Development of Novel ß-Carboline/Furylmalononitrile Hybrids as Type I/II Photosensitizers with Chemo-Photodynamic Therapy and Minimal Toxicity.

Chemo-photodynamic therapy is a treatment method that combines chemotherapy and photodynamic therapy and has demonstrated significant potential in cancer treatment. However, the development of chemo-photodynamic therapeutic agents with fewer side effects still poses a challenge. Herein, we designed and synthesized a novel series of ß-carboline/furylmalononitrile hybrids 10a-i and evaluated their chemo-photodynamic therapeutic effects. Most of the compounds were photodynamically active and exhibited cytotoxic effects in four cancer cells. In particular, 10f possessed type-I/II photodynamic characteristics, and its 1O2 quantum yield increased by 3-fold from pH 7.4 to 4.5. Most interestingly, 10f exhibited robust antiproliferative effects by tumor-selective cytotoxicities and hypoxic-overcoming phototoxicities. In addition, 10f generated intracellular ROS and induced hepatocellular apoptosis, mitochondrial damage, and autophagy. Finally, 10f demonstrated extremely low acute toxicity (LD50 = 1415 mg/kg) and a high tumor-inhibitory rate of 80.5% through chemo-photodynamic dual therapy. Our findings may provide a promising framework for the design of new photosensitizers for chemo-photodynamic therapy.

Research progress of prodrugs for the treatment of cerebral ischemia.

It is well-known that pharmacotherapy plays a pivotal role in the treatment and prevention of cerebral ischemia. Nevertheless, existing drugs, including numerous natural products, encounter various challenges when applied in cerebral ischemia treatment. These challenges comprise poor brain absorption due to low blood-brain barrier (BBB) permeability, limited water solubility, inadequate bioavailability, poor stability, and rapid metabolism. To address these issues, researchers have turned to prodrug strategies, aiming to mitigate or eliminate the adverse properties of parent drug molecules. In vivo metabolism or enzymatic reactions convert prodrugs into active parent drugs, thereby augmenting BBB permeability, improving bioavailability and stability, and reducing toxicity to normal tissues, ultimately aiming to enhance treatment efficacy and safety. This comprehensive review delves into multiple effective prodrug strategies, providing a detailed description of representative prodrugs developed over the past two decades. It underscores the potential of prodrug approaches to improve the therapeutic outcomes of currently available drugs for cerebral ischemia. The publication of this review serves to enrich current research progress on prodrug strategies for the treatment and prevention of cerebral ischemia. Furthermore, it seeks to offer valuable insights for pharmaceutical chemists in this field, offer guidance for the development of drugs for cerebral ischemia, and provide patients with safer and more effective drug treatment options.

Research on structural strengthening technology for regenerative denitration catalysts.

The cost of replacing failed selective catalytic reduction (SCR) catalysts and their disposal as hazardous solid waste is high. If failed catalysts are recovered and regenerated into new SCR denitration catalysts, the cost of flue gas denitration can be effectively reduced. However, regenerated SCR catalysts have relatively low structural strength and activity and cannot yet form an effective replacement. In this study, aluminum dihydrogen phosphate, aluminum nitrate, and aluminum sulfate were used as structural strengthening agents in the regeneration of SCR catalysts, and over-impregnation, drumming-assisted impregnation, and ultrasonic-assisted preparation techniques were compared. The corresponding regenerated SCR catalysts were then prepared and analyzed for compressive strength, wear strength, H2-TPR, NH3-TPD, and in situ IR. Factors influencing the structural strength, physical properties, and catalytic activity of the regenerated catalysts were investigated. The best results were obtained as follows: compressive strength of 4.57 MPa, wear rate of 0.088% kg-1, and denitration of 58% after 10 min of drumming-assisted impregnation in an aluminum sulfate solution with a concentration of 16%. Based on this, a synergistic method for catalyst activity and structural strengthening was explored to support the design of better SCR catalysts for regeneration.

Precise tumor delineation in clinical tissues using a novel acidic tumor microenvironment activatable near-infrared fluorescent contrast agent.

Tumor selective near-infrared (NIR) fluorescent contrast agents has the potential to greatly enhance the efficiency and precision of tumor surgery by enabling real-time tumor margin identification for tumor resection guided by imaging. However, the development of these agents is still challenging. In this study, based on the acidic tumor microenvironment (TME), we designed and synthesized a novel pH-sensitive NIR fluorescent contrast agent OBD from ß-carboline. The fluorescence quantum yield of OBD exhibited a notable increase at pH 3.6, approximately 12-fold higher compared to its value at pH 7.4. After cellular uptake, OBD lighted up the cancer cells with high specificity and accumulated in the mitochondria. Spraying OBD emitted selective fluorescence in xenograft tumor tissues with tumor-to-normal tissue ratios (TNR) as high as 11.18, implying successful image-guided surgery. Furthermore, OBD was also shown to track metastasis in spray mode. After simple topical spray, OBD rapidly and precisely visualized the tumor margins of clinical colon and liver tissues with TNR over 4.2. Therefore, the small-molecule fluorescent contrast agent OBD has promising clinical applications in tumor identification during surgery.

Rational design of ß-carboline as an efficient type I/II photosensitizer to enable hypoxia-tolerant chemo-photodynamic therapy.

Photodynamic therapy (PDT) is a clinically approved treatment for cancer due to its high spatiotemporal selectivity and non-invasive modality. However, its therapeutic outcomes are always limited to the severe hypoxia environment of the solid tumor. Herein, two novel photosensitizers HY and HYM based on naturally antitumor alkaloids ß-carboline were designed and synthesized. Through a series of experiments, we found HY and HYM can produce type II ROS (singlet oxygen) after light irradiation. HYM had higher singlet oxygen quantum yield and molar extinction coefficient than HY, as well as type I PDT behavior, which further let us find that HYM could exhibit robust phototoxicity activities in both normoxia and hypoxia. Meanwhile, HYM showed tumor-selective cytotoxicity with minimal toxicity toward normal cells. Notably, thanks to HYM's hypoxia-tolerant type I/II PDT and tumor selective chemotherapy, HYM showed synergistic inhibitory effect on tumor growth (inhibition rate > 91%). Our research provides a promising photosensitizer for hypoxia-tolerant chemo-photodynamic therapy, and may also give a novel molecular skeleton for photosensitizer design.

Combined effects of bacteria and antibiotics on surface properties and transport of nanoplastics in porous media.

Currently, research on the individual effects of bacteria and antibiotics on the transport of nanoplastics (NPs) in porous media is in its infancy, while research on their combined effect is absent. It is well known that bacteria and antibiotics also interact with each other, so this synergistic transport of bacteria, antibiotics, and NPs in porous media must be very interesting. For exploring this aspect, we investigated the individual and combined effects of bacteria and antibiotics on the transport of polystyrene NPs (PS-NPs) in saturated porous media. Hydrophobicity, roughness, and the Derjaguin-Landau-Verwey-Overbeek (DLVO) interaction energy were measured and calculated. The PS-NPs' transport in porous media was fitted using a mathematical model. Enhanced roughness and size of PS-NPs with increased bacterial concentration dominated and inhibited the PS-NPs' transport in porous media, although the hydrophilicity of PS-NPs and the energy barrier between PS-NPs and porous media were also increased. An increase in antibiotic concentration reduced the energy barrier between PS-NPs and porous media, thereby decreasing the PS-NPs' transport. Combined effects of bacteria and antibiotics on the PS-NPs' transport were complex and distinct from individual effects, but the mechanisms were clear. Roughness and hydrophilicity of PS-NPs and the DLVO interaction energy between PS-NPs and porous media together influenced this process. In the presence of bacteria, antibiotics could alter the bacterial surface roughness by altering bacterial extracellular polymeric substances, and thus alter the PS-NPs' surface roughness, thereby affecting the PS-NPs' transport in porous media. When antibiotics were present, enhanced bacterial concentration increased the PS-NPs' hydrophilicity and the energy barrier between PS-NPs and porous media, thus promoting the PS-NPs' transport. The findings of this study provided a theoretical basis for clarifying the transport of NPs in porous media under complex environments, facilitating a reduction in environmental pollution of NPs.

The Use of Pyrolytic Char Derived from Waste Tires in the Removal of Malachite Green from Dyeing Wastewater.

The organic dye malachite green (MG) poses a potential risk of cancer and fertility loss in humans and aquatic organisms. This study focused on a modified pyrolytic char (PC) derived from waste tires to efficiently remove MG from wastewater. Modified PC has rich -OH functional groups, higher BET (Brunauer-Emmett-Teller) surfaces of 74.4, 64.95, and 67.31 m2/g, and larger pore volumes of 0.52, 0.47, and 0.62 cm3/g for NaOH, Na2CO3, and CaO modification, respectively. The pseudo-second-order model fit the adsorption well, and the maximum equilibrium adsorption capacity was 937.8 mg/g for PC after CaO activation (CaO-PC). NaOH-modified PC (NaOH-PC) showed the best fit with the Langmuir model (R2 = 0.918). It is suggested that alkali-modified waste tire pyrolytic char could be a potential adsorbent for removing MG from dye-containing wastewater.

Damage evolution and fracture behavior of different materials specimens containing a central hole subjected to local loading.

The strength of the different materials specimens containing a central hole subjected to varying loading areas constitutes lots of underground engineering such as entry arrangement and mining process. In this study, the failure resulted from micro-fracturing in the specimen, which can be characterized by the crack propagation path if the damage events are monitored by using Digital Image Correlation (DIC), infrared thermal imager and high-speed camera. The experimental results demonstrate that there are three different types of typical failure modes for specimens with central holes according to the loading areas. The evolution of the temperature field is shown for various loading areas, the smaller loading area, the greater the stress concentration, and the more pronounced the thermodynamic features. The temperature field can also be associated with material properties in addition to loading area. Additionally, failure around the hole with redistributed stress has been observed, and strain energy density (SED) can help explain the failure mechanisms. The progressive damage process, which takes into account the heterogeneity in elastic modulus and rock strength characteristic, is demonstrated by developing a constitutive model that uses the uniaxial compression and Brazilian disc tests to parameterize it. By comparison with plastic zone, the proposed constitutive model is used to quantitatively evaluate the accumulation of damage. Failure mechanisms are established based on this work and are anticipated to be extensively utilized in engineering applications.

Synthesis of CoFe2O4/Peanut Shell Powder Composites and the Associated Magnetic Solid Phase Extraction of Phenoxy Carboxylic Acid Herbicides in Water.

The magnetic biochar material CoFe2O4/PCPS (peanut shell powder) was prepared based on the hybrid calcination method. The properties of prepared composites and the extraction effect of magnetic solid phase extraction on phenoxy carboxylic acid herbicides were assessed. The morphology, crystal structure, specific surface area, and pore size distribution of the material were analysed using a transmission electron microscope (TEM), infrared Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and N2 absorption surface analysis (BET). The results of the magnetic solid phase extraction of a variety of phenoxy carboxylic acid herbicides in water using CoFe2O4/PCPS composites showed that, when the mass ratio of CoFe2O4 and PCPS was 1:1, 40 mg of the composite was used, and the adsorption time was 10 min at pH 8.50. Methanol was used as the eluent, and the recovery rates of the three phenoxy carboxylic acid herbicides were maintained at 81.95-99.07%. Furthermore, the actual water sample analysis results showed that the established method had good accuracy, stability, and reliability.

Study of water-conducting fractured zone development law and assessment method in longwall mining of shallow coal seam.

Starting from the source of mining, scientific understanding of surface damage law and assessment method in longwall mining of shallow coal seam is conducive to solving the problems of geological hazards and deterioration of the ecological environment, and promoting the coordinated development of efficient coal mining and environmental protection. Based on numerical simulation and theoretical analysis, the surface damage process and spatiotemporal evolution of fracture field are discussed. The influencing factors and assessment method of surface damage are clarified. The results show that surface damage undergone the immediate roof caving stage, the fracture and instability stage of main roof, the spatial amplification stage of separation layer, the instability stage of surface damage control layer and the mining damage stability stage. Under the critical extraction condition, the cracks above the goaf are divided into the crack area outside the cut, the crack area inside the cut, the re-compaction area in the middle goaf, the crack area behind the longwall face, and the crack area in front of the longwall face. The overburden reaches critical failure ahead of surface critical mining. The sensitivity of loose layer thickness to surface subsidence coefficient is greater than that of mining thickness to surface subsidence coefficient. Surface damage control should be adjusted to local conditions, and finally realize zoning treatment and zoning repair. Through the three-step method of "longwall face rapid advancing method, local grouting reinforcement overburden method and zoning treatment ground fissures method", the surface damage control of 12,401 longwall face is realized. This research provides theoretical guidance and application value for surface ecological restoration in similar mining area.

Magnetic Solid-Phase Extraction Based on Fe3O4/g-C3N4 Nanocomposite for the Determination of Polychlorinated Biphenyls and Polychlorinated Diphenyl Ethers in Environmental Waters.

The graphitic carbon nitride (g-C3N4) and the Fe3O4/g-C3N4 magnetic materials were synthesized in this paper. The structures of the materials were confirmed by a series of analysis. The Fe3O4/g-C3N4 was then used as a sorbent to adsorb polychlorinated diphenyl ethers and polychlorinated biphenyls. Different extraction conditions were examined, including adsorbent amount, salinity, pH of the sample matrix, adsorption time, reaction temperature, elution solvent and preconcentration factor. The maximum recoveries were obtained by employing methanol to desorb pollutants on 40.0 mg Fe3O4/g-C3N4 in 120.0 mL environmental water with a salinity of 5% (w/v) at a pH of 7 at 25 °C within 10 min. Using the optimized parameters, the detection limits of the method are between 0.01 and 0.04 µ · L-1 with a satisfying linear relationship. The adsorbent can be recycled at least 10 times with no significant reduction in the extraction efficiency.

Poloxamer 188-mediated anti-inflammatory effect rescues cognitive deficits in paraquat and maneb-induced mouse model of Parkinson's disease.

Mild cognitive impairment in Parkinson's disease (PD-MCI) is considered as a nonmotor clinical symptom in Parkinson's disease (PD). Microglia-mediated inflammation contributes to cognitive function impairment. Poloxamer 188 (P188) is an amphipathic polymer which has cytoprotective effect in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neurons degeneration in PD. But whether P188 could ameliorate cognitive impairment in PD is still illusive. In the present study, we showed in a mouse model that paraquat (10 mg/kg) and maneb (30 mg/kg) (P + M) treatment intraperitoneally twice a week for 6 consecutive weeks resulted in cognitive deficits and synapse loss in hippocampus, together with DA neuron damage in the substantia nigra pars compacta (SNpc). P188 (0.8 g/kg) injection via tail vein 30 min after P + M administration significantly restored DA neuron numbers in SNpc and synapse density in hippocampus, and alleviated P + M-mediated cognitive function impairment in novel object recognition task and morris water maze task (MWM). Pathological synapse loss might be attributed to increased microglial phagocytic activity and cell density, and P188 prevented P + M-induced phagocytic state changes of microglia, such as increase in cell body size and decrease in process length, and upregulated microglia abundance in hippocampus. Consistently, P188 attenuated P + M-mediated increased mRNA levels of microglia proliferation related CSF1r and CSF2ra, microglial engulfment associated CD68, ICAM1, and ICAM2, and pro-inflammatory IL-6, IL-1ß, CD11b, and TNF-α in hippocampus. Together, these findings suggest that the biocompatible polymer P188 blunts microglia activation which may promote synaptic loss and exacerbate cognitive function in a mouse model of PD-MCI.

Poloxamer 188 rescues MPTP-induced lysosomal membrane integrity impairment in cellular and mouse models of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Rupture of lysosome is a major cellular stress condition leading to cell death in PD. We have previously shown that environmental oxidative toxins could impair autophagic flux and lysosomal functions in PD. Poloxamer 188 (P188) is an amphipathic polymer which has cytoprotective effect in traumatic brain injury and stroke. But whether Dyrk1A could rescue lysosome malfunction-mediated DA neuron death and α-synuclein aggregation in PD is still unknown. In the present study, MPTP mice models and MPP+-treated SH-SY5Y cells were used for study, and we found that P188 rescued MPP+-induced lysosomal dysfunction and impaired autophagy flux in mild MPP+-treated SH-SY5Y cells. P188 administration significantly restored lysosomal membrane integrity and prevented cathepsins leakage from the lysosomes into the cytoplasm, which triggered caspase-dependent apoptotic cell death in sub-acute MPTP mouse model and MPP+-treated SH-SY5Y cells. Furthermore, P188 ameliorated α-synuclein accumulation and behavioral impairment in chronic MPTP mouse model with MPTP and probenecid treatment. P188 could alleviate MPTP-induced DA neurons damage by restoring lysosome function.

Enhancing adsorption efficiency of dichloroacetic acid onto mesoporous carbons: Procedure optimization, mechanism and characterization.

Highly ordered mesoporous carbon may be directly synthesized via supramolecular self-assembly with in situ evaporation-induced crystallization process by controlling thermal reaction temperatures and carbon mass loading. In the present study, the effects of thermal reaction temperatures on the structural characterization and adsorption capacity of mesoporous carbon have been investigated and analyzed with orthogonal test experiments. The results show the carbonization temperature (R=32.1) plays a more important role than the self-assembly temperature (R=8.5) and thermal polymerization temperature (R=10.1) in manipulating the pore texture structures. The optimization grouping temperature was 40-110-500 °C. The optimum mesoporous carbon sample had the highest BET specific surface area (474 m(2)/g), the largest pore volume (0.46 cm(3)/g), and with reasonable uniform pore size distribution. The adsorption evaluation also shows the adsorption capacity is strongly correlated with the pore structure of mesoporous carbon, the optimized mesoporous carbon sample displayed the largest adsorption capacity (350 mg/g) at an initial concentration of 20.0 mg/L of dichloroacetic acid. The study results indicate optimization of thermal reaction parameters is an effective approach for synthesis of ordered mesoporous carbons.

[Effect of insulin by local injection on the level of systemic blood glucose and granulation tissue formation of wound in patients with diabetic foot ulcer].

OBJECTIVE: To investigate the effects of local injection of insulin on the level of systemic blood glucose and granulation tissue formation of wound in patients with diabetic foot ulcer. METHODS: Thirty-two patients with diabetic foot ulcer hospitalized in our wards from June 2009 to June 2010 were divided into insulin (I, n = 16) and control (C, n = 16) groups according to the random number table. For patients in I group, after debridement, one half of calculated dose of insulin diluted with equal amount of normal saline was injected diffusely into the base of the ulcer, and another half dose of insulin was subcutaneously injected into abdominal wall for 7 days, two times a day. For patients in C group, after debridement, primary insulin was subcutaneously injected into abdominal wall, 1 mL saline was subcutaneously injected into basal layer of ulcer for 7 days, two times a day. Before injection and 0.5, 1.0, 2.0, and 4.0 hours after injection (PIH), level of fasting blood glucose was determined. Before injection and on post injection day (PID) 3, 5, and 7, the growth of granulation tissue was assessed, and wound specimens were harvested for observation of CD34 expression and calculation of microvessel density (MVD). Data were processed with t test. RESULTS: The levels of fasting blood glucose in both groups during observational time points ranged from 6.6 mmol/L to 12.8 mmol/L with a mean of (10.0 ± 2.2) mmol/L, and there was no statistical difference (with t values from 0.000 to 2.209, P values all above 0.05). Growth of granulation tissue in I group was more exuberant from PID 5, especially on PID 7 [(59.06 ± 1.58)%], which was significantly richer than that in C group [(23.61 ± 1.57)%, t = 17.420, P = 0.000]. New vessels were observed in I group from PID 3 as indicated by CD34 expression. There was no obvious difference in the number of MVD between I group and C group on PID 3 (t = 0.247, P > 0.05). The number of MVD per 200 times visual field in I group was respectively 8.34 ± 0.48, 11.22 ± 0.97 on PID 5 and 7, which was respectively higher than that in C group (4.42 ± 0.14, 5.44 ± 1.13, with t value respectively 16.568, 27.664, P values all below 0.01). CONCLUSIONS: Local injection of insulin has a significant effect on systemic blood glucose in patients with diabetic foot ulcer, and it can promote the growth of granulation tissue and wound healing.