Lenalidomide use in multiple myeloma (Review).

Lenalidomide is a second-generation new immunomodulatory medication used to treat multiple myeloma (MM). Its mechanism of action involves affecting the expression of vascular endothelial growth factor, interleukin-6, cytochrome c, caspase-8, as well as other factors including immunological modulation and the direct killing of cells, among others, rendering it a fundamental medication, useful for the treatment of MM. Combining lenalidomide with other medications such dexamethasone, bortezomib, ixazomib, carfilzomib and daratumumab can markedly alleviate MM. When autologous-hematopoietic stem cell transplantation (ASCT) cannot be utilized to treat newly diagnosed individuals with MM (NDMM), monotherapy maintenance following lenalidomide and dexamethasone may be employed. Following ASCT, single-agent maintenance with lenalidomide can be performed as an additional treatment. The combination of bortezomib and lenalidomide has been demonstrated to be associated with favorable response rates, tolerable toxicity, and therapeutic benefits although caution is warranted to prevent the onset of peripheral neuropathy with its use. A new-generation oral drug with an excellent safety profile, ixazomib, is more practical and therapeutically applicable in relapsed refractory MM. However, the frequent occurrence of cardiovascular events, hematocrit, and infections with it require flexible adjustment in its clinical application. Carfilzomib produces a rapid and profound response in patients with NDMM eligible for transplantation, but its cardiovascular side effects need to be closely monitored. The primary aim of the present review was to examine the pharmacological properties and pharmacokinetics of lenalidomide, as well as the efficacy and safety of lenalidomide-based treatments with reference to data from clinical trials and real-world studies.

Coptisine Inhibits Influenza Virus Replication by Upregulating p21.

The activation of innate antiviral immunity is a promising approach for combatting viral infections. In this study, we screened Chinese herbs that activated human immunity and identified coptisine as a potent inhibitor of the influenza virus with an EC50 of 10.7 µM in MDCK cells. The time of an addition assay revealed that pre-treatment with coptisine was more effective at reducing viral replication than co-treatment or post-treatment. Our bulk RNA-sequencing data showed that coptisine upregulated the p21 signaling pathway in MDCK cells, which was responsible for its antiviral effects. Specifically, coptisine increased the expression of p21 and FOXO1 in a dose-dependent manner while leaving the MELK expression unchanged. Docking analysis revealed that coptisine likely inhibited MELK activity directly by forming hydrogen bonds with ASP-150 and GLU-87 in the catalytic pocket. These findings suggest that coptisine may be a promising antiviral agent that regulates the p21 signaling pathway to inhibit viral replication.

Ratiometric Fluorescent Sensor Based on Tb(III) Functionalized Metal-Organic Framework for Formic Acid.

Formic acid is a common chemical raw material, the effective detection of which is of importance to food safety and environmental quality. In this work, the lanthanide functionalized dual-emission metal-organic framework (TH25) was prepared as a ratiometric fluorescent sensor for formic acid. This ratiometric sensor has a good detection performance with high selectivity, sensitivity, and reproducibility. Together with a low limit of detection of 2.1 ppm, these characters promise the ability to sense at low levels as well as a practical detection ability. This work provides ideas for the design and synthesis of effective chemical sensors for organic acids.

Asymmetric construction of quaternary α-nitro amides by palladium-catalyzed C(sp3)-H arylation.

Pd-Catalyzed enantioselective C(sp3)-H arylation of N-(o-Br-aryl) anilides has been disclosed, and quaternary α-nitro amides were constructed with up to 98% ee. The presence of the nitro group on the substrate enables the progress of the reaction and the ready transformation of the product to optically active quaternary amino acid derivatives.

Mechanism of Duhuo Jisheng decotion in delaying degeneration of nucleus pulposus cells in human intervertebral disc / 中国中药杂志

This paper aimed to investigate the role of Duhuo Jisheng decotion (DHJSD) in delaying human disc degeneration and its possible molecular mechanism. The intervertebral disc specimens were divided into normal and degenerated groups according to Pfirrmann classfication. The expressions of TNF-α, IL-1β, MMP-3 and MMP-13 in intervertebral disc tissue were detected by Western blot and PCR. Then degenerated human primary NPCs were cultured in vitro, the viability of NPCs treated with stromal cell-derived factor-1 (SDF-1，10 μg·L⁻¹)and various concentrations of DHJSD was assessed by the CCK-8 assay, and the appropriate concentration was screened. The experiment was divided into three groups, control group, SDF-1 group and DHJSD plus SDF-1 group. The levels of TNF-α, IL-1β, Agg, coIⅡ, MMP-3 and MMP-13 were detected. The levels of CXCR4, NF-κB major groups P65 phosphorylation (p-P65) and nuclear translocation, after treated with CXCR4 siRNA and NF-κB inhibitor (BAY11-7082) were measured by Western blot and immunofluorescence. At the same time, the expression of cell inflammatory factors and extracellular matrix were also measured. The expressions of TNF-α, IL-1β, MMP-3 and MMP-13 in the degenerated intervertebral disc tissue were significantly increased. In vitro study, the results of CCK-8 indicated that the viability of NPCs was significantly increased when DHJSD concentration was 300 mg·L⁻¹. After the experiment was divided into three groups, compared with SDF-1 group, the expressions of TNF-α, IL-1β, MMP-3 and MMP-13 in DHJSD group were significantly decreased, but the expressions of Agg, coIⅡ were significantly increased. When CXCR4-siRNA was transfected into NPCs, SDF-1 increased expressions of CXCR4 and p-P65 and inhibited nuclear translocation of P65, whose effect was suppressed by CXCR4-siRNA and DHJSD. In addition, when BAY11-7082 was used to treat NPCs, the expression of TNF-α, IL-1β, MMP-3 and MMP-13 were significantly decreased. DHJSD could inhibit the production of inflammatory factors and promote the synthesis of extracellular matrix. The potential mechanism may be related to the SDF-1/CXCR4/NF-κB signaling pathway.

An alternative mebendazole formulation for cystic echinococcosis: the treatment efficacy, pharmacokinetics and safety in mice.

BACKGROUND: Cystic echinococcosis is a serious zoonotic infection worldwide caused by metacestodes of Echinococcus gruanulosus. Mebendazole and albendazole are the only two drugs used in the treatment of this disease with cure rates only about 30% due to the poor oral absorption. Thus an alternative treatment for this disease is needed. METHODS: A mebendazole oily suspension (MBZ-OS) was prepared and orally administrated to mice infected with echinococcus cysts for 8 months at 12.5 mg/kg and 25 mg/kg for 14 consecutive days. Mebendazole suspended in 1% tragacanth (MBZ-1% tragacanth) served as treated control. In addition, liver and serum samples were collected from these treated mice (25 mg/kg) for histopathology examination and liver function test. For pharmacokinetic analysis, plasma, parasite (cyst wall and cyst fluid) and tissue samples were collected at 0.25, 0.5, 1, 2, 4, 8, 16 and 24 h after orally administrating MBZ-OS and MBZ-1% tragacanth to E. granulosus-infected mice at 25 mg/kg. These samples were then processed and quantitatively analyzed by HPLC. RESULTS: The administration of MBZ-OS resulted in a treatment efficacy with the cyst weight reductions higher than 80%, significantly better than the corresponding MBZ-1% tragacanth groups. The better treatment efficacy of MBZ-OS was related to the higher drug concentration in plasma, parasites and tissues. It was also shown that the injury of the liver was not significantly altered by taking MBZ-OS compared to the untreated control. CONCLUSION: These findings demonstrate that MBZ-OS is a promising new formulation of MBZ for treatment of hydatid diseases without showing significantly liver toxicity.

[Preliminary observation on the effect of mefloquine against egg granuloma formation in the liver of mice infected with Schistosoma japonicum].

OBJECTIVE: To explore whether mefloquine possesses the effect on granuloma formation induced by Schistosoma japonicum eggs. METHODS: Seventeen out of twenty-eight mice infected with 20 S. japonicum cercariae for 35 days were treated orally with mefloquine at a single dose of 200 mg/kg, and groups of 2-3 mice were sacrificed at various intervals post-treatment. The livers removed from each group of mice were fixed in 10% formaldehyde. While the remained 11 untreated mice divided into 6 groups (1-2 mice per group) were sacrificed at the same time periods as groups of mice treated with mefloquine, and their livers served as untreated corresponding controls. The granulomas with single egg in the center were counted and their diameters were measured using an ocular micrometer. The liver tissue sections were stained with hematoxylin and eosin (HE), Foot's or Mallory's methods for observation on histopathological alteration of egg granulomas, and on the appearance of reticular and collagen fibers within the granulomas. RESULTS: After infected mice were treated with mefloquine for 3, 7, 14, 21, 28 and 35 days, i.e., 38, 42, 49, 56, 63, and 70 days post-infection, the mean diameters of granuloma with single egg measured in the liver tissues section were (161 +/- 19), (175 +/- 13), (195 +/- 9), (171 +/- 40), (180 +/- 13), and (145 +/- 25) microm, respectively, and each of them was significantly lower than that of its corresponding control group of (189 +/- 18), (197 +/- 11), (211 +/- 12), (208 +/- 19), (203 +/- 16), and (207 +/- 36) microm (P < 0.01 or P < 0.05). Histopathological observation showed that in mice treated with mefloquine, the eosinophil-predominant inflammatory cells around the egg granuloma were sustained to 14-21 d post treatment (49-56 d post infection), which was significantly different from the corresponding control groups that all the eggs were surrounded by fibroblasts at 42 d post infection. Up to 28-35 d post treatment (63-70 d post infection), the boundary of egg granulomas distributed in the liver tissues of mefloquine treated groups was nearer in comparison to the corresponding control groups. Further observation on the reticular and collagen fibers within the egg granulomas by using specially staining methods demonstrated that in groups of mice treated with mefloquine for 2 weeks, the emergence and amount of the two kinds of fibers were delayed and less in comparison with corresponding control groups. After infected mice treated with mefloquine for 21 d (56 d post infection), the amount of the two kinds of fibers revealed in some egg granulomas was similar to the corresponding control group, but no further increase in the amount of the fibers, and seldom spread over the boundary of egg granuloma were seen 28 d and 35 d after treatment (63 d and 60 d post infection). While in corresponding control groups, the two kinds of fibers increased continuously with time post infection to become thick, and spread over the boundary of granuloma to further interconnect with the fibers stretched from the adjacent granuloma, and separate the liver tissue to form the grid-like structure. CONCLUSION: Preliminary observation demonstrates that mefloquine possesses suppressive effect on granuloma formation induced by S. japonicum eggs.

Histopathological changes of juvenile Schistosoma japonicum harbored in mice treated orally with mefloquine at a smaller single dose.

The histopathological changes of 14-day-old Schistosoma japonicum induced by a smaller single dose of mefloquine have been studied. Twenty-three mice infected with 60-80 S. japonicum cercariae for 14 days were treated orally with mefloquine at a single dose of 200 mg/kg (free base), and groups of three mice were killed at various intervals posttreatment. The liver of each mouse was removed, fixed and processed routinely, and examined by light microscopy. Eight hours posttreatment, 38.2% and 39.8% of schistosomulum sections were classified as degenerated and dead, respectively. The degenerated schistosomula revealed in high dilatation of gut with disruption of gut mucosa, swelling of the worm body accompanied by looseness or extensive lysis of parenchymal tissues, and focal swelling or peeling of tegument, while dead worms showed that their damaged tegument adhered to the vessel and inflammatory cell attached on and penetrated into the worm body. Twenty-four hours to 3 days posttreatment, the degenerated schistosomulum sections decreased from 28.1% to 8.2%, while the sections of dead schistosomula increased from 60.0% to 74.8%. At these time periods, the damage intensity of degenerated schistosomula aggravated, while dead schistosomula showed disintegration of internal structures infiltrated by eosinophil-predominant inflammatory cells to form the dead worm abscess. Seven days to 14 days posttreatment, no normal schistosomulum section was observed, and the percentages of degenerated and dead worms further decreased from 3.4% to 3.0% and 34.4% to 12.6%, respectively. Meanwhile, 62.2% to 84.4% of dead worms developed to dead worm granulomas and part of them situated in early stage. Twenty-eight days posttreatment, only dead worm granulomas were observed in the liver sections and part of them developed to late stage. The results indicate that a smaller single mefloquine dose 200 mg/kg exhibits a potential and fast killing effect against S. japonicum juvenile and induces severe histopathological lesions.

Further observation on histopathological alterations of adult Schistosoma japonicum harbored in mice following treatment with mefloquine at a smaller single dose.

The purpose of the present study is to assess the histopathological alterations of adult schistosomes caused by a smaller dose of mefloquine. Mice were infected with Schistosoma japonicum cercariae for 35 days and then treated with a single 200 mg/kg oral dose of mefloquine. Groups of mice were killed between 12 h and 28 days posttreatment, and the livers were removed, fixed, and processed routinely and examined by light microscopy. Twelve hours to 48 h or 3 days posttreatment, 10.3% to 53.3% of male worms and 10% to 25% of female worms shifted to the liver revealed normal appearance. However, 46.7% to 69.2% of male worms and 45.5% to 75% of female worms showed signs of degeneration, including moderate or high swelling of tegument and/or muscles with roughing surface or formation of small vesicles beneath the tegument or collapse of damaged tegument, light swelling of parenchymal tissues, and light dilatation of gut. These histopathological changes aggravated either in extent or in severity along with time, especially the speed of emergence of dead worm granuloma that was faster in female worms than in male ones. In female worms, severe damage to the vitelline glands was universal, which was characterized by necrosis and karyopyknosis of vitelline cells and emergence of small vacuoles among the vitelline gland lobules. Seven days to 28 days posttreatment, almost all of the female worms shifted to the liver were classified as dead or dead worm granuloma, while the percentage of dead male worm and its granuloma examined in the liver was 52.1% to 53.3%. The results indicate that smaller dose of mefloquine (200 mg/kg) still shows strong histopathological response to kill female schistosomes, but its lethal effect against male worms is weakened.

Histopathological alteration of juvenile Schistosoma japonicum in mice following treatment with single-dose mefloquine.

This study aims to observe the histopathological alterations in schistosomula of Schistosoma japonicum induced by mefloquine. Mice were infected with S. japonicum cercariae, and after 14 days, a single dose of mefloquine (400 mg/kg) was administered orally. After 8 h, 24 h, 3 days, 7 days, and 14 days, groups of two to three mice were sacrificed, and livers were removed, fixed and processed routinely, and examined by light microscopy. After 8 h, 51.5% of the schistosomula examined showed degeneration, which included high dilatation of gut, desquamation of gut epithelial cells, swelling of tegument, muscles, and parenchymal tissues, and adherence of inflammatory cells to the damaged tegument of the juveniles. After 24 h, the percentage of dead worm and degenerated worm were 43.2% and 48.4%, respectively, and the intensity of damage increased, including severe swelling and vesiculation of tegument, collapse of damaged gut, and loss of definition in the internal structure. In addition, dead worms were infiltrated by eosinophil-predominated inflammatory cells. After 3 days, more than 96% of schistosomula were severely degenerated and dead, and some of them were focally or extensively infiltrated by inflammatory cells accompanied by necrosis of internal structure. Seven to 14 days after treatment, most dead schistosomula developed to dead worm granulomas with the percentages of 60.1-86.3%, while those of dead schistosomula were 26.7-8.4%. The results indicate that mefloquine exhibits an extensive and severe damage to juvenile S. japonicum harbored in mice.

Histopathological changes in adult Schistosoma japonicum harbored in mice treated with a single dose of mefloquine.

New research has shown that mefloquine, an arylaminoalcohol used against malaria, is active against Schistosoma japonicum and Schistosoma mansoni in vivo. To enhance our understanding of the potential mechanism of action of mefloquine against schistosomiasis, we examined the dynamics of histopathological changes in adult S. japonicum. Mice infected with S. japonicum for 35 days were treated intragastrically with a single dose of mefloquine (400 mg/kg). One to 35 days after mefloquine administration, drug-induced histopathological alterations were studied. Twenty-four hours after treatment, S. japonicum showed signs of degeneration, including focal roughing and swelling of the tegument and/or muscles, dilatation of the gut, focal desquamation of gut epithelial cells, and a decrease in pigment particles. There was extensive degeneration of vitelline cells and appearance of pigment particles visible in the cytoplasm in female worms. The extent and severity of histopathological changes increased over time; 48 h posttreatment, two thirds of female worms and a quarter of male worms were classified as dead. Three to 14 days posttreatment, typical histological changes observed in surviving male worms were vesiculation, swelling of parenchymal tissues, and dilatation of gut. In females, there was disintegration and infiltration of inflammatory cells, forming dead worm abscesses and early stage of dead worm granuloma. Finally, 35 days posttreatment, only dead male and female worm granuloma were found. Our results provide further evidence of in vivo activity of mefloquine against adult schistosomes.

Angiostrongylus cantonensis: morphological and behavioral investigation within the freshwater snail Pomacea canaliculata.

An infection with Angiostrongylus cantonensis, the main causative agent for human eosinophilic encephalitis, can be acquired through the consumption of the freshwater snail Pomacea canaliculata. This snail also provides a suitable model to study the developmental morphology and behavior of A. cantonensis larvae, facilitated by the snail's distinct lung structure. We used microanatomy for studying the natural appearance and behavior of A. cantonensis larvae while developing within P. canaliculata. The distribution of refractile granules in the larval body and characteristic head structures changed during the developmental cycle. Two well-developed, rod-like structures with expanded knob-like tips at the anterior part were observed under the buccal cavity as early as the late second developmental stage. A "T"-shaped structure at the anterior end and its tenacity distinguished the outer sheath from that shed during the second molting. Early first-stage larvae obtained from fresh rat feces are free moving and characterized by a coiled tail, whereas a mellifluous "Q"-movement was the behavioral trait of third-stage A. cantonensis larvae outside the host tissue. In combination, the distribution of refractive granules, distinct head features, variations in sheaths, and behavioral characteristics can be utilized for differentiation of larval stages, and for distinguishing A. cantonensis larvae from those of other free-living nematodes.

[Morphology of III stage larvae of Angiostrongylus cantonensis in Pomacea canaliculata].

OBJECTIVE: To observe the morphologic characteristics of III stage larvae of Angiostrongylus cantonensis from Pomacea canaliculata. METHODS: P. canaliculata, the intermediate host snail of A. cantonensis, was infected with I stage larvae of A. cantonensis in laboratory. After 61 days, III stage larvae of A. cantonensis were harvested from snail's lungs and muscle of head-foot, followed by HE stain to observe morphological characteristics. RESULTS: The whole body of III stage larva was curling with obtuse head. Its pharyngeal canal extends from the buccal hole on the top of the head to the intestines at the pharyngeal intestine joint place, with apex cauda and clear anal tube. The tegument of the III stage larva was eosin-stained, with a transparent sheath outside of tegument. Some of the larvae cauda showed in circular cylinder, and some larvae presented ventral gland with two very short uterine which used to be the feature only showed in early IV stage larva. CONCLUSION: Morphologically characteristics of the III stage larvae is helpful to better understand the life-cycle and the control of A. cantonensis.