Structural, mechanical, electronic, vibrational properties and hydrogen bonding of a novel energetic ionic 5, 5'-dinitroamino-3, 3'-azo-oxadiazole 4, 7-diaminopyridazino [4, 5-c] furoxan salt.

CONTEXT AND RESULTS: The structure, mechanical, electronic, vibration, and hydrogen bonding properties of a novel high-energy and low-sensitivity 5, 5'-dinitroamino-3, 3'-azo-oxadiazole 4, 7-diaminopyridazino [4, 5-c] furoxan salt have been studied by density functional theory. The calculated vibrational properties show that the low-frequency mode is mainly contributed by the vibration of the -NO2 group, and the high-frequency mode is mainly contributed by the vibration of the -NH2 group and the N7-H3 bond which protonates the cation. In addition, it is analyzed that the first bond to break may be the N-NO2 bond. The calculated hydrogen bond properties indicate that the hydrogen bond between water molecules and cations is N7-H3… O5 (1.563 Å), which is the shortest hydrogen bond among all hydrogen bonds. The presence of this exceptionally short hydrogen bond renders the N7-H3 and H6-O5 bonds resistant to disruption at high frequencies, underscoring the pivotal role of hydrogen bonding in stabilizing the structure of energetic materials. Given the absence of experimental and theoretical data on the electronic, mechanical, and vibrational properties of the material thus far, our calculations offer valuable theoretical insights into the ionic salts of high energy and low sensitivity. COMPUTATIONAL METHODS: All calculations have been carried out based on density functional theory (DFT) and implemented in the CASTEP code. The mode-conserving pseudopotential is utilized to describe the plane wave expansion function, while the PBE functional within the generalized gradient approximation (GGA) is employed to characterize the exchange-correlation interaction. Additionally, dispersion correction is applied using Grimme's DFT-D method.

Molecular Structures, Dipole Moments, and Electronic Properties of ß-HMX under External Electric Field from First-Principles Calculations.

In order to investigate the impact of an external electric field on the sensitivity of ß-HMX explosives, we employ first-principles calculations to determine the molecular structure, dipole moment, and electronic properties of both ß-HMX crystals and individual ß-HMX molecules under varying electric fields. When the external electric field is increasing along the [100], [010], and [001] crystallographic directions of ß-HMX, the calculation results indicate that an increase in the bond length (N1-N3/N1'-N3') of the triggering bond, an increase in the main Qnitro (N3, N3') value, an increase in the minimum surface electrostatic potential, and a decrease in band gap all contribute to a reduction in its stability. Among these directions, the [010] direction exhibits the highest sensitivity, which can be attributed to the significantly smaller effective mass along the [010] direction compared with the [001] and [100] directions. Moreover, the application of an external electric field along the Y direction of the coordinate system on individual ß-HMX molecules reveals that the strong polarization effect induced by the electric field enhances the decomposition of the N1-N3 bonds. In addition, due to the periodic potential energy of ß-HXM crystal, the polarization effect of ß-HMX crystal caused by an external electric field is much smaller than that of a single ß-HXM molecule.

Therapeutic effects and molecular mechanisms of natural products in thrombosis.

Thrombotic disorders, such as myocardial infarction and stroke, are the leading cause of death in the global population and have become a health problem worldwide. Drug therapy is one of the main antithrombotic strategies, but antithrombotic drugs are not completely safe, especially the risk of bleeding at therapeutic doses. Recently, natural products have received widespread interest due to their significant efficacy and high safety, and an increasing number of studies have demonstrated their antithrombotic activity. In this review, articles from databases, such as Web of Science, PubMed, and China National Knowledge Infrastructure, were filtered and the relevant information was extracted according to predefined criteria. As a result, more than 100 natural products with significant antithrombotic activity were identified, including flavonoids, phenylpropanoids, quinones, terpenoids, steroids, and alkaloids. These compounds exert antithrombotic effects by inhibiting platelet activation, suppressing the coagulation cascade, and promoting fibrinolysis. In addition, several natural products also inhibit thrombosis by regulating miRNA expression, anti-inflammatory, and other pathways. This review systematically summarizes the natural products with antithrombotic activity, including their therapeutic effects, mechanisms, and clinical applications, aiming to provide a reference for the development of new antithrombotic drugs.

Dual Drug-Loaded Nanoliposomes Encapsulating Curcumin and 5-Fluorouracil with Advanced Medicinal Applications: Self-Monitoring and Antitumor Therapy.

Due to the presence of physiological barriers, it is difficult to achieve the desired therapeutic efficacy of drugs; thus, it is necessary to develop an efficient drug delivery system that enables advanced functions such as self-monitoring. Curcumin (CUR) is a naturally functional polyphenol whose effectiveness is limited by poor solubility and low bioavailability, and its natural fluorescent properties are often overlooked. Therefore, we aimed to improve the antitumor activity and drug uptake monitoring by simultaneously delivering CUR and 5-Fluorouracil (5-FU) in the form of liposomes. In this study, dual drug-loaded liposomes (FC-DP-Lip) encapsulating CUR and 5-FU were prepared by the thin-film hydration method; their physicochemical properties were characterized; and their biosafety, drug uptake distribution in vivo, and tumor cell toxicity were evaluated. The results showed that the nanoliposome FC-DP-Lip showed good morphology, stability, and drug encapsulation efficiency. It showed good biocompatibility, with no side effects on zebrafish embryonic development. In vivo uptake in zebrafish showed that FC-DP-Lip has a long circulation time and presents gastrointestinal accumulation. In addition, FC-DP-Lip was cytotoxic against a variety of cancer cells. This work showed that FC-DP-Lip nanoliposomes can enhance the toxicity of 5-FU to cancer cells, demonstrating safety and efficiency, and enabling real-time self-monitoring functions.

Helicobacter pylori regulates stomach diseases by activating cell pathways and DNA methylation of host cells.

One of the most prevalent malignant tumors of the digestive tract is gastric cancer (GC). Age, high salt intake, Helicobacter pylori (H. pylori) infection, and a diet deficient in fruits and vegetables are risk factors for the illness. A significant risk factor for gastric cancer is infection with H. pylori. Infecting gastric epithelial cells with virulence agents secreted by H. pylori can cause methylation of tumor genes or carcinogenic signaling pathways to be activated. Regulate downstream genes' aberrant expression, albeit the precise mechanism by which this happens is unclear. Oncogene, oncosuppressor, and other gene modifications, as well as a number of different gene change types, are all directly associated to the carcinogenesis of gastric cancer. In this review, we describe comprehensive H. pylori and its virulence factors, as well as the activation of the NF-κB, MAPK, JAK/STAT signaling pathways, and DNA methylation following infection with host cells via virulence factors, resulting in abnormal gene expression. As a result, host-related proteins are regulated, and gastric cancer progression is influenced. This review provides insight into the H. pylori infection, summarizes a series of relevant papers, discusses the complex signaling pathways underlying molecular mechanisms, and proposes new approach to immunotherapy of this important disease.

Nano-Liposomes Double Loaded with Curcumin and Tetrandrine: Preparation, Characterization, Hepatotoxicity and Anti-Tumor Effects.

(1) Background: Curcumin (CUR) and tetrandrine (TET) are natural compounds with various bioactivities, but have problems with low solubility, stability, and absorption rate, resulting in low bioavailability, and limited applications in food, medicine, and other fields. It is very important to improve the solubility while maintaining the high activity of drugs. Liposomes are micro-vesicles synthesized from cholesterol and lecithin. With high biocompatibility and biodegradability, liposomes can significantly improve drug solubility, efficacy, and bioavailability. (2) Methods: In this work, CUR and TET were encapsulated with nano-liposomes and g DSPE-MPEG 2000 (DP)was added as a stabilizer to achieve better physicochemical properties, biosafety, and anti-tumor effects. (3) Results: The nano-liposome (CT-DP-Lip) showed stable particle size (under 100 nm) under different conditions, high solubility, drug encapsulation efficiency (EE), loading capacity (LC), release rate in vitro, and stability. In addition, in vivo studies demonstrated CT-DP-Lip had no significant toxicity on zebrafish. Tumor cytotoxicity test showed that CT-DP-Lip had a strong inhibitory effect on a variety of cancer cells. (4) Conclusions: This work showed that nano-liposomes can significantly improve the physical and chemical properties of CUR and TET and make them safer and more efficient.

Near-Infrared Photothermal/Photodynamic-in-One Agents Integrated with a Guanidinium-Based Covalent Organic Framework for Intelligent Targeted Imaging-Guided Precision Chemo/PTT/PDT Sterilization.

Phototherapy holds great promise in the treatment of bacterial infections, especially the multidrug resistant bacterial infections. However, most therapeutic agents are based on the integration of individual photothermal agents and photosensitizers, always in the activated state, and generally lack bacterial specificity, resulting in uncertain pharmacokinetics and serious nonspecific damage to normal tissues. Herein, we report a pH-responsive nanoplatform with synergistic chemo-phototherapy function for smart fluorescence imaging-guided precision sterilization. pH reversible activated symmetric cyanine was designed and prepared as a bacterial-specific imaging unit and PTT/PDT-in-one agent. Meanwhile, a guanidinium-based covalent organic framework (COF) was employed as a nanocarrier and chemotherapy agent to build the intelligent nanoplatform via electrostatic self-assembly. The self-assembly of the PTT/PDT-in-one agent and the COF greatly improves the stability and blood circulation of the PTT/PDT-in-one agent and provides charge-reversed intelligent targeting ability. The developed smart nanoplatform not only enables bacterial-targeted imaging but also possesses chemo/PTT/PDT synergetic high-efficiency bactericidal effects with little side effects, showing great potential in practical applications.

Puerariae Lobatae radix flavonoids and puerarin alleviate alcoholic liver injury in zebrafish by regulating alcohol and lipid metabolism.

Exessive drinking is commonly associated with a wide spectrum of liver injuries. The term alcoholic liver disease (ALD) is generally used to refer to this spectrum of hepatic abnormalities, and the term hepatic steatosis denotes early lesions. Puerariae Lobatae Radix (PLR) is a common traditional Chinese medicine and has been widely used as an efficient treatment for alcohol-induced damage. Flavonoids are the principal components of PLR that could potentially be responsible for the activation of alcohol metabolism and lipid-lowering effects. However, little is known about the mechanisms underlying their activity against alcoholic injury. In this study, PLR flavonoids (PLF) were obtained by microwave extraction. A 2% ethanol solution was used to establish a model of alcoholic fatty liver disease by exposure of zebrafish larvae for 32 h, and then the zebrafish were administered PLF and puerarin. The results showed that PLF and puerarin significantly decreased lipid accumulation and the levels of total cholesterol and triglycerides in zebrafish larvae. Moreover, PLF and puerarin downregulated the expression of genes related to alcohol and lipid metabolism (CYP2y3, CYP3a65, ADH8a, ADH8b, HMGCRB, and FASN), endoplasmic reticulum stress, and DNA damage (CHOP, EDEM1, GADD45αa, and ATF6) and reduced levels of inflammatory factors (IL-1ß, TNF-α) in zebrafish larvae. PLF and puerarin increased the phosphorylation of AMP-activated protein kinase-α (AMPKα) and decreased the total protein level of ACC1. The findings suggested that PLF and puerarin alleviated alcohol-induced hepatic steatosis in zebrafish larvae by regulating alcohol and lipid metabolism, which was closely related to the regulation of the AMPKα-ACC signaling pathway. In conclusion, the study provided a possible therapeutic drug for ALD treatment.

pH Reversibly Switchable Nanocapsule for Bacteria-Targeting Near-Infrared Fluorescence Imaging-Guided Precision Photodynamic Sterilization.

Photodynamic sterilization is the most promising method to combat bacterial infection, especially multidrug-resistant bacterial infection. However, the absorption of conventional photosensitizers is mostly located in the UV-vis region, leading to limited penetration depth and poor therapeutic efficacy for deep-tissue bacterial infection. Besides, most of the photosensitizers are always in the activated state and lack bacteria-targeting ability, which inevitably causes severe nonspecific damage to normal tissues. Here, we show the design of a pH reversibly switchable near-infrared photosensitizer-based nanocapsule for precision bacteria-targeting fluorescence imaging-guided photodynamic sterilization. pH reversibly activatable asymmetric cyanine was synthesized as a bacteria-specific imaging unit and smart photosensitizer to realize precision imaging-guided targeting sterilization without side effects. An allicin mimic was introduced into the smart photosensitizer as the auxiliary bactericidal group to further enhance antibacterial efficiency. Meanwhile, amphipathic functionalized polyethylene glycol was employed to fabricate the nanocapsule by self-assembly to endow the charge-reversed intelligent targeting ability and prolong blood circulation. The developed switchable nanocapsule not only enables precision bacterial infection-targeted imaging without background fluorescence interference but also gives an efficient bactericidal effect with excellent specificity and negligible side effects, holding great potential for practical application.

A pH reversibly activatable NIR photothermal/photodynamic-in-one agent integrated with renewable nanoimplants for image-guided precision phototherapy.

Phototherapy has great potential to revolutionize conventional therapeutic modalities. However, most phototherapeutic strategies based on multicomponent therapeutic agents generally lack tumor-specificity, resulting in asynchronous therapy and superimposed side-effects. Severe heat damage is also inevitable because of the necessity of continuous external irradiation. Here we show the design of an acid-activated and continuous external irradiation-free photothermal and photodynamic (PTT/PDT) synchronous theranostic nanoplatform for precision tumor-targeting near-infrared (NIR) image-guided therapy. pH-reversibly responsive brominated asymmetric cyanine is designed as the tumor-specific NIR PTT/PDT-in-one agent to enhance anticancer efficiency and reduce side-effects. Ultra-small NIR persistent luminescence nanoparticles are prepared as both the imaging unit and renewable nanoimplant. Biotin functionalized polyethylene glycol is introduced to endow active tumor-targeting ability and prolong blood-circulation. The developed smart platform offers merits of reversible activation, PTT/PDT synergetic enhancement, tumor targetability and continuous external irradiation-free properties, allowing autofluorescence-free image-guided phototherapy only in tumor sites. This work paves the way to developing smart theranostic nanoplatforms for precision medicine.

Effect of Rhizobium Symbiosis on Low-Temperature Tolerance and Antioxidant Response in Alfalfa (Medicago sativa L.).

Low temperature-induced stress is a major environmental factor limiting the growth and development of plants. Alfalfa (Medicago sativa L.) is a legume well known for its tolerance of extreme environments. In this study, we sought to experimentally investigate the role of rhizobium symbiosis in alfalfa's performance under a low-temperature stress condition. To do this, alfalfa "Ladak+" plants carrying active nodules (AN), inactive nodules (IN), or no nodules (NN) were exposed to an imposed low temperature stress and their survivorship calculated. The antioxidant defense responses, the accumulation of osmotic regulation substances, the cell membrane damage, and the expression of low temperature stress-related genes were determined in both the roots and the shoots of alfalfa plants. We found that more plants with AN survived than those with IN or NN under the same low temperature-stress condition. Greater activity of oxidation protective enzymes was observed in the AN and IN groups, conferring higher tolerance to low temperature in these plants. In addition, rhizobia nodulation also enhanced alfalfa's ability to tolerate low temperature by altering the expression of regulatory and metabolism-associated genes, which resulted in the accumulation of soluble proteins and sugars in the nodulated plants. Taken together, the findings of this study indicate that rhizobium inoculation offers a practical way to promote the persistence and growth potential of alfalfa "Ladak+" in cold areas.

Pharmacokinetics of salvianolic acids after intravenous injection, with and without Panax quinquefolium protopanaxadiol saponins, in rats.

AIM: The purpose of the present study was to examine the effects of Panax quinquefolium protopanaxadiol saponins (PQDS) extracts on the plasma protein binding and pharmacokinetic of salvianolic acids extracts extracted from the traditional Chinese medical Salvia miltiorrhiza,. Salvianolic acids are used to treat myocardial ischemia, and PQDS has similar functions. It is expected to achieve a better therapeutic efficacy if the two extracts are developed as a compound prescription for injection. MATERIALS AND METHODS: An established high-performance liquid chromatographic technique coupled with microdialysis was used. Male Sprague-Dawley rats were given salvianolic acids extracts and a compound of the two extracts via femoral vein. RESULTS: It was found that there were significant differences in the percentage protein binding as well as the pharmacokinetic parameters. The rat plasma protein binding of the four salvianolic acids increased by different degrees at three dose levels (25, 50, 100mg/kg of salvianolic acid B) when the two extracts were administered together. Also, their elimination half-life was prolonged, and their plasma concentrations remained stable longer after administration of a dose of 50mg/kg (salvianolic acid B). CONCLUSIONS: The results indicated that the PQDS extracts could delay the excretion of salvianolic acids as well as maintain the blood concentration higher than salvianolic acids extracts administered alone.

[Risk factors and the management of anastomotic leakage after anus-preserving operation for rectal cancer].

OBJECTIVE: To investigate the risk factors and management of anastomotic leakage after radical resection for rectal cancer and preservation of anal sphincter. METHODS: The clinical data of 190 rectal cancer patients, undergone sphincter preserving procedures from Jan. 2004 to Jan. 2006, were analyzed retrospectively. RESULTS: The incidence of anastomotic leakage among the 190 rectal cancer patients was 7.9% (15 patients). The leakage occurred from 2 to 17 days postoperatively and the average time of appearance was 5.8 days. Thirteen cases of anastomotic leakage were healed by conservative therapy. The treatment included nutritional support, catheter drainage of abdominal abscesses and the use of antibiotics. Healing time ranged from 10 to 60 days and the mean time was 21.8 days. The other 2 patients were healed by abdominal perineal resection and loop colostomy of transverse colon respectively. The complication of anastomotic leakage was associated with age (10.2% in older than 60 years versus 3.2% in younger than 60 years), physical status (20.7% in poor condition patients versus 5.6% in good condition patients), bowel obstruction (19.1% with obstruction versus 6.5% without obstruction), anastomotic procedure (12.2% in Parks' anastomosis versus 6.7% Dixon anastomosis), anastomotic location (9.2% for outside of peritoneal anastomosis versus 2.7 for inside of peritoneal anastomosis). The rates of anastomotic leakage in staple-line manual reinforce group and postoperative anorectal drainage group were significantly decreased than those in control groups (1.9% versus 11.4% and 2.9% versus 10.7%)(P<0.05). CONCLUSIONS: Elderly patients, poor general condition, preoperative tumor obstruction, outside of peritoneal anastomosis are independent risk factors for the development of anastomotic leakage. Manual staple-line reinforce after stapled anastomosis and postoperative placement of drainage in rectum may be effective in decreasing the rate of anastomotic failure. Early and active conservative approach should be considered as the main treatment of anastomotic leakage.

Portal vein entrance of splenic erythrocytic progenitor cells and local hypoxia of liver, two events cause intrahepatic splenosis.

Intrahepatic splenosis is a rare disorder of ectopic erythropoiesis in the liver. Although traumatic splenic rupture is the common factor in public cases, the mechanism of long latency is still unknown. The correlation between aging and hepatitis virus infection with the diagnosed occurrence was reported in a limited number of cases; nevertheless, it suggested that ectopic erythropoiesis in the liver could be induced by the hepatic disorder. Based on the susceptibility of the splenic erythropoiesis response to hypoxia and the inevitability of hypoxia caused by aging or pathological changes, we hypothesized that the two events caused the occurrence of the intrahepatic splenosis, the migration of the erythrocytic progenitor cells via the portal vein following traumatic splenic rupture, and the local induction of erythropoiesis by hypoxia.

Synthesis and bioactivities of two multiple antigen peptides as potential vaccine against schistosoma.

Based on the two antigenic peptides, 26-43 (P26) and 116-131 (P116), derived from 28 kDa glutathione S-transferase of Schistosoma mansoni (Sm28GST), two multiple antigenic peptides (MAPs), (P26)4-MAP and (P116)4-MAP with the same oligomeric lysine core, were synthesized by stepwise solid-phase peptide synthesis method. The antigenicities and protective effects of these two MAPs were examined on experimental animals. As shown in the dot-ELISA result, the synthetic MAPs could be recognized and bound by immunoglobins in both patient's and infected-rabbit's sera. After Kunming mice were immunized with (P26)4-MAP, the worm burden reduction rate and the liver egg reduction rate were 59.9% and 61.1%. In (P26)4-MAP or (P116)4-MAP immunized BALB/c mice, the worm burden reduction rates were 37.5% and 62.5%, respectively, and the liver egg reduction rates were 35.1% and 54.0%, respectively.