Polyethylenimine Triggers Dll4 Degradation to Regulate Angiogenesis In Vitro.

The Dll4-Notch signaling pathway plays a crucial role in the regulation of angiogenesis and is a promising therapeutic target for diseases associated with abnormal angiogenesis, such as cancer and ophthalmic diseases. Here, we find that polyethylenimine (PEI), a cationic polymer widely used as nucleic acid transfection reagents, can target the Notch ligand Dll4. By immunostaining and immunoblotting, we demonstrate that PEI significantly induces the clearance of cell-surface Dll4 and facilitates its degradation through the lysosomal pathway. As a result, the activation of Notch signaling in endothelial cells is effectively inhibited by PEI, as evidenced by the observed decrease in the generation of the activated form of Notch and expression of Notch target genes Hes1 and Hey1. Furthermore, through blocking Dll4-mediated Notch signaling, PEI treatment enhances angiogenesis in vitro. Together, our study reveals a novel biological effect of PEI and establishes a foundation for the development of a Dll4-targeted biomaterial for the treatment of angiogenesis-related disease.

Effects of coal mining and climate-environment factors on the evolution of a typical Eurasian grassland.

Coal mining can significantly impact vegetation evolution, yet the limited information on its patterns and driving factors hampers efforts to mitigate these effects and reclaim abandoned mines. This study aimed to 1) examine vegetation evolution in a semiarid steppe watershed in northeast China; and 2) characterize the driving factors behind this evolution. We analyzed the impact of twelve selected driving factors on fractional vegetation coverage (FVC) from 2000 to 2021 using a dimidiate pixel model, Sen's slope analysis, Mann-Kendall trend test, coefficient of variation analysis, and Geodetector model. At a significance level of α = 0.05, our findings revealed a south-to-north decline pattern in FVC, a significant decrease trend in proximity to coal mines, and a notable increase trend adjacent to river channels. Approximately 37% of the watershed exhibited low FVC, while the overall temporal trend across the watershed was deemed insignificant. Areas surrounding the mines experienced a substantial reduction in FVC due to coal mining activities, while FVC variations across the watershed were linked to precipitation, temperature, and soil type. FVC predictions improved notably when interactions between multiple two-way factors were considered. Each driving factors displayed an optimal range (e.g., precipitation = 63-71 mm) for maximizing FVC. Given the study watershed's status as a national energy base, understanding vegetation responses to coal mining and climate-environment changes is crucial for sustaining fragile terrestrial ecosystems and socioeconomic development. Achieving a long-time balance between coal extraction and ecological protection is essential. The study outcomes hold significant promise for advancing ecological conservation, vegetation restoration, and mitigation of environmental degradation in semiarid regions affected by extensive coal mining and climate fluctuations. These findings contribute to the strategic management of such areas, promoting sustainable practices amidst evolving environmental challenges.

[Hydrochemical Characteristics and Control Factors of Groundwater in the Northwest Salt Lake Basin].

Taking the Tugeligaole sub-basin of the Jilantai Salt Lake Basin in Inner Mongolia as the typical study area, the groundwater samples of 22 points were collected, and their main characteristic indexes were tested during the wet season and the dry season separately in 2021. Mathematical statistics, Piper triangular diagrams, a Gibbs plot, ionic relations, and factor analysis were used to analyze and discuss the hydrochemical characteristics and formation mechanism of groundwater in different periods. Based on the evaluation of the groundwater quality using the water quality index(WQI) method, the potential risks of groundwater Cr6+ and F- were evaluated using the health risk evaluation model. The results showed that the groundwater was overall weakly alkaline; the dominant anions and cations during the different periods were Cl- and Na+, and the water chemistry type was mainly Cl--Na+; the groundwater quality was generally good, and the difference in water quality between the wet season and the dry season was not significant; adults and children had higher carcinogenic health risks in the dry season than that in the wet season, and the health risks of children were significantly higher than those in adults. The maximum carcinogenic health risk of drinking water exposure to Cr6+ in adults and children was higher than the maximum acceptable risk level(5×10-5). The chemical evolution of groundwater was mainly affected by evaporative concentration, evaporative salt rock dissolution, and cation exchange, and the main control factors were evaporative concentration(contribution rate of 54.19%), native geological environment factors(contribution rate of 12.99%), and carbonate rock dissolution(contribution rate of 11.66%). The study results have significance to some degree to the sustainable exploitation and utilization of groundwater resources and environmental protection of the salt lake basin.

Single amino acid-based PROTACs trigger degradation of the oncogenic kinase BCR-ABL in chronic myeloid leukemia (CML).

Proteolysis-targeting chimera (PROTAC) that specifically targets harmful proteins for destruction by hijacking the ubiquitin-proteasome system is emerging as a potent anticancer strategy. How to efficiently modulate the target degradation remains a challenging issue. In this study, we employ a single amino acid-based PROTAC, which uses the shortest degradation signal sequence as the ligand of the N-end rule E3 ubiquitin ligases to degrade the fusion protein BCR (breakpoint cluster region)-ABL (Abelson proto-oncogene), an oncogenic kinase that drives the progression of chronic myeloid leukemia. We find that the reduction level of BCR-ABL can be easily adjusted by substituting different amino acids. Furthermore, a single PEG linker is found to achieve the best proteolytic effect. Our efforts have resulted in effective degradation of BCR-ABL protein by the N-end rule pathway and efficient growth inhibition of K562 cells expressing BCR-ABL in vitro and blunted tumor growth in a K562 xenograft tumor model in vivo. The PROTAC presented has unique advantages including lower effective concentration, smaller molecular size, and modular degradation rate. Demonstrating the efficacy of the N-end rule-based PROTACs in vitro and in vivo, our study further expands the limited degradation pathways currently available for PROTACs in vivo and is easily adapted for broader applications in targeted protein degradation.

Bifunctional Compounds as Molecular Degraders for Integrin-Facilitated Targeted Protein Degradation.

As effective ways to regulate protein levels, targeted protein degradation technologies have attracted great attention in recent years. Here, we established a novel integrin-facilitated lysosomal degradation (IFLD) strategy to degrade extracellular and cell membrane proteins using bifunctional compounds as molecular degraders. By conjugation of a target protein-binding ligand with an integrin-recognition ligand, the resulting molecular degrader proved to be highly efficient to induce the internalization and subsequent degradation of extracellular or cell membrane proteins in an integrin- and lysosome-dependent manner. As demonstrated in the development of BMS-L1-RGD, which is an efficient programmed death-ligand 1 (PD-L1) degrader validated both in vitro and in vivo, the IFLD strategy expands the toolbox for regulation of secreted and membrane-associated proteins and thus has great potential to be applied in chemical biology and drug discovery.

SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. SGLT2 inhibitors are clinically effective in halting DKD progression. However, the underlying mechanisms remain unclear. The serum and kidneys of mice with DKD were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based metabolomic and proteomic analyses. Three groups were established: placebo-treated littermate db/m mice, placebo-treated db/db mice and EMPA-treated db/db mice. Empagliflozin (EMPA) and placebo (10 mg/kg/d) were administered for 12 weeks. EMPA treatment decreased Cys-C and urinary albumin excretion compared with placebo by 78.60% and 57.12%, respectively (p < 0.001 in all cases). Renal glomerular area, interstitial fibrosis and glomerulosclerosis were decreased by 16.47%, 68.50% and 62.82%, respectively (p < 0.05 in all cases). Multi-omic analysis revealed that EMPA treatment altered the protein and metabolic profiles in the db/db group, including 32 renal proteins, 51 serum proteins, 94 renal metabolites and 37 serum metabolites. Five EMPA-related metabolic pathways were identified by integrating proteomic and metabolomic analyses, which are involved in renal purine metabolism; pyrimidine metabolism; tryptophan metabolism; nicotinate and nicotinamide metabolism, and glycine, serine and threonine metabolism in serum. In conclusion, this study demonstrated metabolic reprogramming in mice with DKD. EMPA treatment improved kidney function and morphology by regulating metabolic reprogramming, including regulation of renal reductive stress, alleviation of mitochondrial dysfunction and reduction in renal oxidative stress reaction.

A nanomaterial targeting the spike protein captures SARS-CoV-2 variants and promotes viral elimination.

The global emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can only be solved with effective and widespread preventive and therapeutic strategies, and both are still insufficient. Here, we describe an ultrathin two-dimensional CuInP2S6 (CIPS) nanosheet as a new agent against SARS-CoV-2 infection. CIPS exhibits an extremely high and selective binding capacity (dissociation constant (KD) < 1 pM) for the receptor binding domain of the spike protein of wild-type SARS-CoV-2 and its variants of concern, including Delta and Omicron, inhibiting virus entry and infection in angiotensin converting enzyme 2 (ACE2)-bearing cells, human airway epithelial organoids and human ACE2-transgenic mice. On association with CIPS, the virus is quickly phagocytosed and eliminated by macrophages, suggesting that CIPS could be successfully used to capture and facilitate virus elimination by the host. Thus, we propose CIPS as a promising nanodrug for future safe and effective anti-SARS-CoV-2 therapy, and as a decontamination agent and surface-coating material to reduce SARS-CoV-2 infectivity.

Dearomatization-rearomatization strategy of tyrosine for peptide/protein modification through thiol-addition reactions.

We have developed a dearomatization-rearomatization strategy for the modification of peptides/proteins through a thiol-Michael addition to the electrophilic cyclohexadienone intermediate that is generated in situ via the oxidation of tyrosine. This strategy enriches the conjugation toolbox and has great potential for applications in medicinal chemistry and chemical biology.

Synthesis of 5H-Chromeno[2,3-d]pyrimidin-5-one Derivatives via Microwave-Promoted Multicomponent Reaction.

A microwave-promoted multicomponent reaction of 3-formylchromones, amines, and paraformaldehyde was achieved under catalyst-free and solvent-free conditions, delivering 5H-chromeno[2,3-d]pyrimidin-5-one derivatives in good to excellent yields via an unexpected annulation pathway, which further expanded the synthetic application of paraformaldehyde as a C1 building block.

Intrinsic bioactivity of black phosphorus nanomaterials on mitotic centrosome destabilization through suppression of PLK1 kinase.

Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle's centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.

A novel pyrrole-imidazole polyamide targets Aurora kinase A and suppresses tumor growth in vivo.

Aurora kinase A (Aurora A) plays a critical role in regulating cell mitotic progression and has been considered as a promising drug target for cancer therapy. To develop a novel molecule targeting Aurora A with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide (PIP) Hoechst conjugate, PIP-Ht, targeting to a cell-cycle regulated DNA sequence locating at the promoter of human Aurora A gene (AURKA). PIP-Ht potently suppressed AURKA promoter activities, mRNA expression and protein level, induced tumor cell cycle delay and inhibited tumor cell proliferation in vitro. Furthermore, subcutaneous injection of PIP-Ht into mice bearing human cancer xenografts induced significant tumor growth suppression and cell apoptosis. Collectively, PIP-Ht exhibits the potential as an effective therapeutic candidate for the tumor treatment.

Tyrosine-Specific Modification via a Dearomatization-Rearomatization Strategy: Access to Azobenzene Functionalized Peptides.

Azobenzene functionalized peptides are of great importance in photoresponsive biosystems and photopharmacology. Herein, we report an efficient approach to prepare azobenzene functionalized peptides through late-stage modification of tyrosine-containing peptides using a dearomatization-rearomatization strategy. This approach shows good chemoselectivity and site selectivity as well as sensitive group tolerance to various peptides. This method enriches the postsynthetic modification toolbox of peptides and has great potential to be applied in medicinal chemistry and chemical biology.

Characteristics and environmental driving factors of water transformation in the Balaguer River watershed of Inner Mongolia steppe.

Inner Mongolian steppe is one of the ecological barriers in China. The variation of water resources is very important for the development of social-economy and the protection of eco-environment. We collected 254 water samples of precipitation, river, and shadow groundwater during wet-season and dry-season of 2018-2019 from Balaguer River watershed and meansured the physical-chemical indicators, δD and δ18O of water samples. The stable isotope technology, mathematical statistics, and the inverse distance weighting method were used to analyze the stable isotope composition, spatial-temporal variation, and impact factors. Moreover, the d-excess and the isotopic mixing ratio formula were used to analyze the conversion characteristics of different water and to identify their environment driving variables. The results showed that δD and δ18O of precipitation, river and shallow groundwater were higher in wet season than in dry season. The driving factors of different water transformation in the watershed were air temperature, altitude, and groundwater depth. Altitude was significantly negatively correlated with river δD, and the δD and δ18O of groundwater. δD and δ18O of groundwater fluctuated significantly in the area with groundwater depth less than 10 m, but were stable in other areas. There was a positive correlation between precipitation δ18O and air temperature. The d-excess in wet season was higher than that in dry season, with a decreasing distribution characteristic from southern to northern part in the study area. More than 50% river in upper stream came from precipitation, while more than half river water converted to groundwater, with different recharge-drainage relationships existed between surface water and groundwater in different river reaches.

Coibamide A kills cancer cells through inhibiting autophagy.

Natural products are useful tools for biological mechanism research and drug discovery. Due to the excellent tumor cell growth inhibitory profile and sub-nanomolar potency, Coibamide A (CA), an N-methyl-stabilized depsipeptide isolated from marine cyanobacterium, has been considered as a promising lead compound for cancer treatment. However, the molecular anti-cancer mechanism of the action of CA remains unclear. Here, we showed that CA treatment induced caspase-independent cell death in breast cancer cells. CA treatment also led to severe lysosome defects, which was ascribed to the impaired glycosylation of lysosome membrane protein LAMP1 and LAMP2. As a consequence, the autophagosome-lysosome fusion was blocked upon CA treatment. In addition, we presented evidence that this autophagy defect partially contributed to the CA treatment-induced tumor cell death. Together, our work uncovers a novel mechanism underlying the anti-cancer action of CA, which will promote its further application for cancer therapy.

Novel N-Methylated Cyclodepsipeptide Prodrugs for Targeted Cancer Therapy.

Coibamide A (1) is a highly N-methylated cyclodepsipeptide with low nanomolar antiproliferative activities against various cancer cell lines. In previous work, we discovered a simplified analogue, [MeAla3-MeAla6]-coibamide (1a), which exhibited the same inhibitory abilities as coibamide A. Herein, to reduce the whole-body toxicity and improve the solubility of 1a, two novel peptide-drug conjugates RGD-SS-CA (2) and RGD-VC-CA (3) were designed, synthesized, and evaluated. Composed of cyclodepsipeptide 1a, a tumor-homing RGD motif, and a conditionally labile linker, the conjugates are expected to release 1a tracelessly in specific tumor microenvironments. Compared with RGD-VC-CA (3), RGD-SS-CA (2) proved to be superior in in vitro drug release and cytotoxicity tests. Notably, intravenous injection of RGD-SS-CA (2) into mice-bearing human tumor xenografts induced significant tumor growth suppression with negligible toxicity. Therefore, as a novel prodrug of the coibamide A analogue, conjugate 2 has great potential for further exploration in cancer drug discovery.

A systematic review and meta-analysis of combined carotid endarterectomy with ipsilateral proximal intervention (hybrid approach) for tandem carotid artery lesions.

OBJECTIVE: The safety and effectiveness of using the hybrid approach to treat tandem carotid lesions is controversial, and the clinical significance of the technical variants on the perioperative outcomes has not been evaluated. The present meta-analysis was performed to evaluate the technique, safety, effectiveness, and long-term outcomes of the hybrid approach. METHODS: The PubMed, Embase, and Cochrane Library databases were searched to identify studies from January 1, 1996 to January 11, 2020. The baseline patient characteristics, comorbidities, procedural details, and perioperative and long-term outcomes were collected and analyzed. A pooled overall survival curve was drawn. Univariate analysis was performed to compare the perioperative stroke risk between subgroups. RESULTS: Overall, 275 patients (mean age, 66.94 years) from 15 studies were included. All the patients had presented with tandem stenosis of ≥50%, and 67.2% were symptomatic. The overall technical success rate was 99.8% (95% confidence interval [CI], 98.0%-100.0%). The pooled perioperative complications rates were as follows: death, 1.5% (95% CI, 0.0%-2.9%); stroke, 2.6% (95% CI, 0.7%-4.4%); combined stroke/death, 3.3% (95% CI, 1.2%-5.4%); and myocardial infarction, 3.2% (95% CI, 0.7%-9.1%). The overall primary patency rates were 99.2% (95% CI, 96.0%-100.0%) and 88.2% (95% CI, 78.8%-95.4%) at 1 and 2 years, respectively. Reintervention was performed in 6.6% of the patients (95% CI, 3.0%-11.2%). The pooled overall survival rates were 89.9% (95% CI, 83.7%-96.7%), 83.7% (95% CI, 75.9%-92.2%), and 75.9% (95% CI, 66.5%-86.7%) at 1, 3, and 5 years, respectively. Operations in which carotid endarterectomy was performed first carried a significantly greater risk of perioperative stroke compared with those in which proximal intervention had been performed first (5.7% vs 0.0%; P = .01). No difference was found in perioperative stroke risk between the subgroups of baseline symptomatic status (asymptomatic, 5.1%; symptomatic, 1.9%; P = .32), preoperative antiplatelet therapy (dual, 3.6%; single, 5.8%; P = .79), and carotid clamping during intervention (clamping, 2.8%; unclamping, 6.3%; P = .40). CONCLUSIONS: For patients with a presumed high risk of neurologic events because of carotid tandem lesions, the hybrid approach could be considered a reasonable option with high technical success and acceptable perioperative and long-term results. Performing carotid artery stenting before carotid endarterectomy and administering perioperative dual antiplatelet therapy should be considered to promote technical success and better outcomes. Prospective and randomized controlled studies are needed to confirm the results and provide recommendations on patient selection for the hybrid approach.

Infrapopliteal endovascular intervention and the angiosome concept: intraoperative real-time assessment of foot regions' blood volume guides and improves direct revascularization.

OBJECTIVE: There is no consensus for determining which vessel should be revascularized in patients with multiple diseased infrapopliteal arteries. The angiosome concept may guide a more efficient targeted direct revascularization. Therefore, we conducted a study to assess whether the regional evaluation of foot blood volume may guide direct revascularization (DR) and if it will lead to better perfusion improvement than indirect revascularization (IR). METHODS: We performed a prospective single-center observational cohort study in patients treated in the Department of Vascular Surgery of Peking Union Medical College Hospital from November 2016 to April 2019. Twenty-seven patients treated with endovascular intervention were included. The intraoperative parenchymal blood volume of different foot regions was obtained for each patient using C-arm CT before and after intervention. RESULTS: The intervention procedure significantly increased the overall blood volume (48.95 versus 81.97 ml/1000 ml, p = 0.002). Patients with direct revascularization had a 197% blood volume increase while patients with indirect revascularization had a 39% increase (p = 0.028). The preoperative blood volume was higher in patients with mild symptoms than in patients with severe symptoms (58.20 versus 30.45 ml/1000 ml, p = 0.039). However, in regard to postoperative blood volume, no significant difference was discovered between these two groups (75.05 versus 95.01 ml/1000 ml, p = 0.275). CONCLUSION: Based on quantitative measurements, we conclude that overall blood volume can rise significantly after the intervention. Revascularizing the supplying vessel of the ischemic area directly will result in better perfusion improvement than restoring blood supply through the collateral circulation. Preoperative blood volume is associated with preoperative symptoms. KEY POINTS: • Flat panel detector CT can obtain intraoperative perfusion status and guide treatment in endovascular intervention. • Revascularizing the supplying vessel of the ischemic area directly will result in better perfusion improvement than restoring the blood supply through the collateral circulation. • Patients with severer clinical manifestations have lower blood volumes.

Chlorotoxin-derived bicyclic peptides for targeted imaging of glioblastomas.

A convenient and efficient strategy was developed for accessing chlorotoxin-derived bicyclic peptide-biomolecule conjugates by cyclizing fully-unprotected linear peptides with a designed tetrafunctional chemical linker. Among these peptides, bicycle-P3 bearing the N-terminal sequence of chlorotoxin shows high tumor selectivity and penetration ability, which is promising for treatment of gliomas.

Long-term outcomes of conservative treatment and endovascular treatment in patients with symptomatic spontaneous isolated superior mesenteric artery dissection: a single-center experience.

BACKGROUND: Spontaneous isolated superior mesenteric artery dissection (SISMAD) is a rare vascular disorder, and the treatment strategies remain controversial. This study aimed to compare outcomes of conservative and endovascular treatments in symptomatic patients with SISMAD. METHODS: Forty-two consecutive SISMAD patients who were admitted to a single center between October 2009 and May 2018 were enrolled in this study. Based on their symptoms, 15 had conservative treatment, and 27 had endovascular treatment. The baseline characteristics, treatments, and follow-up results of the conservative group and endovascular group were analysed. RESULTS: The rates of symptom relief were 93.3% in the conservative group and 96.3% in the endovascular group. The procedure-related complications in the endovascular group included one case of pseudoaneurysm formation in the left brachial artery. During the follow-up period (median 28.5 months), a higher proportion of patients in the conservative group had symptom recurrence (42.9% in the conservative group versus 4.8% in the endovascular group, p < 0.001). Four patients in the conservative group and one patient in the endovascular group had additional endovascular intervention during follow-up. Compared with the conservative group, patients in the endovascular group had statistically significantly longer symptom-free survival (p = 0.014) and a higher rate of superior mesenteric artery (SMA) remodeling (p < 0.001). CONCLUSIONS: For symptomatic SISMAD, endovascularly treated patients had a lower rate of symptom recurrence and a higher rate of SMA remodeling in the long term. Prospective, multi-center studies are needed to confirm the long-term outcomes of both treatments.

One-year results of drug-coated balloons for long and occlusive Femoropopliteal artery disease: a single-arm trial.

BACKGROUND: The performance of drug-coated balloons (DCBs) in femoropopliteal interventions has been proven through randomized trials in short lesions and lesions with relatively low proportion of occlusions. There is limited evidence of DCBs in long or occlusive lesions. This study is to investigate the efficacy of the paclitaxel-coated balloon for treatment of long and occlusive femoropopliteal arterial lesions. METHODS: A single-arm trial including 44 femoropopliteal lesions (chronic total occlusion (CTO) plus > 10 cm) treated with DCBs was performed to collect data of average 1-year follow-up. Endpoints contain primary patency, target lesion revascularization (TLR), amelioration of the Rutherford classification, change of ankle brachial index (ABI) and major adverse events. RESULTS: Technical success is 97.7% while device success is 100%. Mean lesion length was 186 ± 86.3 cm. Stent implantation was performed in 13.6%. Cumulative probability of primary patency was 78.8% ± 6.8% at 1 year while that of freedom from TLR was 91.4% ± 4.9%. Rutherford classification improved from average 3.3 ± 1.0 to 2.1 ± 1.4 (p < 0.001) at follow-up with a 72.7% amelioration rate. Ankle-branchial index changed from 0.33 ± 0.40 to 0.67 ± 0.37 (p = 0.002). No major adverse event was observed. CONCLUSION: These results suggest that it is safe and effective to treat long and totally occlusive femoropopliteal artery disease with DCBs. Further studies are demanded to confirm these results.