Overexpression of Os-microRNA408 enhances drought tolerance in perennial ryegrass.

As a conserved microRNA (miRNA) family in plants, miR408 is known to be involved in different abiotic stress responses, including drought. Interestingly, some studies indicated a species- and/or cultivar-specific drought-responsive characteristic of miR408 in plant drought stress. Moreover, the functions of miR408 in perennial grass species are unknown. In this study, we investigated the role of miR408 in perennial ryegrass (Lolium perenne L.) by withholding water for 10 days for both wild type and transgenic plants with heterologous expression of rice (Oryza sativa L.) miR408 gene, Os-miR408. The results showed that transgenic perennial ryegrass plants displayed morphological changes under normal growth conditions, such as curl leaves and sunken stomata, which could be related to decreased leaf water loss. Moreover, transgenic perennial ryegrass exhibited improved drought tolerance, as demonstrated by maintaining higher leaf relative water content (RWC), lower electrolyte leakage (EL), and less lipid peroxidation compared to WT plants under drought stress. Furthermore, the transgenic plants showed higher antioxidative capacity under drought. These results showed that the improved drought tolerance in Os-miR408 transgenic plants could be due to leaf morphological changes favoring the maintenance of water status and to increased antioxidative capacity protecting against the reactive oxygen species damages under stress. These findings implied that miR408 could serve as a potential target for genetic manipulations to engineer perennial grass plants for improved water stress tolerance.

Targeting Peroxiredoxin 1 by a Curcumin Analogue, AI-44, Inhibits NLRP3 Inflammasome Activation and Attenuates Lipopolysaccharide-Induced Sepsis in Mice.

Aberrant activation of the NLRP3 inflammasome contributes to the onset and progression of various inflammatory diseases, making it a highly desirable drug target. In this study, we screened a series of small compounds with anti-inflammatory activities and identified a novel NLRP3 inflammasome inhibitor, AI-44, a curcumin analogue that selectively inhibited signal 2 but not signal 1 of NLRP3 inflammasome activation. We demonstrated that AI-44 bound to peroxiredoxin 1 (PRDX1) and promoted the interaction of PRDX1 with pro-Caspase-1 (CASP1), which led to the suppression of association of pro-CASP1 and ASC. Consequently, the assembly of the NLRP3 inflammasome was interrupted, and the activation of CASP1 was inhibited. Knockdown of PRDX1 significantly abrogated the inhibitory effect of AI-44 on the NLRP3 inflammasome. Importantly, AI-44 alleviated LPS-induced endotoxemia in mice via suppressing NLRP3 inflammasome activation. Taken together, our work highlighted PRDX1 as a negative regulator of NLRP3 inflammasome activation and suggested AI-44 as a promising candidate compound for the treatment of sepsis or other NLRP3 inflammasome-driven diseases.

Synthesis and Biological Evaluation of Novel Benzimidazole Derivatives and Analogs Targeting the NLRP3 Inflammasome.

A series of benzo[d]imidazole analogues of thiabenzole were synthesized and their antiinflammatory activities toward NLRP3 (nucleotide-binding domain leucine-rich repeat containing protein family，pyrin domain-containing 3，also known as cryopyrin or NALP3) inflammasome were evaluated in vitro. Two lead compounds, TBZ-09 and TBZ-21, were identified by antiproduction of IL-1ß. In the second round of biological evaluation, based on the lead, 34 more compounds were synthesized and their in vitro anti-inflammatory activities were investigated. Several compounds were identified as anti-inflammatory agents that can reduce IL-1ß expression in a dosedependent manner. A preliminary structure-activity relationship is also summarized here.

The genome of the warm-season turfgrass African bermudagrass (Cynodon transvaalensis).

Cynodon species can be used for multiple purposes and have high economic and ecological significance. However, the genetic basis of the favorable agronomic traits of Cynodon species is poorly understood, partially due to the limited availability of genomic resources. In this study, we report a chromosome-scale genome assembly of a diploid Cynodon species, C. transvaalensis, obtained by combining Illumina and Nanopore sequencing, BioNano, and Hi-C. The assembly contains 282 scaffolds (~423.42 Mb, N50 = 5.37 Mb), which cover ~93.2% of the estimated genome of C. transvaalensis (~454.4 Mb). Furthermore, 90.48% of the scaffolds (~383.08 Mb) were anchored to nine pseudomolecules, of which the largest was 60.78 Mb in length. Evolutionary analysis along with transcriptome comparison provided a preliminary genomic basis for the adaptation of this species to tropical and/or subtropical climates, typically with dry summers. The genomic resources generated in this study will not only facilitate evolutionary studies of the Chloridoideae subfamily, in particular, the Cynodonteae tribe, but also facilitate functional genomic research and genetic breeding in Cynodon species for new leading turfgrass cultivars in the future.

Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-κB pathways.

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a severe, life-threatening medical condition characterized by widespread inflammation in the lungs, and is a significant source of morbidity and mortality in the patient population. New therapies for the treatment of ALI are desperately needed. In the present study, we examined the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on lipopolysaccharide (LPS)-induced ALI and inflammation. Andrographolide sulfonate was administered by intraperitoneal injection to mice with LPS-induced ALI. LPS-induced airway inflammatory cell recruitment and lung histological alterations were significantly ameliorated by andrographolide sulfonate. Protein levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were reduced by andrographolide sulfonate administration. mRNA levels of pro-inflammatory cytokines in lung tissue were also suppressed. Moreover, andrographolide sulfonate markedly suppressed the activation of mitogen-activated protein kinase (MAPK) as well as p65 subunit of nuclear factor-κB (NF-κB). In summary, these results suggest that andrographolide sulfonate ameliorated LPS-induced ALI in mice by inhibiting NF-κB and MAPK-mediated inflammatory responses. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating inflammatory lung disorders.

MALT1 inhibitors prevent the development of DSS-induced experimental colitis in mice via inhibiting NF-κB and NLRP3 inflammasome activation.

Mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1), a paracaspase and essential regulator for nuclear factor kB (NF-κB) activation, plays an important role in innate and adaptive immunity. Suppression of MALT1 protease activity with small molecule inhibitors showed promising efficacies in subtypes of B cell lymphoma and improvement in experimental autoimmune encephalomyelitis model. However, whether MALT1 inhibitors could ameliorate colitis remains unclear. In the present study, we examined the pharmacological effect of two specific MALT1 inhibitors MI-2 and mepazine on the dextran sulfate sodium (DSS)-induced experimental colitis in mice, followed by mechanistic analysis on NF-κB and NLRP3 inflammasome activation. Treatment with MI-2 and mepazine dose-dependently attenuated symptoms of colitis in mice, evidenced by reduction in the elevated disease activity index, the shortening of colon length as well as the histopathologic improvement. Moreover, protein and mRNA levels of DSS-induced proinflammatory cytokines in colon, including TNF, IL-1ß, IL-6, IL-18, IL-17A and IFN-γ, were markedly suppressed by MALT1 inhibitors. The underlying mechanisms for the protective effect of MALT1 inhibitors in DSS-induced colitis may be attributed to its inhibition on NF-κB and NLRP3 inflammasome activation in macrophages. The in vitro study showed that MALT1 inhibitors decreased production of IL-1ß/IL-18 in phorbol myristate acetate-differentiated THP-1 cells and bone marrow derived macrophage via suppressing the activation of NF-κB and NLRP3 inflammasome. Taken together, our results demonstrated that inhibition of the protease activity of MALT1 might be a viable strategy to treat inflammatory bowel disease and the NLRP3 inflammasome and NF-κB activation are critical components in MALT1 signaling cascades in this disease model.