The serine/threonine protein kinase MpSTE1 directly governs hyphal branching in Monascus spp.

Monascus spp. are commercially important fungi due to their ability to produce beneficial secondary metabolites such as the cholesterol-lowering agent lovastatin and natural food colorants azaphilone pigments. Although hyphal branching intensively influenced the production of these secondary metabolites, the pivotal regulators of hyphal development in Monascus spp. remain unclear. To identify these important regulators, we developed an artificial intelligence (AI)-assisted image analysis tool for quantification of hyphae-branching and constructed a random T-DNA insertion library. High-throughput screening revealed that a STE kinase, MpSTE1, was considered as a key regulator of hyphal branching based on the hyphal phenotype. To further validate the role of MpSTE1, we generated an mpSTE1 gene knockout mutant, a complemented mutant, and an overexpression mutant (OE::mpSTE1). Microscopic observations revealed that overexpression of mpSTE1 led to a 63% increase in branch number while deletion of mpSTE1 reduced the hyphal branching by 68% compared to the wild-type strain. In flask cultures, the strain OE::mpSTE1 showed accelerated growth and glucose consumption. More importantly, the strain OE::mpSTE1 produced 9.2 mg/L lovastatin and 17.0 mg/L azaphilone pigments, respectively, 47.0% and 30.1% higher than those of the wild-type strain. Phosphoproteomic analysis revealed that MpSTE1 directly phosphorylated 7 downstream signal proteins involved in cell division, cytoskeletal organization, and signal transduction. To our best knowledge, MpSTE1 is reported as the first characterized regulator for tightly regulating the hyphal branching in Monascus spp. These findings significantly expanded current understanding of the signaling pathway governing the hyphal branching and development in Monascus spp. Furthermore, MpSTE1 and its analogs were demonstrated as promising targets for improving production of valuable secondary metabolites. KEY POINTS: • MpSTE1 is the first characterized regulator for tightly regulating hyphal branching • Overexpression of mpSTE1 significantly improves secondary metabolite production • A high-throughput image analysis tool was developed for counting hyphal branching.

Modular and Flexible Molecular Device for Simultaneous Cytosine and Adenine Base Editing at Random Genomic Loci in Filamentous Fungi.

Random base editing is regarded as a fundamental method for accelerating the genomic evolution in both scientific research and industrial applications. In this study, we designed a modular interaction-based dual base editor (MIDBE) that assembled a DNA helicase and various base editors through dockerin/cohesin-mediated protein-protein interactions, resulting in a self-assembled MIDBE complex capable of editing bases at any locus in the genome. The base editing type of MIDBE can be readily controlled by the induction of cytidine or/and adenine deaminase gene expression. MIDBE exhibited the highest editing efficiency 2.3 × 103 times greater than the native genomic mutation rate. To evaluate the potential of MIDBE in genomic evolution, we developed a removable plasmid-based MIDBE tool, which led to a remarkable 977.1% increase of lovastatin production in Monascus purpureus HJ11. MIDBE represents the first biological tool for generating and accumulating base mutations in Monascus chromosome and also offers a bottom-up strategy for designing the base editor.

Mental health literacy of Chinese nurses from public general and psychiatric hospitals: a cross-sectional study.

Background: Mental health literacy (MHL) is crucial to address issues related to mental illness. Nurses' MHL is even more important because they are expected to deal with both the physical and psychological consequences of mental disorders. Objective: This study investigated the level, discrepancy, and characteristics of MHL among Chinese nurses from both public general and psychiatric hospitals; identified influential factors; and explored the relationship between MHL and mental health status. Methods: Using a stratified cluster sampling method to select participants, a cross-sectional survey was conducted to describe the MHL of 777 nurses from 13 general and 12 psychiatric hospitals using the Chinese version of the Mental Health Literacy Scale, Patient Health Questionnaire-2, Generalized Anxiety Disorder-2, and a demographic questionnaire. A multiple regression analysis was used to determine the factors influencing MHL among the nurses recruited. Results: The participants' total score on the Chinese version of the Mental Health Literacy Scale was 93.25 (SD = 10.52). Multiple regression analysis revealed that nurses who worked in psychiatric or higher-level hospitals, with higher professional titles or higher education had higher levels of overall MHL and core MHL, while those working in general hospitals, with shorter work duration, or who were unmarried had higher social acceptance of patients. Nurses' MHL was closely correlated with their mental health status. Conclusion: The overall and core MHL of Chinese nurses were at a moderate level, with social acceptance remaining at a relatively low level. There is an urgent need for MHL promotion programs to improve the MHL of clinical nurses. The focus must be given to overall MHL, especially core MHL, for non-psychiatric nurses to enhance their competence in mental health promotion and identification; more emphasis should be placed on the social acceptance of patients with mental illnesses for psychiatric nurses to improve their provision of professional services. Better MHL would be a formula for improving nurses' own mental health and their mental health service competence.

Synthesis and cytotoxicity of diam(m)ineplatinum(II) complexes with 2,2-bis(hydroxymethyl)malonate as the leaving group.

Six diam(m)ineplatinum(II) complexes with 2,2-bis(hydroxymethyl)malonate as the leaving group were synthesized and characterized by elemental analysis, FAB-MS, FT-IR, (1)H and (13)C NMR along with a single crystal X-ray diffraction for a representative compound. All the complexes were evaluated for the cytotoxicity against human cancer cell lines A549/ATCC, HT-29, SGC-7901. The activity is related to the nature of the am(m)ine ligand. cis-[Pt(II)(1R,2R-Diaminocyclohexane)·2,2-bis(hydroxymethyl)malonate] (complex 5) exhibits the greatest activity among those six complexes, and is even more active than its parent compound oxaliplatin. LD(50) was found to be 115 mg/kg by iv administration to ICR mice, much larger than that of oxaliplatin (LD(50)=19 mg/kg).

Abnormal Antennal Olfactory Sensilla Phenotypes Involved in Olfactory Deficit in Bactrocera correcta (Diptera: Tephritidae).

The guava fruit fly, Bactrocera correcta, is one of the most destructive pests in the genus Bactrocera and detects environmental odorants mainly through antennal olfactory sensilla phenotypes with nanopores. However, it is unclear whether there are naturally occurring abnormal antennal olfactory sensilla phenotypes that affect olfaction. Here, we found that there were abnormal bulges besides nanopores on the surface of trichoid and basiconic olfactory sensilla in the antennal flagellum of long-term laboratory rearing colony (LTC), and that nanopore number in these olfactory sensilla was also remarkably reduced. Notably, the electroantennogram (EAG) responses of LTC insects to methyl eugenol or ß-caryophyllene were inhibited, and their behavioral responses elicited by the same odorants were also impaired. These results revealed naturally occurring abnormal antennal olfactory sensilla phenotypes which were involved in olfactory deficit in B. correcta, providing a platform to further study nanopore-targeted pest control technologies in the future.

A novel water-soluble heptaplatin analogue with improved antitumor activity and reduced toxicity.

A novel water-soluble heptaplatin analogue, cis-[(4R,5R)-4,5-bis-(aminomethyl)-2-isopropyl-1,3-dioxolane](3-hydroxy-1,1-cyclobutanedicarboxylato)platinum(II), has been synthesized and biologically evaluated. The complex shows more activity and less toxicity than its parent drug heptaplatin, exhibiting the great potential for further development.

Unusual dimeric chemical structure for a carboplatin analogue as a potential anticancer complex.

An unexpected and unusual dimeric platinum(II) tetracarboxylate complex was obtained by the reaction of cis-[Pt(NH(3))(2)I(2)] with disilver dicarboxylate. The complex exhibits greater in vitro anticancer activity and lower toxicity in mice than its parent compound, carboplatin, and is therefore worthy of further evaluation as a potential antitumor dinuclear platinum agent.

Bis(acetyl-acetonato-κO,O')-aqua-(diacetyl-methanido-κC)iridium(III).

In the crystal structure of the title compound, [Ir(C(5)H(7)O(2))(3)(H(2)O)], the Ir(III) atom is six-coordinated and situated in a slightly distorted octa-hedral environment. The complex contains both Ir-O and Ir-C bonds and was isolated from a reaction mixture of IrCl(3)(H(2)O)(x), pentane-2,5-dione and NaHCO(3). O-H⋯O hydrogen bonding between the water molecules and the carbonyl O atoms of adjacent molecules leads to a layered motif extending parallel to (010).

Synthesis and anticancer activity of lipophilic platinum(II) complexes of 3,5-diisopropylsalicylate.

Novel lipophilic platinum(II) complexes (LSPt-1-3), containing 3,5-diisopropylsalicylate (DIPS) as a leaving group and 2NH(3) or 1R,2R-diaminocyclohexane or (4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane as the carrier, have been synthesized, characterized and evaluated in vitro and in vivo. The octanol/water distribution coefficient of the complexes has also been measured. The results showed that the complexes achieved a typical square planar and the octanol/water distribution coefficient logP was 4.27, 4.37 and 4.31. The complexes were tested by SRB method to be more cytotoxic than Carboplatin, Oxaliplatin and Eptaplatin against 3AO, A549, NCI-H460 and SGC-7901 human cancer cell lines. Among complexes, LSPt-2 was much more effective than Carboplatin and Oxaliplatin in treating the NCI-H460 non-small-cell lung tumor-bearing mice. Its optimal activity was 38.8% (T/C) at a dose of 30 mg/kg following i.p. administration. LD(50) for the complex was found to be 230.9 mg/kg. LSPt-2 exhibited great anticancer activity, good lipophilic ability and low toxicity and therefore, it is a promising candidate for effective and stable pharmaceutical liposomal platinum anticancer drug.

Bis(alpha-furancarboxylato)oxovanadium(IV) prevents and improves dexamethasone-induced insulin resistance in 3T3-L1 adipocytes.

Previous studies showed that bis(alpha-furancarboxylato)oxovanadium(IV) (BFOV), an orally active anti-diabetic organic vanadium complex, could improve insulin resistance in animals with type 2 diabetes. The present study has been carried out to evaluate the effects of BFOV on insulin-resistant glucose metabolism using dexamethasone-treated 3T3-L1 adipocytes as an in-vitro model of insulin resistance. The results showed that BFOV, similar to vanadyl sulfate and rosiglitazone, caused a concentration-dependent increase in glucose consumption by insulin-resistant adipocytes. Moreover, BFOV enhanced the action of insulin and completely prevented the development of insulin resistance induced by dexamethasone, leading to glucose consumption equal to that by normal cells. In addition, dexamethasone reduced the mRNA expression of insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT4) in 3T3-L1 adipocytes, while BFOV normalized the expression of IRS-1 and GLUT4. These findings suggest that BFOV prevents and improves dexamethasone-induced insulin resistance in 3T3-L1 adipocytes by enhancing expression of IRS-1 and GLUT4 mRNA.

Effects of bis(alpha-furancarboxylato)oxovanadium(IV) on glucose metabolism in fat-fed/streptozotocin-diabetic rats.

Bis(alpha-furancarboxylato)oxovanadium(IV) (BFOV) is a new orally active anti-diabetic organic vanadium complex. In the previous studies, we found that BFOV exhibited a glucose-lowering activity following oral administration to type 1-like diabetic mice induced by alloxan and rats induced by streptozotocin, and the mechanism was not related to enhancing the insulin synthesis and secretion. Since the enhancement of insulin sensitivity is involved in one of the mechanisms by which vanadium exerts its anti-diabetic effects, BFOV has been further tested on fat-fed/streptozotocin-treated rats, a type 2-like diabetic animal model, in the present study. The results showed that 4 weeks of BFOV treatment significantly improved hyperglycemia, glucose intolerance and hyperinsulinemia, as well as increased insulin sensitivity index in the fat-fed/streptozotocin-diabetic rats. Furthermore, BFOV efficiently activated glucokinase, increased hepatic glycogen content and suppressed phosphoenolpyruvate carboxykinase gene expression in the liver and kidney of the diabetic rats, which contributed to augmentation of hepatic glucose disposal and maintenance of blood glucose homeostasis. These findings suggested that BEOV had anti-diabetic and insulin-sensitizing effects in the diabetic rats, exhibiting the potential to be developed as a new therapeutic agent for the treatment of type 2 diabetes.

Synthesis and in vitro cytotoxicity of cis-[Pt(NH(3))(NH(2)OH)Cl(2)].

A novel mixed NH(3)/NH(2)OH platinum(II) complex cis-[Pt(NH(3))(NH(2)OH)Cl(2)] was synthesized and characterized by elemental analysis, FAB-MS, FT-IR and (1)H NMR spectroscopy. This complex was determined to have a good water-solubility and satisfactory stability. The pertinent complex was evaluated for its in vitro cytotoxicity against 3AO, HCT-116, LNcap, A549/ATCC and SGC-7901 human carcinoma cell lines. It shows appreciable cytotoxic activity that is comparable with cisplatin and is much more active than carboplatin.

Synthesis, characterization and cytotoxicity of dihalogeno-platinum(II) complexes with L-histidine ligand.

Diiodo-, dibromo- and dichloro-platinum(II) complexes containing L-histidine ligand were prepared. Their spectra and X-ray crystal structure of the dibromo-platinum(II) complex were described. Only the dichloro-platinum(II) complex showed comparable cytotoxic activity with carboplatin against A549/ATCC, HT-29, and LNcap cell lines. Nevertheless the complexes with COOH-substituted ligands histidine may be good starting materials to synthesize targeting platinum complexes since they could be easily linked to suitable carrier molecules via esterification.

Preparation, characterization and in vitro anticancer activity of platinum(II) complexes with N-Cyclohexyl-1,3-propanediamine as the carrier.

New JM118 (active form of satraplatin) analogues with N-cyclohexyl-1,3-propanediamine (N-chpda) as the carrier, cis-[Pt(N-chpda)X2] (X2=2Cl(-) (1), oxalate (2), malonate (3), 1,1-cyclobutanedicarboxylate (CBDCA) (3), and 3-hydroxy-1,1-cyclobutanedicarboxylate(HO-CBDCA) (4)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X-ray crystal structure for a representative compound cis-[Pt(N-chpda)Cl2]. The complexes have also been evaluated for their in vitro anticancer activity. All these analytical data are in good agreement with the structures of the desired compounds. The Pt(II) is in a square planar environment and is coordinated by a chelating N-chpda ligand and 2Cl(-) in cis position, and there are two crystallographically independent cis-[Pt(N-chpda)Cl2] molecules linked together by intermolecular N-H...Cl hydrogen bonds. Compounds 1 and 2 are very active against human lung cancer cell line (AGZY) and human lymphocytic leukemia cell line (Raji), and are much more active than carboplatin. Platinum(II) complexes with N-cyclohexyl-1,3-propanediamine is an alternative choice for mixed ammine/aminoplatinum anticancer drugs.

Synthesis and anticancer activity of [2-hydroxy-1,3-diaminopropane-kappa 2N,N'] platinum(II) complexes.

A series of novel platinum(II) complexes involving a carrier with HO- peripheral functional group, 2-hydroxy-1,3-propanediamine (HO-pda), cis-[Pt(HO-dpa)X(2)] (X(2)=2Cl(-) (1), C(2)O(4)(2-) (2), malonate (3), 1,1-cyclobutane dicarboxylate (CBDCA) (4), 3-hydroxy-1,1-cyclobutanedicarboxylate (HO-CBDCA) (5)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X-ray diffraction for three representative complexes 1, 4 and 5. The Pt(II) is in a square planar environment and is coordinated in cis position by a chelating HO-pda and 2Cl(-) for 1 and CBDCA for 4 and 5. Pt-N, Pt-Cl and Pt-O distances and coordinate bond angles of N-Pt-N, Cl-Pt-Cl and O-Pt-O are in the normal range. There are two independent molecules in the asymmetric unit of 5, held together by intermolecular hydrogen bonded chain. All the complexes show significant cytotoxicity on the sensitive cell lines SGC-7901, LNcap and A549, and are more active than carboplatin. 4 is also found to be active against the resistant cell A549/ATCC, which suggests that it has less cross-resistance with cisplatin than carboplatin. Moreover 4 shows much greater inhibition of tumor growth than carboplatin in S180-bearing mice, and is therefore worthy of further development as a potential anti-tumor platinum drug.

Synthesis and cytotoxicity of platinum(II) complexes of a physiologically active carrier histamine.

A series of novel platinum(II) complexes involving a physiologically active carrier histamine as the carrier, cis-[Pt(histamine)X2] (X2=2Cl-, oxalate, malonate, 1,1-cyclobutanedicarboxylate (CBDCA), 3-hydroxy-1,1-cyclobutanedicarboxylate (HO-CBDCA)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X-ray crystal structure for a representative complex cis-[Pt(histamine)Cl2]. The cytotoxicity of the complexes has also been assessed in the human cancer cell lines A549/ATCC, HT-29, and LNcap. One complex, cis-[Pt(histamine)Cl2], is more active than carboplatin against both the sensitive and resistant cells.

Synthesis, characterization and cytotoxicity of diam(m)-ineplatinum(II) complexes containing beta-phenylisosuccinate ligand.

Four diam(m)ineplatinum(II) complexes containing beta-phenylisosuccinate as the leaving groups were prepared, characterized, and evaluated for their cytotoxicity against A549/ATCC human lung cancer cell line and SGC-7901 human gastric cancer cell line. One of the complexes, (trans-1R,2R-diaminocyclohexane)-beta-phenylisosuccinatoplatinum(II) 4, was much more active than cisplatin and carboplatin.

Synthesis and in vitro cytotoxicity of novel lipophilic (diamine)platinum(II) complexes of salicylate derivatives.

Novel lipophilic (diamine)platinum(II) complexes of salicylate derivatives as the leaving groups were synthesized and characterized by elemental analysis, FAB(+)-MS, FT-IR, and (1)H NMR spectroscopy. Most of the resulting platinum complexes had high solubility in organic solvents such as ethanol, acetone, and ether, and had right partition coefficient suited to be encapsulated in liposomes. The pertinent complexes were evaluated for their in vitro cytotoxicity against A549 human lung carcinoma and SGC-7901 human gastric carcinoma cell lines. They showed better cytotoxic activity than carboplatin and oxaliplatin.

[Analysis of a novel platinum anticancer compound HJ5 by high performance liquid chromatography].

Cis-dichloroamine (4-amino-2, 2, 6, 6-tetramethylpiperidine-1-oxyl) platinum (II) (abbreviated to HJ5) is a novel platinum anticancer compound which has prospects for research and application. In order to establish a conventional analytical method, an HPLC has been studied. Under the conditions of acetonitrile-water (10:90, volume ratio) as mobile phase, detection wavelength of 210 nm, a Phenomenex column C18(150 mm x 3.9 mm i.d., 10 microns). The linear equation, recovery and accuracy of the method were determined with external standard method. The HPLC has satisfactory resolution between the peaks of HJ5 and impurities. The peak areas of HJ5 were linear to its amounts detected and the detection limit was 0.07 microgram. The hydration of HJ5 can be inhibited effectively by NaCl solution. In a 9 g/L NaCl solution, the stability can be kept for more than 2 hours which is enough for analysis.