Xianglian Pill combined with 5-fluorouracil enhances antitumor activity and reduces gastrointestinal toxicity in gastric cancer by regulating the p38 MAPK/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Perioperative or postoperative adjuvant chemotherapy based on 5-fluorouracil (5-FU) is a common first-line adjuvant therapy for gastric cancer (GC). However, drug resistance and the side effects of 5-FU have reduced its efficacy. Among these side effects, gastrointestinal (GI) toxicity is one of the most common. Xianglian Pill (XLP) is a Chinese patent medicine that is commonly used for the treatment of diarrhoea. It can reduce inflammation and has a protective effect on the intestinal mucosa. Recent studies have shown that many components of XLP can inhibite tumor cell growth. However, the therapeutic effect of XLP in combination with 5-FU on GC is unclear. AIM OF THE STUDY: To investigate whether the combination of XLP and 5-FU can enhance anti-GC activity while reducing GI toxicity. MATERIALS AND METHODS: XLP was administered orally during intraperitoneal injection of 5-FU in GC mice model. Mice were continuously monitored for diarrhea and xenograft tumor growth. After 2 weeks, the mice were sacrificed and serum was collected to determine interleukin-6 levels. Pathological changes, the expression of pro-inflammatory factors and p38 mitogen-activated protein kinase (MAPK) in GI tissue were determined by Western blot analysis. Pathological changes, apoptosis levels and p38 MAPK expression levels in xenograft tissues were also determined. RESULTS: The results showed that XLP could alleviate GI mucosal injury caused by 5-FU, alleviated diarrhea, and inhibited the expression of nuclear factor (NF)-κB and myeloid differentiation primary response-88. Besides, XLP could promote the 5-FU-induced apoptosis of GC cells and enhance the inhibitory effect of 5-FU on tumor xenografts. Further study showed that XLP administration could regulate the expression of p38 MAPK. CONCLUSIONS: XLP in combination with 5-FU could alleviate its GI side effects and enhance its inhibitory effect on xenograft tumor. Moreover, these effects were found to be related to the regulation of the p38 MAPK/NF-κB pathway.

[Therapeutic effect of Leonuri Herba aqueous decoction on primary dysmenorrhea in rats and its metabolomic analysis].

This study aimed to investigate the therapeutic effect of Leonuri Herba aqueous decoction on primary dysmenorrhea(PD) and explore the underlying mechanism in conjunction with untargeted metabolomics. Forty adult female rats were randomly divi-ded into a normal group, a model control group, ibuprofen(0.12 g·kg~(-1)) group, and high-and low-dose Leonuri Herba aqueous decoction(5 and 2.5 g·kg~(-1)) groups, with eight rats in each group. The PD rat model was prepared using intramuscular injection of estradiol benzoate combined with intraperitoneal injection of pitocin. Drugs were administered by gavage from the 4th day of modeling for 7 d. After the last administration, pitocin was injected intraperitoneally, and the writhing latency and writhing times within 30 min were recorded. The uterine and ovarian coefficients were determined. Estradiol(E_2), progesterone(Prog), oxytocin(OT), cyclooxyge-nase 2(COX-2), prostaglandin E_2(PGE_2), prostaglandin F_(2α)(PGF_(2α)), and Ca~(2+) levels in uterine tissues were measured by ELISA and biochemical kits. Morphological changes in uterine and ovarian tissues were observed by hematoxylin-eosin(HE) staining. The protein expression of oxytocin receptor(OTR), prostaglandin E_2 receptor 3(EP3), and estrogen receptor alpha(ERα) in uterine tissues was detected by immunohistochemistry. The mRNA expression of OTR, PGE_2 receptors 1-4(EP1, EP2, EP3, and EP4), and PGF_(2α) receptor(FP) in uterine tissues was detected by quantitative real-time PCR. Untargeted metabolomics analysis was performed by ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(LC-QTOF-MS) technology to screen potential biomarkers and enrich metabolic pathways. The results showed that Leonuri Herba was able to significantly reduce the writhing times in PD rats(P<0.05 or P<0.01), significantly reduce the uterine and ovarian coefficients(P<0.01), and improve their histomorphology. After treatment with Leonuri Herba, PGE_2 content was significantly increased(P<0.05), COX-2, PGF_(2α) and Ca~(2+) content, and PGF_(2α)/PGE_2 was significantly decreased(P<0.05 or P<0.01), and OT content was decreased, while E_2 and Prog content tended to further increase in uterine tissues of PD rats. Correspondingly, OTR and EP3 protein expression was significantly downregulated(P<0.05 or P<0.01) and ERα protein expression was upregulated(P<0.05) in uterine tissues. The mRNA expression of FP and EP4 in uterine tissues was significantly downregulated(P<0.01), and the mRNA expression of EP1, EP3, and OTR showed a decreasing trend. The untargeted metabolomics results showed that 10 differential metabolites were restored in the plasma of PD rats after Leonuri Herba treatment. The results indicate that Leonuri Herba is effective in the prevention and treatment of PD, and the underlying mechanism may be attributed to the regulation of PGs synthesis and corresponding receptor binding.

1.7 µm figure-9 Tm-doped ultrafast fiber laser.

The evolution of multiphoton microscopy is critically dependent on the development of ultrafast laser technologies. The ultrashort pulse laser source at 1.7 µm waveband is attractive for in-depth three-photon imaging owing to the reduced scattering and absorption effects in biological tissues. Herein, we report on a 1.7 µm passively mode-locked figure-9 Tm-doped fiber laser. The nonreciprocal phase shifter that consists of two quarter-wave plates and a Faraday rotator introduces phase bias between the counter-propagating beams in the nonlinear amplifying loop mirror. The cavity dispersion is compensated to be slightly positive, enabling the proposed 1.7 µm ultrafast fiber laser to deliver the dissipative soliton with a 3-dB bandwidth of 20 nm. Moreover, the mode-locked spectral bandwidth could be flexibly tuned with different phase biases by rotating the wave plates. The demonstration of figure-9 Tm-doped ultrafast fiber laser would pave the way to develop the robust 1.7 µm ultrashort pulse laser sources, which could find important application for three-photon deep-tissue imaging.

Isorhamnetin: A Novel Natural Product Beneficial for Cardiovascular Disease.

Cardiovascular disease (CVD) has become a severe threat to human beings with increasing morbidity and mortality. Isorhamnetin (Iso) shows multiple bioactivities, especially in the cardiovascular system. A literature retrieval strategy was conducted in databases of PubMed, GeenMedical, Sci-Hub, Web of Science, China National Knowledge Infrastructure (CNKI), and Baidu Scholar, with keywords defined as: "Isorhamnetin", "cardiovascular diseases", "pharmacological effects", "phytochemistry", "pharmacokinetics", "clinical application" and "toxicity". The language is restricted to Chinese and English, and publish date ranges from January, 2011 to September, 2021. So far, Iso has been isolated and identified from several natural medicines, including Hippophae rhamnoides L., Ginkgo biloba L. and Typha angustifolia L., etc. The effects of Iso on CVD are pharmacological, including anti-atherosclerosis, reducing blood fat, anti-inflammation, antioxidation, endothelial protection, antithrombosis, antiplatelet aggregation, myocardial protection, and anti-hypertension. Iso could inhibit the activities of CYPs in liver microsomes and suppress hepatocyte injury in vitro. However, no toxicity was observed in vivo. Taken together, Iso has a wide range of positive effects on CVD with safe and multiple pharmacological activities on the cardiovascular system and may be an ideal candidate drug for the prevention and treatment of CVD. Therefore, further studies, especially on its clinic use, need to be conducted. The present review summarizes the recent progress in phytochemistry, pharmacology, and mechanisms of action and provides a reference for future studies on Iso.

Rhein activated Fas-induced apoptosis pathway causing cardiotoxicity in vitro and in vivo.

Rhein, one of the main active components of rhubarb (Dahuang) and Polygonum multiflorum (Heshouwu), has a wide range of effective pharmacological effects. Recently, increasing studies have focused on its potential hepatorenal toxicity, but the cardiotoxicity is unknown. In this study, we found that the IC50 of rhein to H9c2 cells at 24 h and 48 h were 94.5 and 45.9µmol/L, respectively, with positive correlation of dose-toxicity and time-toxicity. After the treatment of rhein (106, 124 and 132µmol/L), the number of H9c2 cells decreased significantly, and the morphology of H9c2 cells showed atrophy, round shape and wall detachment. Moreover, the proportion of apoptotic cells in H9c2 cells treated with rhein was significantly increased in a dose-dependent manner. And rhein induced S phase arrest of H9c2 cells and inhibited cell proliferation. Rhein up-regulated ROS, LDH levels and low MMP but down-regulated SOD content in H9c2 cells. Additionally, the results showed that the cardiac function LVEF and LVFS of rhein high-medium-low dose groups (350, 175, 87.5 mg/kg) were significantly reduced. And the contents of Ca2+, cTnT, CK and LDH in serum of KM mice were significantly up-regulated by rhein. Furthermore, western blot results suggested that rhein the above effects via promoting Fas-induced apoptosis pathway in vitro and in vivo. In general, rhein may cause cardiotoxicity via Fas-induced apoptosis pathway in vivo and in vitro, which provides reference for the safe use of medicinal plant containing rhein and its preparations.

Asymmetric Petasis reaction for the synthesis of chiral α- and ß-butadienyl amines.

The Petasis reaction using (1S,2R)-1-amino-2-indanol as the substrate and an activator to construct α- and ß-butadienyl amines in optically pure forms was realized, which are otherwise difficult to prepare. The reactions feature a metal-free nature, broad substrate scope, complete regioselectivities (γ-selectivity of pinacol homoallenyl- and isoprenylboronates), and high to excellent chirality induction (up to >20 : 1 dr). The favored nucleophilic addition across the Si-face of the imine intermediate was explained using DFT calculations of the six-membered chair-like transition state.

Liuweibuqi capsules improve pulmonary function in stable chronic obstructive pulmonary disease with lung-qi deficiency syndrome by regulating STAT4/STAT6 and MMP-9/TIMP-1.

Context: Liuweibuqi (LWBQ) capsule has been reported to influence symptoms of patients with chronic obstructive pulmonary disease (COPD); however, specific function of LWBQ capsules in COPD with lung-qi deficiency syndrome remains elusive.Objective: This study investigates effect of LWBQ capsules on STAT4/STAT6 and MMP-9/TIMP-1 expression and pulmonary function in stable COPD with lung-qi deficiency syndrome.Materials and methods: Totally, 429 patients diagnosed with stable COPD and lung-qi deficiency syndrome were treated with starch capsules (each time for 9 capsules), or different doses: low (each dose for 8 capsules and 1 LWBQ capsules), medium (each time for 6 capsules and 3 LWBQ capsules), or high (each time for 9 LWBQ capsules) of LWBQ capsules for 30 days, 3 times a day. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC% and DLco%pred were evaluated by pulmonary function meter. STAT4/STAT6 and MMP-9/TIMP-1 expression was assessed by RT-qPCR and western blot analysis, and serum concentrations of IL-4, IFN-γ and IL-6 by ELISA.Results: Spearman rank correlation analysis and ROC curve showed that STAT4/STAT6 and MMP-9/TIMP-1 affected pulmonary functions and curative effect of stable COPD with lung-qi deficiency syndrome. After LWBQ capsule treatment, FEV1, FVC, FEV1/FVC% and DLco%pred elevated; STAT4/STAT6, MMP-9/TIMP-1, IFN-γ and IL-6 expression declined whereas IL-4 expression increased (p < 0.05). Logistic regression analysis demonstrated that FEV1/FVC was negatively correlated with STAT4/STAT6 and MMP-9/TIMP-1 expression in COPD patients.Conclusions: LWBQ capsules play a beneficial role in pulmonary function of stable COPD with lung-qi deficiency syndrome via STAT4/STAT6 and MMP-9/TIMP-1.

Importance of Isobar Density Distributions on the Chiral Magnetic Effect Search.

Under the approximate chiral symmetry restoration, quark interactions with topological gluon fields in quantum chromodynamics can induce a chirality imbalance and parity violation in local domains. An electric charge separation (CS) could be generated along the direction of a strong magnetic field (B), a phenomenon called the chiral magnetic effect (CME). CS measurements by azimuthal correlators are contaminated by major backgrounds from elliptic flow anisotropy (v_{2}). Isobaric _{44}^{96}Ru+_{44}^{96}Ru and _{40}^{96}Zr+_{40}^{96}Zr collisions have been proposed to identify the CME (expected to differ between the two systems) out of the backgrounds (to be almost the same). We show, by using the density functional theory calculations of the proton and neutron distributions, that these expectations may not hold as originally anticipated because the two systems may have sizable differences in eccentricity and v_{2}.

Petasis-Type gem-Difluoroallylation Reactions Assisted by the Neighboring Hydroxyl Group in Amines.

A three-component Petasis-type gem-difluoroallylation reaction of using pinacol gem-difluoroallylboronates, aldehydes or isatin, and ß-amino alcohols enabled by the neighboring hydroxyl group in amine is reported, affording various racemic and chiral gem-difluorohomoallylamine derivatives with good to excellent results. Based on the control experiment and stereochemistry of the product, a proposed reaction pathway is illustrated to clarify the origin of regio- and stereoselectivity under protic solvent conditions.

Oxidative dual C-H thiolation of imidazopyridines with ethers or alkanes using elemental sulphur.

Dual C-H thiolation reactions using elemental sulphur remain a challenge. This communication discloses an oxidative radical dual sp2/sp3 C-H thiolation strategy for the coupling of imidazopyridines with ethers or alkanes using elemental sulphur.

The complete mitochondrial genome of a parasitic flatworm Senga ophiocephalina (Cestoda: Bothriocephalidae).

Mitochondrial DNA of nematodes undergoes frequent rearrangements, so it is a very good model for studying the mitochondrial genome evolution. The complete mitochondrial genome of a parasitic nematode Senga ophiocephalina was sequenced and annotated. The 13,816 bp-long genome contained 12 protein-coding genes (atp8 gene was missing), two ribosomal RNAs, 22 transfer RNAs, and a 391 bp non-coding region. Phylogenetic analysis showed that S. ophiocephalina forms a monophyletic cluster with the remaining two Bothriocephalidae species.

Analysis of the height dependence of site-specific cancer risk in relation to organ mass.

BACKGROUND: Cancer risks at multiple cancer sites have been shown to correlate positively with height. An existing idea is that taller people have more cells and thus more prone to mutations that will lead to cancer, and the hypothesis is that cancer risk is proportional to the organ mass. In this study we quantitatively test this hypothesis. METHODS: We perform an analysis of large-scale data on the height dependence of site-specific cancer risks. We also perform an analysis of the height dependence of measured organ masses. We then compare the cancer risk data with the expectations based on the organ mass hypothesis. Our study includes 16 cancer sites of women and 14 cancer sites of men. RESULTS: For the relative risk (RR) per 10 cm increase in height for cancer incidence, the averaged expected value is within the 95% confidence interval (CI) of the averaged cancer risk data for 8 out of the 15 cancer sites for which the comparison can be made. Also, a large proportion of the sex difference of cancer risks for pancreas and lungs could come from the sex difference of the organ mass. CONCLUSIONS: The hypothesis that cancer risk is proportional to the organ mass partially explains the height dependence of cancer risks. It also helps explain the sex difference of cancer risks, especially for pancreas and lungs.

Flavor ordering of elliptic flows at high transverse momentum.

Based on the quark coalescence model for the parton-to-hadron phase transition in relativistic heavy ion collisions, we relate the elliptic flow (upsilon(2)) of high p(T) hadrons to that of high p(T) quarks. For high p(T) hadrons produced from an isospin-symmetric and quark-antiquark-symmetric partonic matter, magnitudes of their elliptic flows follow a flavor ordering as (upsilon(2,pi)=upsilon(2,N))>(upsilon(2,Lambda)=upsilon(2,Sigma))>upsilon(2,K)>upsilon(2,Xi)>(upsilon(2,phi)=upsilon(2,Omega)) if strange quarks have a smaller elliptic flow than light quarks. The elliptic flows of high p(T) hadrons further follow a simple quark counting rule if strange quarks and light quarks have the same high p(T) spectrum and coalescence probability.

Partonic effects on pion interferometry at the relativistic heavy-ion collider.

Using a multiphase transport model that includes both initial partonic and final hadronic interactions, we study the pion interferometry at the Relativistic Heavy-Ion Collider. We find that the two-pion correlation function is sensitive to the magnitude of the parton-scattering cross section, which controls the parton density at which the transition from the partonic to hadronic matter occurs. Also, the emission source of pions is non-Gaussian, leading to source radii that can be more than twice larger than the radius parameters extracted from a Gaussian fit to the correlation function.