Identification of FTY720 and COH29 as novel topoisomerase I catalytic inhibitors by experimental and computational studies.

The development of novel topoisomerase I (TOP1) inhibitors is crucial for overcoming the drawbacks and limitations of current TOP1 poisons. Here, we identified two potential TOP1 inhibitors, namely, FTY720 (a sphingosine 1-phosphate antagonist) and COH29 (a ribonucleotide reductase inhibitor), through experimental screening of known active compounds. Biological experiments verified that FTY720 and COH29 were nonintercalative TOP1 catalytic inhibitors that did not induce the formation of DNA-TOP1 covalent complexes. Molecular docking revealed that FTY720 and COH29 interacted favorably with TOP1. Molecular dynamics simulations revealed that FTY720 and COH29 could affect the catalytic domain of TOP1, thus resulting in altered DNA-binding cavity size. The alanine scanning and interaction entropy identified Arg536 as a hotspot residue. In addition, the bioinformatics analysis predicted that FTY720 and COH29 could be effective in treating malignant breast tumors. Biological experiments verified their antitumor activities using MCF-7 breast cancer cells. Their combinatory effects with TOP1 poisons were also investigated. Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1.

SESAM mode-locked Yb:GdScO3 laser.

We report on the investigation of continuous-wave (CW) and SEmiconductor Saturable Absorber Mirror (SESAM) mode-locked operation of a Yb:GdScO3 laser. Using a single-transverse-mode, fiber-coupled InGaAs laser diode at 976 nm as a pump source, the Yb:GdScO3 laser delivers 343 mW output power at 1062 nm in the CW regime, which corresponds to a slope efficiency of 52%. Continuous tuning is possible across a wavelength range of 84 nm (1027-1111 nm). Using a commercial SESAM to initiate mode-locking and stabilize soliton-type pulse shaping, the Yb:GdScO3 laser produces pulses as short as 42 fs at 1065.9 nm, with an average output power of 40 mW at 66.89 MHz. To the best of our knowledge, this is the first demonstration of passively mode-locking with Yb:GdScO3 crystal.

Growth, spectroscopy and SESAM mode-locking of a "mixed" Yb:Ca(Gd,Y)AlO4 disordered crystal.

We present the growth, spectroscopy, continuous-wave (CW) and passively mode-locked (ML) operation of a novel "mixed" tetragonal calcium rare-earth aluminate crystal, Yb3+:Ca(Gd,Y)AlO4. The absorption, stimulated-emission, and gain cross-sections are derived for π and σ polarizations. The laser performance of a c-cut Yb:Ca(Gd,Y)AlO4 crystal is studied using a spatially single-mode, 976-nm fiber-coupled laser diode as a pump source. A maximum output power of 347 mW is obtained in the CW regime with a slope efficiency of 48.9%. The emission wavelength is continuously tunable across 90 nm (1010 - 1100 nm) using a quartz-based Lyot filter. With a commercial SEmiconductor Saturable Absorber Mirror to initiate and maintain ML operation, soliton pulses as short as 35 fs are generated at 1059.8 nm with an average output power of 51 mW at ∼65.95 MHz. The average output power can be scaled to 105 mW for slightly longer pulses of 42 fs at 1063.5 nm.

Continuous-wave and SESAM mode-locked operation of a Yb:YSr3(PO4)3 laser.

We report on the continuous-wave (CW) and, for what we believe to be the first time, passively mode-locked (ML) laser operation of an Yb3+-doped YSr3(PO4)3 crystal. Utilizing a 976-nm spatially single-mode, fiber-coupled laser diode as pump source, the Yb:YSr3(PO4)3 laser delivers a maximum CW output power of 333 mW at 1045.8 nm with an optical efficiency of 55.7% and a slope efficiency of 60.9%. Employing a quartz-based Lyot filter, an impressive wavelength tuning range of 97 nm at the zero level was achieved in the CW regime, spanning from 1007 nm to 1104 nm. In the ML regime, incorporating a commercially available semiconductor saturable absorber mirror (SESAM) to initiate and maintain soliton-like pulse shaping, the Yb:YSr3(PO4)3 laser generated pulses as short as 61 fs at 1062.7 nm, with an average output power of 38 mW at a repetition rate of ∼66.7 MHz.

Metabolic dysfunction-associated fatty liver disease and nonalcoholic fatty liver disease from clinical to pathological characteristics: a multi-center cross-sectional study in real world.

BACKGROUND: The evaluation of patients with fatty liver as defined by metabolic dysfunction-associated fatty liver disease (MAFLD) in the real world remains poorly researched. This study aimed to analyse the clinical and histological features of patients with MAFLD and nonalcoholic fatty liver disease (NAFLD) and to characterize each metabolic subgroup of MAFLD. METHODS: A total of 2563 patients with fatty liver confirmed by ultrasonography and/or magnetic resonance tomography and/or liver biopsy-proven from three hospitals in China were included in the study. Patients were divided into different groups according to diagnostic criteria for MAFLD and NAFLD, and MAFLD into different subgroups. RESULTS: There were 2337 (91.2%) patients fitting the MAFLD criteria, and 2095 (81.7%) fitting the NAFLD criteria. Compared to patients with NAFLD, those with MAFLD were more likely to be male, had more metabolic traits, higher liver enzyme levels, and noninvasive fibrosis scores. Among the patients with liver biopsy, the extent of advanced fibrosis in cases with MAFLD was significantly higher than those with NAFLD, 31.8% versus 5.2% (P < .001); there was no significant difference in advanced fibrosis between obese cases and lean individuals in MAFLD (P > .05); MAFLD complicated with diabetes had significantly higher advanced fibrosis than those without diabetes (43.3% and 17.2%, respectively; P < .001). CONCLUSIONS: Patients with MAFLD have a higher degree of liver fibrosis than NAFLD patients. In addition, diabetic patients should be screened for fatty liver and liver fibrosis degree.

LncRNA SNHG1: role in tumorigenesis of multiple human cancers.

Small nucleolar RNA host gene 1 (SNHG1) is an important member of the SNHG family. This family is composed of a group of host genes that can be processed into small nucleolar RNAs and play important biological functions. In an oncogenic role, the SNHG1 expression is increased in various cancers, which has immense application prospects in the diagnosis, treatment, and prognosis of malignant tumors. In this review, we have summarized the role and molecular mechanism of SNHG1 in the development of various cancers. In addition, we have emphasized the clinical significance of SNHG1 in cancers in our article. This molecule is expected to be a new marker for potential usage in the diagnosis, prognosis, and treatment of cancer.

Identification of N-(3-(methyl(3-(orotic amido)propyl)amino)propyl) oleanolamide as a novel topoisomerase I catalytic inhibitor by rational design, molecular dynamics simulation, and biological evaluation.

DNA topoisomerase I (TOP1) catalytic inhibitors are a promising class of antitumor agents. Oleanolic acid derivatives are potential TOP1 catalytic inhibitors. However, their inhibitory activity still needs to be enhanced, and the stability and hotspot residue sites of their interaction with TOP1 remain to be elucidated. Herein, a novel oleanolic acid derivative, OA4 (N-(3-(methyl(3-(orotic amido)propyl)amino)propyl)oleanolamide), was identified by rational design. Subsequently, molecular dynamics simulations were performed to explore the stability and conformational dynamics of the TOP1-OA4 complex. The molecular mechanics/generalized Born surface area method calculated the binding free energy and predicted Arg488, Ile535, and His632 to be hotspot residues. Biological experiments verified that OA4 is a nonintercalative TOP1 catalytic inhibitor. OA4 exhibits better proliferation inhibitory activity against tumor cells than normal cells. Furthermore, OA4 can induce apoptosis and effectively suppress the proliferation and migration of cancer cells. This work provides new insights for the development of novel TOP1 catalytic inhibitors.

Diode-pumped mode-locked Yb:Sc2SiO5 laser generating 38 fs pulses.

We report on sub-40 fs pulse generation from a Yb:Sc2SiO5 laser pumped by a spatially single-mode fiber-coupled laser diode at 976 nm. A maximum output power of 545 mW was obtained at 1062.6 nm in the continuous-wave regime, corresponding to a slope efficiency of 64% and a laser threshold of 143 mW. A continuous wavelength tuning across 80 nm (1030 -1110 nm) was also achieved. Implementing a SESAM for starting and stabilizing the mode-locked operation, the Yb:Sc2SiO5 laser delivered soliton pulses as short as 38 fs at 1069.5 nm with an average output power of 76 mW at a pulse repetition rate of ∼79.8 MHz. The maximum output power was scaled to 216 mW for slightly longer pulses of 42 fs, which corresponded to a peak power of 56.6 kW and an optical efficiency of 22.7%. To the best of our knowledge, these results represent the shortest pulses ever achieved with any Yb3+-doped rare-earth oxyorthosilicate crystal.

56-fs diode-pumped SESAM mode-locked Yb:YAl3(BO3)4 laser.

We report on the first sub-60 fs pulse generated from a diode-pumped SESAM mode-locked Yb-laser based on a non-centrosymmetric Yb:YAl3(BO3)4 crystal as a gain medium. In the continuous-wave regime, pumping with a spatially single-mode, fiber-coupled 976 nm InGaAs laser diode, the Yb:YAl3(BO3)4 laser generated 391 mW at 1041.7 nm with a slope efficiency as high as 65.1%, and a wavelength tuning across 59 nm (1019 to 1078 nm) was achieved. By implementing a commercial SESAM to initiate and sustain the soliton type mode-locking, and using only a 1 mm-thick laser crystal, the Yb:YAl3(BO3)4 laser delivered pulses as short as 56 fs at a central wavelength of 1044.6 nm with an average output power of 76 mW at a pulse repetition rate of ∼67.55 MHz. To the best of our knowledge, this result represents the shortest pulses ever achieved from Yb:YAB crystal.

Sub-50 fs diode-pumped SESAM mode-locked Yb:SrF2 laser.

We report on sub-50 fs pulse generation from a passively mode-locked Yb:SrF2 laser pumped with a spatially single-mode, fiber-coupled laser diode at 976 nm. In the continuous-wave regime, the Yb:SrF2 laser generated a maximum output power of 704 mW at 1048 nm with a threshold of 64 mW and a slope efficiency of 77.2%. A continuous wavelength tuning across 89 nm (1006 - 1095 nm) was achieved with a Lyot filter. By implementing a SEmiconductor Saturable Absorber Mirror (SESAM) for initiating and sustaining the mode-locked operation, soliton pulses as short as 49 fs were generated at 1057 nm with an average output power of 117 mW at a pulse repetition rate of ∼75.9 MHz. The maximum average output power of the mode-locked Yb:SrF2 laser was scaled up to 313 mW for slightly longer pulses of 70 fs at 1049.4 nm, corresponding to a peak power of 51.9 kW and an optical efficiency of 34.7%.

Kerr-lens mode-locking of an Yb:CLNGG laser.

We report on a Kerr-lens mode-locked laser based on an Yb3+-doped disordered calcium lithium niobium gallium garnet (Yb:CLNGG) crystal. Pumping by a spatially single-mode Yb fiber laser at 976 nm, the Yb:CLNGG laser delivers soliton pulses as short as 31 fs at 1056.8 nm with an average output power of 66 mW and a pulse repetition rate of ∼77.6 MHz via soft-aperture Kerr-lens mode-locking. The maximum output power of the Kerr-lens mode-locked laser amounted to 203 mW for slightly longer pulses of 37 fs at an absorbed pump power of 0.74 W, which corresponds to a peak power of 62.2 kW and an optical efficiency of 20.3%.

Revealing the Active Constituents and Mechanisms of Semiliquidambar cathayensis Chang Roots against Rheumatoid Arthritis through Network Pharmacology, Molecular Docking, and in Vivo Experiment.

Semiliquidambar cathayensis Chang roots (SC) are traditional Chinese medicine for treating rheumatoid arthritis (RA). However, the effect and potential mechanism of SC remain unclear. This study aims to reveal the anti-RA constituents and mechanisms of SC based on network pharmacology, molecular docking, and adjuvant-induced arthritis (AIA) model rat experiment. In this work, 9 potential active constituents, including kaempferol, quercetin, naringenin, paeoniflorin, catechin, fraxin, gentianin, hesperetin, and ellagic acid 3,3',4-trimethyl ether, in SC crossed 65 target genes of RA. In addition, 28 core targets were enriched in inflammation and others, among which interleukin-17 (IL-17) and tumor necrosis factor (TNF) were the major targets. The binding of bio-constituents with IL-17 and TNF were performed using molecular docking. Rat experiment demonstrated that the extract of SC restored body weight loss, reduced arthritis score and the indices of thymus and spleen, alleviated ankle joint histopathology, decreased the levels of rheumatoid factor (RF), C-reactive protein (CRP), IL-17, TNF-α, IL-1ß, IL-6, cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and matrix metalloproteinase-2 (MMP-2), whereas elevated the levels of IL-4 and IL-10. Collectively, it was the first time to comprehensively reveal the anti-RA efficacy and mechanism of SC via suppressing the inflammatory pathway based on network pharmacology, molecular docking, and experimental verification, which provide chemical and pharmacological evidences for the clinical application of SC.

Semiconductor saturable absorber mirror mode-locked Yb:YAP laser.

We report on sub-30 fs pulse generation from a semiconductor saturable absorber mirror mode-locked Yb:YAP laser. Pumping by a spatially single-mode Yb fiber laser at 979 nm, soliton pulses as short as 29 fs were generated at 1091 nm with an average output power of 156 mW and a pulse repetition rate of 85.1 MHz. The maximum output power of the mode-locked Yb:YAP laser amounted to 320 mW for slightly longer pulses (32 fs) at an incident pump power of 1.52 W, corresponding to a peak power of 103 kW and an optical efficiency of 20.5%. To the best of our knowledge, this result represents the shortest pulses ever achieved from any solid-state Yb laser mode-locked by a slow, i.e., physical saturable absorber.

Kerr-lens mode-locked Yb:YAlO3 laser generating 24-fs pulses at 1085 nm.

We report on a Kerr-lens mode-locked Yb:YAlO3 laser generating soliton pulses as short as 24 fs at 1085 nm with an average output power of 186 mW and a pulse repetition rate of 87.5 MHz, representing the shortest pulses ever achieved from any mode-locked laser based on Yb3+-doped structurally ordered crystal. Optimized for power-scalable operation, the Yb:YAlO3 laser delivers 1.9 W at 1060 nm at the expense of a longer pulse duration of 44 fs, corresponding to a peak power of 462 kW and an optical efficiency of 43.2%.

Natural phenylethanoid glycosides diuretics derived from Lagopsis supina: Biological activity, mechanism, molecular docking, and structure-activity relationship.

Aquaporins (AQPs) and vasopressin type 2 receptor (V2R) play a crucial role in urine excretion and are widely used to explore novel diuretics. In this study, three phenylpropanoids including stachysoside A (L1), acteoside (L2), and glucopyranosyl (1 â†’ 6) martynoside (L3) were isolated from Lagopsis supina (Steph. ex Willd.) lk. -Gal. ex Knorr. Their diuretic activity, mechanism, molecular docking, and structure-activity relationships were explored. The results suggest that L1, L2, and L3 exhibit acute (6 h) and prolonged (6 d) activities including increased urinary excretion volume, diuretic action, and diuretic activity, without affecting the urinary pH and minor altering the electrolyte balance in saline-loaded rats. Further, L1, L2, and L3 significantly reduced the levels of angiotensin II (Ang II), anti-diuretic hormone (ADH), and aldosterone (ALD), AQPs 1-4 and 7, and V2R, and remarkably elevated the atriopeptin (ANP) level. Besides, L1, L2, and L3 obviously suppressed mRNA and protein levels of AQPs 1-4 and 7, and V2R. The hypothetical binding modes of L1, L2, and L3 with these proteins were determined by molecular docking, and a tight structure-activity relationship was also proposed. Collectively, L1, L2, and L3 represent three natively novel phenylethanoid glycoside diuretics, which inhibit AQP and V2R-mediated molecular mechanisms. They are superior to furosemide as long-term diuretics.

Kerr-lens mode-locked ytterbium-activated orthoaluminate laser.

We report on the first, to the best of our knowledge, Kerr-lens mode-locked laser based on an Yb3+-doped perovskite-type orthoaluminate crystal exploiting two different principal light polarizations. The Yb:(Y,Gd)AlO3 laser delivers soliton pulses as short as 32 fs at 1067 nm with an average output power of 328 mW and a pulse repetition rate of ∼84.6 MHz for E || a polarization. For the orthogonal E || b polarization, 33-fs pulses are generated at 1057 nm with an average output power of 305 mW. Power scaling to a maximum average output power reaching 2.07 W is achieved at the expense of longer pulse duration (72 fs for E || b), corresponding to an optical efficiency of 43.9% and a peak power of 303 kW.

Diode-pumped SESAM mode-locked Yb:(Y,Gd)AlO3 laser.

We report on the continuous-wave (CW) and mode-locked (ML) laser performance of an Yb3+-doped yttrium-gadolinium orthoaluminate crystal, Yb:(Y,Gd)AlO3. Pumping by a single-transverse-mode fiber-coupled 976 nm InGaAs laser diode, the maximum output power in the CW regime amounted to 429 mW at 1041.8 nm corresponding to a slope efficiency of 51.1% and a continuous wavelength tuning across 84 nm (1011-1095 nm) was achieved. The self-starting ML operation of the Yb:(Y,Gd)AlO3 laser was stabilized by a semiconductor saturable absorber mirror. Soliton pulses as short as 43 fs were generated at 1052.3 nm with an average output power of 103 mW and a pulse repetition rate of ∼70.8 MHz. To the best of our knowledge, our result represents the first report on the passively mode-locked operation of a Yb:(Y,Gd)AlO3 laser, and the shortest pulse duration ever achieved from any Yb3+-doped orthorhombic perovskite aluminate crystals.

Soliton mode-locked Yb:Ca3Gd2(BO3)4 laser.

We report on a soliton mode-locked Yb:Ca3Gd2(BO3)4 laser at ∼1.06 µm stabilized by a semiconductor saturable absorber mirror. Pumping with a single-transverse mode, fiber-coupled laser diode at 976 nm, the Yb:Ca3Gd2(BO3)4 laser delivers soliton pulses as short as 39 fs at a central wavelength of 1059.2 nm with an average output power of 70 mW and a pulse repetition rate of ∼67.3 MHz.

SESAM mode-locked Yb:Sr3Y2(BO3)4 laser.

We demonstrate the first sub-40 fs soliton pulse generation from a diode-pumped Yb:Sr3Y2(BO3)4 laser passively mode-locked by a semiconductor saturable absorber mirror. Pulses as short as 38 fs at a central wavelength of 1051.7 nm were achieved with an average output power of 115 mW and a pulse repetition rate of 67.7 MHz. The maximum average output power reached 303 mW at 1057.8 nm with a slightly longer pulse duration of 52 fs, which corresponded to a peak power of 76.9 kW and an optical efficiency of 25.3%.

Diode-pumped mode-locked Yb:BaF2 laser.

We report on a continuous-wave (CW) and passively mode-locked operation of a fluorite-type Yb:BaF2 crystal. Pumped with a spatially single-mode, fiber-coupled InGaAs laser diode at 976 nm, the Yb:BaF2 laser generated a maximum CW output power of 512 mW at 1054.4 nm, corresponding to a laser threshold of 36.5 mW and a slope efficiency of 65.0%. A continuous wavelength tuning across 85 nm (1007-1092 nm) was achieved. By implementing a semiconductor saturable absorber mirror for initiating and sustaining the soliton pulse shaping, near Fourier-transform-limited pulses as short as 52 fs were generated at 1058.2 nm with an average output power of 129 mW at a pulse repetition rate of ∼79.5 MHz. To the best of our knowledge, this is the first report on the passively mode-locked operation of the Yb:BaF2 crystal.