Pillararenes: a new frontier in antimicrobial therapy.

Pillararenes have gained great interest among researchers in many fields due to their symmetric structure and facile functionalization. In this review, we summarize recent progress for pillararenes as antimicrobial agents, ranging from cationic pillararenes and peptide-modified pillararenes to sugar-functionalized pillararenes. Moreover, their structure-activity relationships are presented, and their mechanisms of action are discussed. As a state-of-the-art technology, their opportunities and outlook are also outlined in this emerging field. Overall, their potent inhibitory activity and high biocompatibility give them potential for the development of novel antimicrobial agents.

KRAS inhibition activates an actionable CD24 'don't eat me' signal in pancreas cancer.

KRAS G12C inhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the tumor biology of the KRAS G12C allele and possible bypass mechanisms, we developed a novel autochthonous KRAS G12C -driven PDAC model. Compared to the classical KRAS G12D PDAC model, the G12C model exhibit slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRAS G12C tumors produced modest impact despite stimulating a 'hot' tumor immune microenvironment. Immunoprofiling revealed that CD24, a 'do-not-eat-me' signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRAS G12D -driven PDAC. Our study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. Significance: Lack of faithful preclinical models limits the exploration of resistance mechanisms to KRAS G12C inhibitor in PDAC. We generated an autochthonous KRAS G12C -driven PDAC model, which revealed allele-specific biology of the KRAS G12C during PDAC development. We identified CD24 as an actionable adaptive mechanisms in cancer cells induced upon KRAS G12C inhibition and blocking CD24 sensitizes PDAC to KRAS inhibitors in preclinical models.

Effect on the conformation of monosubstituted pillar[5]arene: solvent, temperature, concentration and linker length.

A series of monosubstituted pillar[5]arenes (PIn) bearing a fluorescent probe (E)-4-[4-(dimethylamino)styryl-]-1-pyridinium were synthesized and characterized. The conformations of the monosubstituted pillar[5]arenes were investigated systematically by NMR and fluorescence spectroscopy and were found to be dependent on solvent polarity, concentration, temperature and linker length. PI1 with a short linker remained uncomplexed in DMSO, whereas it formed a polymer at high concentration in chloroform. As the linker length increased, PI2-4 could exist in equilibrium between self-inclusion monomer and intermolecular complexes. The increase of concentration led to the formation of a polymer in DMSO and a self-penetrating dimer in chloroform. The results provided information on the modulation of supramolecular assemblies by various factors.

Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition.

Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and to identify druggable targets to improve PDAC treatment. KRAS mutations dominate the genetic landscape of PDAC and lead to activation of multiple downstream pathways and cellular processes. Here, we investigated the requirement of these pathways for tumor maintenance using an inducible KrasG12D -driven PDAC mouse model (iKras model), identifying that RAF-MEK-MAPK signaling is the major effector for oncogenic KRAS-mediated tumor maintenance. However, consistent with previous studies, MEK inhibition had minimal therapeutic effect as a single agent for PDAC in vitro and in vivo. Although MEK inhibition partially downregulated transcription of glycolysis genes, it failed to suppress glycolytic flux in PDAC cells, which is a major metabolic effector of oncogenic KRAS. Accordingly, an in vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MEK inhibition. Inhibition of glucose metabolism with low-dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D -driven PDAC cells in vitro. The combination also inhibited xenograft PDAC tumor growth and prolonged overall survival in a genetically engineered PDAC mouse model. Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal endoplasmic reticulum stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC. SIGNIFICANCE: This study demonstrates the critical role of glucose metabolism in resistance to MAPK inhibition in KRAS-driven pancreatic cancer, uncovering a potential therapeutic approach for treating this aggressive disease.

[Effects of different concentrations of nitrogen,phosphorus and potash on Glycyrrhiza uralensis and its relationship with soil element content].

With annual Glycyrrhiza uralensis seedlings as experimental material, using "3414" optimal regression design and applied fertilizer, through the sampling of G. uralensis at harvest, root fresh weight and content of active components were measured in Lanzhou, Bayan Nur city, Chifeng, Jiuquan. Combined with NPK content in soil, potted experiments were used to study the effects of different nitrogen and phosphorus ratios on the dry matter accumulation and accumulation of active components of G. uralensis. The results reported as follows: the optimum fertilizer treatment in Lanzhou, Bayan Nur city, Chifeng, Jiuquan was N1P2K1,N2P2K1,N1P1K2 and N2P1K2, respectively. The efforts of single fertilizer on the fresh root weight acted as parabolic type.There was no significant effect of fertilizer treatment on the accumulation of active components of G. uralensis. Furthermore, in terms of nitrogen and phosphorus, the type of fertilizers that restricted the growth of the region was the type of elements with lower content in the soil. The optimal fertilizer usage was in inverse proportion to content of elements in soil. When the content of phosphorus in soil was low, nitrogen fertilizer and potash fertilizer showed positive interaction with phosphorus fertilizer, whereas, they showed negative interaction.

[Methane Cycle Anaerobic Membrane Bioreactor with Desulfurization for Treating High Sulfate Organic Wastewater at Normal Temperature].

The operational performance of a methane cycle anaerobic membrane bioreactor (MCAnMBR) with desulfurization for the treatment of high sulfate organic wastewater was investigated. Within 63 days, the MCAnMBR with desulfurization was started successfully at a normal temperature of 26-34℃. The two main problems at the beginning of debugging, sludge loss and increased pH, were effectively solved by adjusting the gas path system and adding methanol to the inflow for acclimation. The results show that the inflow concentration of SO42- from 650 mg·L-1to 5800 mg·L-1can be treated well with the conditions of hydraulic retention time (HRT)=120 h, a volume loading of 3.61-4.36 kg·(m3·d)-1, pH of 7.18-7.61, and temperature of 23.3-25.4℃. The effluent chemical oxygen demand (COD) concentration could be lowered to 23 mg·L-1. The total removal rate of COD could remain stable at 96.23%-99.77%, and the SO42- conversion rate was about 83.83%-95.51%. These results indicated that the MCAnMBR reactor with desulfurization could effectively solve the problem of secondary sulfide inhibition. A gradient experiment revealed that the high Na2SO4 inflow could be treated when the influent COD ranged from 18000 mg·L-1to 21000 mg·L-1, the concentration of SO42- ranged between 9082 mg·L-1 and 9600 mg·L-1, and the COD/SO42-=2.

[Effects of plant growth regulator uniconazole on plant morphology and biomass allocation of Salvia miltiorrhiza].

In this study, we use pot experiment to evaluate the effect of plant growth regulator on plant morphology and biomass allocation of Salvia miltiorrhiza. Different concentrations of uniconazole were supplied to S. miltioohiza by means of foliar spray. Height, breadth and stem diameter were measured dynamically, the biomass of leaf, stem, flower and fruit, root biomass and biomass ratio were also examined at the harvest time. Owing to the treatment, plant morphology showed significant changes, the height had been greatly reduced and the breadth decreased largely. Meanwhile, the biomass allocation changed too. The biomass ratio of leaf and stem had been notably reduced while the biomass ratio of root had been increased remarkably. It appears that foliar application of uniconazole during vigorous growth period in S. miltioohiza has dramatic effect on dwarfing plant and improving resistant to lodging. This measure could also be applied to condensed cultivation of S. miltioohiza to increase production.

[Effect of shentong zhuyu decoction on pain behavior and spinal cord astrocytes model of osteocarcinoma pain].

OBJECTIVE: To study the analgesic effect of shentong zhuyu decoction (SZD) and its effect on the expression of the spinal cord glial fibrillary acidic protein (GFAP). METHODS: One hundred C3H/HeNCrlVr male mice were randomly divided into the normal group (n=8), the sham operation group (n=30), the model group (n=30), the Chinese medicine (CM) group 1 (n=8), the CM group 2 (n=8), the CM group 3 (n=8), and the vehicle group (n=8). 0.1 g crude drug of SZD/0.4 mL, 0.3 g crude drug of SZD/0.4 mL, 0.9 g crude drug of SZD/0.4 mL, and 0.4 mL normal saline were respectively given by gastrogavage to mice in CM 1, 2, 3 groups and the vehicle group, once daily for seven days starting from Day 14. The paw withdrawal thermal latency (PWTL), as the behavior indicator, was assessed in mice using radiant thermal stimulator. The lumbar enlargement of the spinal cord was taken after the behavioral test on Day 21. GFAP mRNA and protein expressions were detected using real-time quantitative RT-PCR and Western blot. RESULTS: Compared with the normal group (Day 0) (PWTL: 15.91 +/- 1.65 s) and the sham operation group (PWTL: Day 4: 13.33 +/- 1.44 s; Day 7: 11.28 +/- 0.61 s; Day 10: 15.47 +/- 2.46 s; Day 14: 15.69 +/- 1.98 s; Day 21: 15.69 +/- 1.68 s), the PWTL value in the model group (Day 4: 13.24 +/- 1.02 s; Day 7: 11.30 +/- 1.09 s; Day 10: 9.12 +/- 0.54 s; Day 14: 7.79 +/- 0.77 s; Day 21: 6.36 +/- 0.59 s) progressively decreased (P < 0.05) as time went by, while the spinal cord GFAP mRNA and protein expressions gradually increased. Compared with the normal group (Day 0) and the sham operation group (Day 14), the PWTL value in the CM groups and the vehicle group obviously decreased on Day 14 (P < 0.05). The PWTL value was not significantly different among the model group, CM groups, and the vehicle group on Day 14 (P > 0.05). On Day 21 the PWTL value of CM group 2 and 3 increased and the spinal cord GFAP mRNA and protein expression levels decreased when compared with the model group and the vehicle group (P < 0.05). But no significant difference in the PWTL value or GFAP expression levels was shown among the CM 1 group, the vehicle group, and the model group (P > 0.05). CONCLUSION: SZD had analgesic effect. Inhibition of the proliferation and activation of the spinal cord astrocytes might be one of its mechanisms.

The role of N-methyl-D-aspartate receptor subunit NR2B in spinal cord in cancer pain.

Cancer pain is one kind of the most common and severe kinds of chronic pain. No breakthrough regarding the mechanisms and therapeutics of cancer pains has yet been achieved. Based on the well established involvement of the NMDA (N-methyl-D-aspartate) receptor containing NR2B in inflammatory pain and neuropathic pain and the effective pain relief obtained with ketamine in cancer patients with intractable pain, we supposed that NR2B in the spinal cord was an important factor for cancer pain. In this study, we investigated the possible role of NR2B in the spinal cord using a murine model of bone cancer pain. C3H/HeJ mice were inoculated into the intramedullary space of the right femur with Osteosarcoma NCTC 2472 cells to induce ongoing bone cancer-related pain behaviors. At day 14 after operation, the expression of NR2B mRNA and NR2B protein in the spinal cord were higher in tumor-bearing mice compared to the sham mice. Intrathecal administration of 5 and 10 microg of NR2B subunit-specific NMDA receptor antagonist ifenprodil attenuated cancer-evoked spontaneous pain, thermal hyperalgesia and mechanical allodynia. These results suggest that NR2B in the spinal cord may participate in bone cancer pain in mice, and ifenprodil may be a useful alternative or adjunct therapy for bone cancer pain. The findings may lead to novel strategies for the treatment of bone cancer pain.