnostic value for CHD. Conclusion: DELC is an independent risk factor for CHD after adjusting for sex, age, hypertension, diabetes mellitus, smoking index, LP (a), Cys C, and HDL-C. Our model can be used clinically for assessing the risk of CHD.

Efficacy and Safety of a Pharmaco-Invasive Strategy Using Half-Dose Recombinant Human Prourokinase in Patients with ST-Segment Elevation Myocardial Infarction During Hospitalization.

This study investigated the efficacy and safety of pharmaco-invasive strategy with half-dose recombinant human prourokinase (PHDP) during hospitalization for patients with ST-segment elevation myocardial infarction (STEMI) to provide references for the treatment of STEMI. Patients with STEMI who fulfilled the inclusion and exclusion criteria and attended Chengde Central Hospital, Hebei Province, China, between September 3, 2019, and December 28, 2021, were included in this study. The experimental group received PHDP and the control group underwent primary percutaneous coronary intervention (PPCI). This study enrolled 150 patients with STEMI, 75 in the experimental group and 75 in the control group. Coronary angiography revealed successful thrombolysis in 64 (85.33%) patients. Compared with the control group, the experimental group had shorter first medical contact-reperfusion time (P < 0.001), less slow flow/no-reflow (P < 0.001), and a lower utilization rate of Tirofiban (P < 0.001). Validity endpoints: no statistically significant differences between the two groups. Safety endpoints: no statistically significant differences between bleeding and major adverse cardiovascular and cerebrovascular events (MACCEs), but the experimental group was more prone to arrhythmias (P = 0.040), particularly premature ventricular beats (PVB) (P = 0.008). In conclusion, the efficacy and safety of PHDP in the treatment of patients with STEMI were positive. Complete epicardial and myocardial reperfusion rates, risk for bleeding during hospitalization, and incidence of MACCEs were similar to those of the PPCI strategy. Although the PHDP group has a higher incidence of PVB, it does not increase the incidence of malignant arrhythmia. This study aimed to provide a new therapeutic strategy for the treatment of STEMI in hospitals without adequate PPCI resources condition.

A Semisynthesis Platform for the Efficient Production and Exploration of Didemnin-Based Drugs.

Plitidepsin (or dehydrodidemnin B), an approved anticancer drug, belongs to the didemnin family of cyclic depsipeptides, which are found in limited quantities in marine tunicate extracts. Herein, we introduce a new approach that integrates microbial and chemical synthesis to generate plitidepsin and its analogues. We screened a Tistrella strain library to identify a potent didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in a didemnin B titer of approximately 75 mg/L. Next, we developed two straightforward chemical strategies to convert didemnin B into plitidepsin, one of which involved a one-step synthetic route giving over 90 % overall yield. Furthermore, we synthesized 13 new didemnin derivatives and three didemnin probes, enabling research into structure-activity relationships and interactions between didemnin and proteins. Our study highlights the synergistic potential of biosynthesis and chemical synthesis in overcoming the challenge of producing complex natural products sustainably and at scale.

Charge transfer doping of graphene oxide with nickel oxide nanoparticles for stable and efficient carbon-based, all-inorganic CsPbBr3 perovskite solar cells.

All-inorganic CsPbBr3 perovskite solar cells have received growing attention in the photovoltaic field due to their high stability, low cost, and simple preparation processes. However, the high-density defects in perovskite films and the large energy differences at interfaces have been the main challenges for achieving high power conversion efficiency and good stability. In this work, nickel oxide (NiOx) decorated graphene oxide (GO) is used as a hole collector at the perovskite/carbon interface for a carbon-based CsPbBr3 perovskite solar cell. The crystallinity of the CsPbBr3 perovskite layer and the hole extraction ability are markedly enhanced because of the p-type charge transfer doping of GO from oxygenic groups to NiOx. Finally, the all-inorganic CsPbBr3 perovskite solar cell achieves a power conversion efficiency of 8.59%. More importantly, the best solar cell free of encapsulation retains 94.2% of its initial efficiency in an air environment over 21 days.

Bavachin induces apoptosis in colorectal cancer cells through Gadd45a via the MAPK signaling pathway.

Bavachin is a dihydroflavonoid compound isolated from Psoralea corylifolia, and exhibits anti-bacterial, anti-inflammatory, anti-tumor and lipid-lowering activities. Recent attention has gradually drawn on bavachin-induced apoptosis in many human cancer cell lines. However, the anti-cancer effects and related mechanisms in colorectal cancer remain unknown. Here, we investigated the effects of bavachin on colorectal cancer in vivo and in vitro. The results showed that bavachin inhibited the proliferation of human colorectal cancer cells and induce apoptosis. These changes were mediated by activating the MAPK signaling pathway, which significantly up-regulated the expression of Gadd45a. Furthermore, Gadd45a silencing obviously attenuated bavachin-mediated cell apoptosis. Inhibition of the MAPK signaling pathway by JNK/ERK/p38 inhibitors also weakened the up-regulation of Gadd45a by bavachin. The anticancer effect of bavachin was also validated using a mouse xenograft model of human colorectal cancer. In conclusion, these findings suggest that bavachin induces the apoptosis of colorectal cancer cells through activating the MAPK signaling pathway.

Strain Modulation for Light-Stable n-i-p Perovskite/Silicon Tandem Solar Cells.

Perovskite/silicon tandem solar cells are promising to penetrate photovoltaic market. However, the wide-bandgap perovskite absorbers used in top-cell often suffer severe phase segregation under illumination, which restricts the operation lifetime of tandem solar cells. Here, a strain modulation strategy to fabricate light-stable perovskite/silicon tandem solar cells is reported. By employing adenosine triphosphate, the residual tensile strain in the wide-bandgap perovskite absorber is successfully converted to compressive strain, which mitigates light-induced ion migration and phase segregation. Based on the wide-bandgap perovskite with compressive strain, single-junction solar cells with the n-i-p layout yield a power conversion efficiency (PCE) of 20.53% with the smallest voltage deficits of 440 mV. These cells also maintain 83.60% of initial PCE after 2500 h operation at the maximum power point. Finally, these top cells are integrated with silicon bottom cells in a monolithic tandem device, which achieves a PCE of 26.95% and improved light stability at open-circuit.

Corrigendum: Baicalein and Baicalin Promote Melanoma Apoptosis and Senescence via Metabolic Inhibition.

[This corrects the article DOI: 10.3389/fcell.2020.00836.].

Novel ABA block copolymers: preparation, temperature sensitivity, and drug release.

A new PEGylated macroiniferter was prepared based on the polycondensation reaction of polyethylene oxide (PEO), methylene diphenyl diisocyanate (MDI), and 1,1,2,2-tetraphenyl-1,2-ethanediol (TPED). The macroiniferter consists of PEO end groups and readily reacts with acrylamides (such as N-isopropylacrylamide, NIPAM) and forms ABA block copolymers (PEO-PNIPAM-PEO). This approach of making amphiphilic ABA block copolymers is robust, versatile, and useful, particularly for the development of polymers for biomedical applications. The resulting amphiphilic PEO-PNIPAM-PEO block copolymers are also temperature sensitive, and their phase transition temperatures are close to human body temperature and therefore they have been applied as drug carriers for cancer treatment. Two PEO-PNIPAM-PEO polymers with different molecular weights were prepared and selected to make temperature-sensitive micelles. As a result of the biocompatibility of these micelles, cell viability tests proved that these micelles have low toxicity toward cancer cells. The resultant polymer micelles were then used as drug carriers to deliver the hydrophobic anticancer drug doxorubicin (DOX), and the results showed that they exhibit significantly higher cumulative drug release efficiency at higher temperatures. Moreover, after loading DOX into the micelles, cellular uptake experiments showed easy uptake and cell viability tests showed that DOX-loaded micelles possess a better therapeutic effect than free DOX at the same dose.

Keratin-tannic acid complex nanoparticles as pH/GSH dual responsive drug carriers for doxorubicin.

Drug-loaded nanoparticles have been widely used in the field of tumor treatment due to their low side effects and reduced frequency of administration. In this study, pH and glutathione (GSH) dual-responsive keratin-tannic acid (TA) complex nanoparticles were established to trigger drug release under tumor microenvironments. Reductive keratin was first extracted using a reduction method. Then, keratin-TA complex nanoparticles (KNPs) were self-assembled via non-covalent interaction and further stabilized by self-crosslinking of thiols. This method was facile and green without chemicals during the whole procedure. KNPs exhibited pH and GSH dual responsiveness as well as charge reversibility in the simulated tumor microenvironment. The anticancer drug of doxorubicin (DOX) was loaded on KNPs by hydrophobicity and hydrogen bonds. Drug-loaded KNPs accelerated drug release under mimicked tumor microenvironments, performing high toxic against A549 cells while low toxic on normal cells. Besides, drug-loaded nanoparticles could be endocytosed by tumor cells. Based on these results, KNPs may serve as drug carriers for therapeutic delivery.

Baicalein and Baicalin Promote Melanoma Apoptosis and Senescence via Metabolic Inhibition.

Malignant melanoma is one of the most common and dangerous skin cancers with a high rate of death every year. Furthermore, N-RAS and B-RAF mutations in melanoma cells increase the difficulties for clinical treatment in patients. Therefore, development of effective and universal drugs against melanoma is urgently needed. Here we demonstrate that baicalein and baicalin, the active components of the Chinese traditional medicinal plant Scutellaria baicalensis Georgi, can significantly inhibit melanoma cell growth and proliferation, suppress tumor cell colony formation and migration, as well as induce apoptosis and senescence in melanoma cells. The anti-tumor effects mediated by baicalein and baicalin are independent of N-RAS and B-RAF mutation statuses in melanoma cells. Mechanistically, we identify that the suppression of baicalein and baicalin on melanoma cells is due to inhibition of tumor cell glucose uptake and metabolism by affecting the mTOR-HIF-1α signaling pathway. In addition, we demonstrated that baicalein and baicalin can suppress tumorigenesis and tumor growth in vivo in the melanoma model. These studies clearly indicate that baicalein and baicalin can control tumor growth and development metabolically and have great potential as novel and universal drugs for melanoma therapy.

Keratin-dopamine conjugate nanoparticles as pH/GSH dual responsive drug carriers.

Drug-loaded nanoparticles have been widely used in the field of tumor treatment due to their low side effects and reduced frequency of administration. In this study, keratin-dopamine conjugate was first synthesized by amidation reaction and then formed nanoparticles by self-polymerization of dopamine segment. Keratin-dopamine conjugate nanoparticles (KNPs) exhibited pH and glutathione (GSH) dual responsiveness in the simulated tumor environment. These nanoparticles were able to load anti-cancer drug doxorubicin (DOX) through electrostatic interactions and hydrogen bonds. These drug-loaded KNPs (DKNPs) exhibited controlled drug release in a tumor simulation environment. Meanwhile, DKNPs performed a stronger inhibitory effect on tumor cells compared with human normal tissue cells. Based on the above results, keratin-dopamine conjugate based drug carriers had a broad prospect in the field of cancer treatment.

Self-crosslinked keratin nanoparticles for pH and GSH dual responsive drug carriers.

Nano-drug delivery system (NDDS) has attracted widespread attention for their controlled drug release. In this work, keratin nanoparticles (KNPs) were prepared by self-crosslinking. No toxic chemical crosslinkers were added in the whole procedure. The morphology and size of KNPs were tested by transmission electron microscopy (TEM) and dynamic light scattering (DLS), respectively. The KNPs exhibited GSH and pH dual responsiveness as well as charge conversion, which were beneficial to tumor therapy. In addition, the anticancer drug of doxorubicin (DOX) could be loaded on KNPs by hydrophobicity and hydrogen bonds. The drug-loaded keratin nanoparticles (KDNPs) accelerated drug release under mimicked tumor microenvironments. In addition, KDNPs could effectively inhibit tumor cell growth while performing low toxicity on normal cells. Moreover, KDNPs could be uptaken by tumor cells through endocytosis. Based on the results, keratin-based nanoparticles were suitable candidates for drug microcarriers.

Keratin-Poly(2-methacryloxyethyl phosphatidylcholine) Conjugate-Based Micelles as a Tumor Micro-Environment-Responsive Drug-Delivery System with Long Blood Circulation.

Drug-loaded micelles with long circulation time in blood and stimuli-responsiveness under the tumor micro-environment can significantly enhance therapeutic efficacy. In this report, human hair keratin was extracted with a reduction method and then conjugated with zwitterionic poly(2-methacryloxyethyl phosphatidylcholine, MPC) via thiol chain transfer polymerization (thiol CTP). Subsequently, keratin-polyMPC conjugates (KPC) were prepared into micelles and loaded with doxorubicin (DOX) by self-assembly. These micelles exhibited pH, glutathione (GSH), and enzyme triple-responsiveness as well as charge reversibility under the tumor micro-environment. In addition, these micelles showed high toxicity against A549 cells while low toxicity to normal cells. In vivo anticancer efficacy results revealed that these micelles showed better therapeutic efficiency than free DOX. Furthermore, these carriers exhibited prolonged circulation time, good stability, and no hemolysis in blood. Based on the results, these drug delivery systems of micelles were proper candidates as drug carriers.

PCL/sulfonated keratin mats for vascular tissue engineering scaffold with potential of catalytic nitric oxide generation.

Heparin-like polymers have a good anticoagulant effect due to some groups similar to heparin. Herein, sulfonated keratin(SK) was prepared by chain transfer radical polymerization of 3-sulfopropyl methacrylate(SPMA) to improve blood coagulation nature of keratin. Poly(ε-caprolactone)(PCL)/SK nanofibrous mats with the ratio of 7 and 3 were then fabricated by electrospinning. In vitro cytotoxicity and blood compatibility tests were performed to assess the biocompatibility. Viability of NIH 3T3 cells on PCL/SK mats was higher than that on the pristine PCL mats, indicating their good cytocompatibility. These sulfonated keratin-containing mats enhanced endothelial cell growth, while inhibited smooth muscle cell proliferation and reduced platelet adhesion in the presence of GSH and GSNO, as a result of NO generation. Furthermore, the biocomposite mats prolonged the activated partial thromboplastin time(APTT) effectively without hemolysis. Taken together, PCL/SK mats are potential for applications in vascular tissue engineering.

Polysaccharide enhanced NK cell cytotoxicity against pancreatic cancer via TLR4/MAPKs/NF-κB pathway in vitro/vivo.

A polysaccharide isolated from Strongylocentrotus nudus eggs (SEP) reportedly displays immune activity in vivo. Here, its effect and underlying mechanism in the treatment of pancreatic cancer were investigated. SEP obviously inhibited pancreatic cancer growth by activating NK cells in vitro/vivo via TLR4/MAPKs/NF-κB signaling pathway, The tumor inhibitory rate achieved to 44.5% and 50.8% at a dose of 40 mg/kg in Bxpc-3 and SW1990 nude mice, respectively. Moreover, SEP obviously augmented the Gemcitabine (GEM) antitumor effect by upregulating NKG2D, which improved the sensitivity of NK cells targeting to its ligand MICA; meanwhile, the antitumor inhibitory rate was 68.6% in BxPC-3 tumor-bearing mice. Moreover, SEP reversed GEM-induced apoptosis and atrophy in both spleen and bone marrow via suppressing ROS secretion in vivo. These results suggested that pancreatic cancer was effectively inhibited by SEP-enhanced NK cytotoxicity mediated primarily through TLR4/MAPKs/NF-κB signaling pathway, representing a potential immunotherapy candidate for the treatment of pancreatic cancer.