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Targeted drug delivery platforms can increase the concentration of drugs in specific cell populations, reduce adverse effects, and hence improve the therapeutic effect of drugs. Herein, we designed two conjugates by installing the targeting ligand GalNAc (N- acetylgalactosamine) onto atorvastatin (AT). Compared to the parent drug, these two conjugates, termed G2-AT and G2-K-AT, showed increased hepatic cellular uptake. Moreover, both conjugates were able to release atorvastatin, and consequently showed dramatic inhibition of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase and increased LDL receptors on cell surface. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Daratumumab, an FDA approved antibody drug, displays specific targeting ability to abnormal white blood cells overexpressing CD38 and provides efficacious therapy for multiple myeloma. Here, in order to achieve enhanced remission of multiple myeloma, we designed Dara-DM4 , antibody drug conjugates (ADCs) by conjugating Daratumumab and DM4 via a disulfide linker. Dara-DM4 showed significantly higher cellular uptake and inhibitory efficacy on MM1S cells that overexpressing CD38 with an IC 50 of 0.88 µg/mL post 72 hr treatment. These results support a promising ADCs strategy for multiple myeloma treatment. [ABSTRACT FROM AUTHOR]

Hard end is a physiological disorder of pear fruit that is frequently observed in the ‘Whangkeumbae’ ( Pyrus pyrifolia ) variety, however, the mechanisms that are involved in its development are poorly understood. In this study, we explored the causes of hard end disorder in pear fruit in relation to calcium deficiency. During fruit development, the ratio of Ca/N, Ca/K, Ca/Mg and the content of B were significantly lower in the hard end fruit as compared to normal fruit. However, no calcium deficiency was detected in the soil and leaves of the orchard where the hard end fruit were located. Additionally, the Ca 2+ influx in the calyx of hard end fruit was lower than that of normal fruit at 90 d after anthesis. The free Ca 2+ and storage Ca 2+ in the flesh cells of hard end fruit were less than that of normal fruit during fruit development, while an opposite tendency was observed at 120 d after anthesis (harvest day). In hard end fruit, the Ca 2+ transport-related gene, PpCNGC1 (Cyclic nucleotide-gated ion channel 1), was up-regulated; whereas the Ca 2+ sensor-related genes of PpCIPKs , PpCDPK28 and PpCML41 were all down-regulated. Spraying with a 2% calcium chloride (CaCl 2 ) solution inhibited the incidence rate of hard end disorder and decreased fruit firmness and lignin content during storage. Additionally, the ratio of Ca/N, Ca/K, Ca/Mg and the content of B all increased on harvest day. Our study suggests that low Ca 2+ influx leads to less Ca 2+ into the pear fruit, which results in an intracellular imbalance of Ca 2+ and consequently triggers the development of hard end disorder. [ABSTRACT FROM AUTHOR]

Lignin, a natural macromolecular compound, plays an important role in the texture and taste of fruit. Hard end is a physiological disorder of pear fruit, in which the level of lignification in fruit tissues is dramatically elevated. Cinnamyl alcohol dehydrogenase and expansin genes ( PpCAD2 and PpEXP2 , respectively) exhibit higher levels of expression in ‘Whangkeumbae’ ( Pyrus pyrifolia ) pear fruit exhibiting this physiological disorder, relative to control fruit without symptoms. These genes were isolated from pear fruit and subsequently expressed in tobacco ( Nicotiana tabacum ) to investigate their function. Histochemical staining for lignin revealed that the degree of lignification in leaf veins and stem tissues increased in plants transformed with sense constructs and decreased in plants transformed with antisense constructs of PpCAD2 . The expression of native NtCADs was also inhibited in the antisense PpCAD2 transgenic tobacco. Sense and antisense PpCAD2 transgenic tobacco exhibited an 86.7% increase and a 60% decrease in CAD activity, respectively, accompanied by a complementary response in lignin content in root tissues. The basal portion of the stem in PpEXP2 transgenic tobacco was bent and highly lignified. Additionally, the level of cellulose also increased in the stem of PpEXP2 transgenic tobacco. Collectively, these results suggested that PpCAD2 and PpEXP2 genes play a significant role in lignin accumulation in transgenic tobacco plants, and it is inferred that these two genes may also participate in the increased lignification observed in hard end pear fruit. [ABSTRACT FROM AUTHOR]

Abstract: Fluorescent probes for hydrogen sulfide have received considerable attention because of the biological significance of H2S recognized recently. Two-photo microscopy offers advantages of increased penetration depth, localized excitation, and prolonged observation time. However, two-photon fluorescent probes for H2S are still rare. In this work, we introduced a dinitrophenyl ether group into the 4-position of 1,8-naphthalimide, which acts as the H2S reactive site, to efficiently yield compound NI–NHS as a two-photo fluorescent probe for H2S. The probe NI–NHS has a high selectivity for H2S over competitive anions and sulfide-containing analytes. This probe exhibits turn-on fluorescence detection of H2S in bovine serum and two-photon fluorescent imaging of H2S in living cells. [Copyright &y& Elsevier]

Summary Previously, researchers discovered a series of anti-CRISPR proteins that inhibit CRISPR-Cas activity, such as Cas9 and Cpf1 (Cas12a). Herein, we constructed crRNA variants consisting of chemically modified DNA-crRNA and RNA-crRNA duplexes and identified that phosphorothioate (PS)-modified DNA-crRNA duplex completely blocked the function of Cpf1. More important, without prehybridization, these PS-modified DNA oligonucleotides showed the ability to suppress DNA double-strand breaks induced by two Cpf1 orthologs, AsCpf1 and LbCpf1. Time-dependent inhibitory effects were validated in multiple loci of different human cells. Further studies demonstrated that PS-modified DNA oligonucleotides were able to serve as Cpf1 inhibitors in a sequence-independent manner. Mechanistic studies indicate that PS-modified DNA oligonucleotides hinder target DNA binding and recognition by Cpf1. Consequently, these synthetic DNA molecules expand the sources of CRISPR inhibitors, providing a platform to inactivate Cpf1-mediated genome editing. Graphical Abstract Highlights • Phosphorothioate-modified DNA oligonucleotides inhibit Cpf1-mediated genome editing • Inhibition of Cpf1 activity is time and dose dependent and target sequence independent • psDNA oligonucleotides may block the complex formation of Cpf1-crRNA-DNA • psDNA oligonucleotides inhibit Cas9-mediated genome editing Li et al. show that phosphorothioate-modified DNA (psDNA) oligonucleotides inhibit Cpf1-mediated genome-editing activity in a sequence-independent manner in human cells. These psDNA oligonucleotides interact with Cpf1 protein and block the formation of Cpf1-crRNA-target DNA complex. They also display inhibitory effects on the CRISPR-Cas9 system. [ABSTRACT FROM AUTHOR]

Leukemia stem cells (LSCs) account for the development of drug resistance and increased recurrence rate in acute myeloid leukemia (AML) patients. Targeted drug delivery to leukemia stem cells remains a major challenge in AML chemotherapy. Overexpressed interleukin-3 receptor alpha chain, CD123, on the surface of leukemia stem cells was reported to be a potential target in AML treatment. Here, we designed and developed an antibody drug conjugate (CD123-CPT) by integrating anti-CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker. The linker is biodegradable in the presence of Glutathione (GSH, an endogenous component in cells), which leads to release of CPT. Anti-CD123 antibody conjugates showed significant higher cellular uptake in CD123-overexpressed tumor cells. More importantly, CD123-CPT demonstrated potent inhibitory effects on CD123-overexpressed tumor cells. Consequently, these results provide a promising targeted chemotherapeutical strategy for AML treatment. [ABSTRACT FROM AUTHOR]

Abstract: Three novel ladder-conjugated chromophores indicated as LT1–LT3 were synthesized and characterized. Further studies on linear, nonlinear optics and electrochemical properties demonstrated their photophysical features respectively. Compound LT1 shows good two-photon absorption cross-section (δ) up to ∼1200 GM at 810 nm in tetrahydrofuran, which is attributed to intramolecular charge transfer effect, as supported by density functional theory theoretical calculations. Compound LT2 and LT3 show considerable molar extinction coefficients, which are more than 105, and higher quantum yields. Structure–function relationship is further discussed, suggesting a rational strategy to develop ladder-conjugated small molecules. [Copyright &y& Elsevier]

Plants would encounter various biotic and abiotic stresses during the growth and development. WRKY transcription factors (TFs) as plant-specific TFs, play an important role in responding to various adverse circumstances. Despite some advances were achieved in functional studies of WRKY TFs in tea plants, systematic analysis of the involvement of CsWRKY TFs when facing cold, salt, drought stresses and pathogen and insect attack was lacked. In present study, a total of 78 CsWRKY TFs were identified following the genomic and transcript databases. The expression patterns of CsWRKYs in various organs of tea plants and the expression profiles in response to biotic and abiotic stresses were investigated by examining representative RNA-seq data. Moreover, the effects of hormone treatments (SA and MeJA) on the transcription levels of WRKY TFs were also investigated. The phylogenetic tree of CsWRKY TFs from different species indicated the functional diversity of WRKY TFs was not closely related to their protein classification. Concurrently, CsWRKY70-2 TF was identified as a positive regulator in response to drought stress. This study provided solid and valuable information, helping us better understand the functional diversity of CsWRKY TFs, and laid the foundation for further research on the function of key WRKY genes in tea plants. In this study, 78 WRKY transcription factors had been identified in tea plants as accurately as possible based on the transcriptome and genomic data. At the transcriptomic level, the expression patterns of CsWRKYs in various organs of tea plants and the expression profiles in response to biotic (Ectropis oblique, tea leafhopper and gray-blight attack), abiotic stresses (Cold, drought, salt) and exogenous hormones (SA and MeJA) were investigated. Expression pattern analysis showed that most Cs WRKYs were involved in the process of tea plants resisting biotic and abiotic stresses. Phylogenetic analysis indicated that the functional diversity of CsWRKY TFs was not closely related to their protein classification. In addition, CsWRKY70-2 TF had been proved to play a positive regulatory role in drought stress tolerance. This study provided solid and valuable information, helping better understand the functional diversity of CsWRKY TFs, and laid the foundation for further research on the function of key WRKY genes in tea plants. [ABSTRACT FROM AUTHOR]

A neutral pH fluorescent probe (Rh-Met) based on rhodamine spirolactam is firstly developed according to the modulation strategy of hydrogen bonds on pKa values. The pKa value of Rh-Met was 6.81 (±0.06) and higher than that of other rhodamine spirolactams known. Rh-Met showed a 240-fold enhancement of fluorescence intensity at 585 nm with attenuation of pH values from 9.7 to 3.5. In addition, Rh-Met displayed an excellent selectivity and reversible response to hydrogen ion. And it was successfully employed for imaging endocellular hydrogen ion in mitochondria and lipid droplets. These results suggested that Rh-Met could be a potential tool to assess pH fluctuation in mitochondria and lipid droplets, and would promote many new opportunities for studying the biological effect of pH in living cells. [ABSTRACT FROM AUTHOR]

Four oleanane-type triterpenoid saponins were isolated from the seed cake of Camellia oleifera Abel.: camelliasaponin B 1 and three new saponins, oleiferasaponin C 1 –C 3 ( 1 – 3 ). Their structures were identified as 22- O -angeloyl-camelliagenin B 3- O -[ β - d -galactopyranosyl-(1 → 2)]-[ β - d -galactopyranosyl-(1 → 2)- α - l -arabinopyranosyl-(1 → 3)]- β - d -glucopyranosiduronic acid methyl ester ( 1 ); 22- O -angeloyl-camelliagenin A 3- O -[ β - d -galactopyranosyl-(1 → 2)]-[ β - d -glucopyranosyl-(1 → 2)- β - d -galactopyranosyl-(1 → 3)]- β - d -glucopyranosiduronic acid methyl ester ( 2 ); and 28- O -cinnamoyl-camelliagenin B 3- O -[ β - d -galactopyranosylz-(1 → 2)] [ β - d -galactopyranosyl(1 → 2)- α - l -arabinopyranosyl-(1 → 3)]- β - d -glucopyranosiduronic acid methyl ester ( 3 ) through 1D and 2D NMR, HR-ESI-MS, as well as GC–MS spectroscopic methods. The anti-proliferative activities of these four compounds were investigated on five human tumor cell lines (BEL-7402, BGC-823, MCF-7, HL-60 and KB). Compounds 1 and 2 and camelliasaponin B 1 showed significant cytotoxic activities. [ABSTRACT FROM AUTHOR]

The regulation factors of rhodamine spirolactam switch has captured great attention because of its great potential applications in super-resolution image and fluorescent probe fields. Herein, we developed two Hg2+ rhodamine probe bearing flexible ɑ-amino acid hydrazines, Rh-SH and Rh-MH, to investigate photo-operated rhodamine switch induced by Hg2+. The Hg2+ binding process with Rh-SH containing serine hydrazines moiety was more sensitive to UV light, owing to weak affinity with Hg2+. On the contrary, UV light had little effect on Hg2+ binding process of Rh-MH bearing methionine hydrazine group. The strong Hg2+ binding affinity of Rh-MH demonstrated a higher sensitivity to Hg2+, and detection limit of Rh-MH was 2.32 × 10−6 M. Probe Rh-MH can also map the distribution of Hg2+ in mitochondria of MCF-7 cells. The modulation of binding affinity of flexible ɑ-amino acid hydrazine with Hg2+ might provide new opportunity and strategy to photo-promoted ring switch of rhodamine spirolactam. • Two rhodamine probe (Rh-SH and Rh-MH) bearing flexible ɑ-amino acid hydrazines were developed to investigate PORS induced by Hg2+. • Compared with Rh-MH, photo-promoted ring switch (PORS) by Hg2+ for Rh-SH was more sensitive to UV light. • Binding affinity from flexible receptor with Hg2+ provided a strategy to PORS of rhodamine spirolactam. • Rh-MH exhibited a high sensitivity to Hg2+, and could map the distribution of Hg2+ in mitochondria of MCF-7 cells. [ABSTRACT FROM AUTHOR]

To confirm the pKa regulation by hydrogen bond, a series of rhodamine alkylamides were developed, and their pKa values were measured in aqueous solution. For Rh-APD, intramolecular hydrogen bond derived from hydroxyl of 2-amino-1,3-propanediol between carbonyl of spirolactam was favorable to the increase of pKa values (pKa 5.7). Gaussian stimulation demonstrated a moderate intramolecular hydrogen bond in Rh-APD at DFT/B3LYP/6–31 G(d) level. Except for pH, neither protic/aprotic solvents nor metal ions induced ring-opening transformation of Rh-APD. Bio-imaging showed that Rh-APD could specifically accumulate in lysosomes and evaluate lysosomal pH fluctuation in living MCF-7 cells. Moreover, Rh-APD also can indicate the acidity of gut and ovary of Daphnia magna. Rh-APD would be a potential reagent for water-quality monitoring with the help of its pH indication in living cells and water fleas. Image 1 • A series of rhodamine alkylamides were developed to assess the effects of hydrogen-bonding assistance for pKa regulation. • The pKa value of Rh-APD was up to 5.77 (±0.02), larger 1.2 pH units than that of Rh-AP. • Gaussian stimulation demonstrated a moderate intramolecular hydrogen bond in Rh-APD at DFT/B3LYP/6–31 G(d) level. • Rh-APD can specifically accumulate in lysosomes and evaluate lysosomal pH fluctuation in living MCF-7 cells. • Rh-APD also can indicate the acidity of gut and ovary of Daphnia magna. [ABSTRACT FROM AUTHOR]