Specificity of blebbistatin, an inhibitor of myosin II

Blebbistatin is a small molecule inhibitor discovered in a screen for inhibitors of nonmuscle myosin IIA. We have examined the specificity and potency of the drug by assaying its effects on the actin-activated MgATPase assay of diverse members of the myosin superfamily. Blebbistatin potently inhibits several striated muscle myosins as well as vertebrate nonmuscle myosin IIA and IIB with IC₅₀ values ranging from 0.5 to 5 μM. Interestingly, smooth muscle which is highly homologous to vertebrate nonmuscle myosin is only poorly inhibited (IC₅₀=80 μM). The drug potently inhibits Dictyostelium myosin II, but poorly inhibits Acanthamoeba myosin II. Blebbistatin did not inhibit representative myosin superfamily members from classes I, V, and X. This revised version was published online in July 2006 with corrections to the Cover Date.     

Juvenile hyaline fibromatosis: A report of two unrelated adult sibling cases and a literature review

Two unrelated adult sibling cases (36- and 32-year-old females) of Juvenile hyaline fibromatosis are presented. The parents of one of these patients were non-consanguineous but natives of a small Island, and one elder sister among four siblings was affected with the same disease. The parents of the other patient were consanguineous, and one other sibling suffered from the identical disease. Both patients presented with multiple subcutaneous nodules, which they had had since infancy, and had undergone numerous surgical excisions. Light microscopy examination of skin lesions from both patients showed identical histology; an abundance of a homogenous, amorphous, eosinophlllc extracellular matrix in which spindle-shaped cells were embedded. Electron microscopically, the spindle-shaped cells had hypertrophic Golgi apparatus and dilated, rough endoplasmlc reticulum. Fine flbrillar and granular material-filled structures, the contents of which were occasionally released into the extracellular matrix, were also seen, immunohistochemically, the spindle-shaped cells were vlmentin-positive but negative for α-smooth muscle actln and S-100 protein, and the hyaline ground substance was positive for type I and type III collagen but negative for type II and type IV collagen and tenascin. Matrix metalloprotelnase-1, -2, and -9, and tissue inhibitor of matrix metalloproteinase (TlMP)-2 was positive but TIMP-1 was negative. A review of 39 cases of juvenile hyaline fibromatosis In the literature is also presented. In summary, skin lesions may be the most outstanding symptoms of juvenile hyaline fibromatosis, but joint contracture and gingival hypertrophy precede the skin manifestation.     

Endocrinology and paracrinology: Roles of growth factors during peri-implantation development

Several growth factor ligand and receptor gene products havebeen shown to play roles during preimplantation mammalian development.Genes for insulin-like growth factors (IGFs), transforming growthfactors (TGFs), fibroblast growth factor (FGF), platelet-derivedgrowth factor (PDGF) and receptors for insulin, IGF, PDGF, TGFand epidermal growth factor (EGF) are expressed by early embryosof several species including mouse, rat, cow and sheep. Rolesof growth factors during early development have been demonstratedby addition of purified growth factors to culture medium orby molecular genetic techniques that interfere with gene expression.In this way, it has been shown that successful development ofthe blastocyst is dependent on the action of epidermal growthfactor (EGF) and leukaemia inhibitory factor (LIF). Recent experimentsshow that both LIF and EGF stimulate secretion of urokinase-typeplasminogen activator (uPA) and gelatinase B/ matrix metalloproteinase-9(MMP-9) in day 7 mouse blastocyst outgrowths. At the same time,tissue inhibitors of MMPs (TIMPs) are also expressed by embryonic,decidual and uterine tissues during the implantation process.It appears that LIF may act directly or indirectly, by inducingthe expression of other cytokines, to regulate the temporaland spatial production and activity of proteases and proteaseinhibitors to create a favourable environment for implantation.     

The effect of a 1-deoxynojirimycin derivative on post-prandial blood glucose and insulin levels in healthy black and white volunteers

Summary BAY m1099 (a 1-deoxynojirimycin derivative) is a glucose analogue which is an -glucosidase inhibitor. Its effects on post-prandial blood glucose and insulin levels was compared with a placebo in 12 healthy male volunteers (6 Blacks and 6 Whites). It produced a similar, significant depression of post-prandial blood glucose and insulin leveles when the groups were assessed separately and when the data were pooled. Although blood insulin levels in Whites were higher than in Blacks, as previously reported, the difference was not statistically significant and did not appear to influence the response to the drug. BAY 1099 produced no objective or subjective untoward effects and appears to warrant further investigation as an adjuvant to dietary control of diabetes mellitus.     

Pharmacology in vivo of the phenylindan derivative,lu 19-005, a new potent inhibitor of dopamine,noradrenaline and 5-hydroxytryptamine uptake in rat brain

Summary Behavioural effects on dopaminergic transmission of a phenylindane derivative, Lu 19-005 [(±)-trans-3-(3,4-dichlorophenyl)-N-methyl-l-indanamine, HCl], with potent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake in rats and the effect on DA, NA and 5-HT activity in mice have been studied and compared with those of other known DA, NA and 5-HT uptake inhibitors with different selectivity ratios.Lu 19-005 induced stereotyped behaviour after parenteral and oral administration with a duration of action of more than 24 h. The stereotyped licking and biting induced by Lu 19-005 was antagonized by reserpine and cis(Z)-flupentixol, but not affected by prazosin, p-chlorophenylalanine and -methyl-p-tyrosine pretreatments. Metergoline slightly facilitated the onset of stereotypy. Lower doses of Lu 19-005 induced ipsilateral circling in unilaterally 6-hydroxy-DA-lesioned rats. Finally, Lu 19-005 antagonized the catalepsy induced by perphenazine. In mice, Lu 19-005 potentiated the apomorphine-induced gnawing, reversed tetrabenazine-induced ptosis and potentiated the behavioural effects of 5-HTP within a similar dose range.The effects of Lu 19-005 were compared with those of other reference compounds. Nomifensine had qualitatively similar effects in rats although of much shorter duration. In mice, nomifensine selectively reversed tetrabenazine-induced ptosis. Weaker effects in all test models were found with bupropion, LR 5182 and GBR 13.069, compounds with inhibitory effect on DA and NA uptake. The DA-, NA-and 5-HT-uptake inhibitor diclofensine, however, had no effect in rats except in the 6-hydroxy-DA-circling test and had low potency in mice. The specific 5-HT-and NA-uptake inhibitors citalopram and talsupram, respectively, were ineffective in all rat models. They selectively potentiated 5-HTP or reversed tetrabenazine0induced ptosis in mice, respectively, as expected according to their in vitro profile. These results indicate that effect on DA mechanisms are responsible for the behavioural activity of the test compounds in the rat models and that the circling model is the most sensitive. Since DA may be involved in some depressive states Lu 19-005 could be an attaactive new antidepressant as it combines the pharmacological profile of established antidepressants (effect on NA and/or 5-HT uptake) with equipotent activity on DA uptake.     

Potentiation of central effects of L-dopa by an inhibitor of catechol-O-methyltransferase

Summary The effects of a COMT-inhibitor, U-0521, and a MAO-B-inhibitor, l-deprenyl, on L-dopa-induced circling behaviour were compared in 6-OHDA-lesioned rats. The actions of U-0521 and l-deprenyl on the anticataleptic effect of L-dopa were also studied. Both U-0521 and l-deprenyl were found to potentiate L-dopa-induced circling behaviour and anticataleptic effect of L-dopa. In both test systems the L-dopa potentiation of l-deprenyl was longer-lasting than that caused by U-0521. Thus inhibition of COMT, like inhibition of MAO, is able to enhance the central effects of L-dopa. This principle might be beneficial in the treatment of Parkinson's disease especially if COMT-inhibitors with greater performance can be developed.     

SARS-CoV-2 neutralizing antibodies after first vaccination dose in breast cancer patients receiving CDK4/6 inhibitors

Undoubtedly, the development of COVID-19 vaccines displays a critical step towards ending this devastating pandemic, considering their protective benefits in the general population. Yet, data regarding their efficacy and safety in cancer patients are limited. Herein we provide the initial analysis of immune responses after the first dose of vaccination in 21 breast cancer patients receiving cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. The levels of neutralizing antibodies post vaccination were similar to the matched healthy controls, whereas no safety issues have been raised. Further exploration is needed to reduce the uncertainty of SARS-CoV-2 immunity among cancer patients under treatment.     

Fifty years of the mitochondrial pyruvate carrier: New insights into its structure,function, and inhibition

The mitochondrial pyruvate carrier (MPC) resides in the mitochondrial inner membrane, where it links cytosolic and mitochondrial metabolism by transporting pyruvate produced in glycolysis into the mitochondrial matrix. Due to its central metabolic role, it has been proposed as a potential drug target for diabetes, non-alcoholic fatty liver disease, neurodegeneration, and cancers relying on mitochondrial metabolism. Little is known about the structure and mechanism of MPC, as the proteins involved were only identified a decade ago and technical difficulties concerning their purification and stability have hindered progress in functional and structural analyses. The functional unit of MPC is a hetero-dimer comprising two small homologous membrane proteins, MPC1/MPC2 in humans, with the alternative complex MPC1L/MPC2 forming in the testis, but MPC proteins are found throughout the tree of life. The predicted topology of each protomer consists of an amphipathic helix followed by three transmembrane helices. An increasing number of inhibitors are being identified, expanding MPC pharmacology and providing insights into the inhibitory mechanism. Here, we provide critical insights on the composition, structure, and function of the complex and we summarize the different classes of small molecule inhibitors and their potential in therapeutics.