Treatment of membranous nephropathy: Perspectives on current and future therapies.

Primary membranous nephropathy remains one of the most frequent causes of nephrotic syndrome in adults. It is an autoimmune disorder in which auto-antibodies target antigens at the podocytes cell membrane-basement membrane interface. Our understanding of membranous nephropathy has expanded dramatically as of late. After the initial discovery of the phospholipase A2 receptor auto-antibody in 2009, eight more antigens have been discovered. These discoveries have led to refinement in our understanding of the pathogenesis, diagnosis, and natural history of primary membranous nephropathy. Now, many experts advocate for redefining primary membranous nephropathy based on antigen, potentially shedding the primary and secondary nomenclature. Recently, therapies for primary membranous have also expanded. Immunosuppressive therapies like cyclophosphamide and rituximab, which primarily target B-cells, remain the cornerstone of therapy. However, there is still significant room for improvement, as many as 30-40% do not respond to this therapy according to recent trials. Additionally, drugs targeting complement, and other novel therapies are also under investigation. In this review we will discuss the available therapies for primary membranous nephropathy in light of recent clinic trials like GEMRITUX, MENTOR, RI-CYCLO, and STARMEN, as well as management strategies. While the last 10 years have seen a boom in our mechanistic understanding of this ever-diversifying disease, we are likely to see a similar boom in the therapeutic options in the years to come.

Stop the crop: Insights into the insecticidal mode of action of cinnamodial against mosquitoes.

Cinnamodial (CDIAL) is a drimane sesquiterpene dialdehyde found in the bark of Malagasy medicinal plants (Cinnamosma species; family Canellaceae). We previously demonstrated that CDIAL was insecticidal, antifeedant, and repellent against Aedes aegypti mosquitoes. The goal of the present study was to generate insights into the insecticidal mode of action for CDIAL, which is presently unknown. We evaluated the effects of CDIAL on the contractility of the ventral diverticulum (crop) isolated from adult female Ae. aegypti. The crop is a food storage organ surrounded by visceral muscle that spontaneously contracts in vitro. We found that CDIAL completely inhibited spontaneous contractions of the crop as well as those stimulated by the agonist 5-hydroxytryptamine. Several derivatives of CDIAL with known insecticidal activity also inhibited crop contractions. Morphometric analyses of crops suggested that CDIAL induced a tetanic paralysis that was dependent on extracellular Ca2+ and inhibited by Gd3+, a non-specific blocker of plasma membrane Ca2+ channels. Screening of numerous pharmacological agents revealed that a Ca2+ ionophore (A23187) was the only compound other than CDIAL to completely inhibit crop contractions via a tetanic paralysis. Taken together, our results suggest that CDIAL induces a tetanic paralysis of the crop by elevating intracellular Ca2+ through the activation of plasma membrane Ca2+ channels, which may explain the insecticidal effects of CDIAL against mosquitoes. Our pharmacological screening experiments also revealed the presence of two regulatory pathways in mosquito crop contractility not previously described: an inhibitory glutamatergic pathway and a stimulatory octopaminergic pathway. The latter pathway was also completely inhibited by CDIAL.

Physiological characterization and regulation of the contractile properties of the mosquito ventral diverticulum (crop).

In adult dipteran insects (flies), the crop is a diverticulum of the esophagus that serves as a food storage organ. The crop pumps stored contents into the alimentary canal for digestion and absorption. The pumping is mediated by peristaltic contractions of the crop musculature. In adult female mosquitoes, the crop (ventral diverticulum) selectively stores sugar solutions (e.g., nectar); proteinaceous blood meals by-pass the crop and are transferred directly to the midgut for digestion. The mechanisms that regulate crop contractions have never been investigated in mosquitoes. Here we provide the first physiological characterization of the contractile properties of the mosquito crop and explore the mechanisms that regulate crop contractions. Using an in vitro bioassay we found that the isolated crop spontaneously contracts in Ringer solution for at least 1 h and its contractions are dependent on extracellular Ca2+. Adding serotonin (5-hydroxytryptamine, 5-HT) or a membrane-permeable analog of cyclic adenosine monophosphate (cAMP) to the extracellular bath increased the frequency of crop contractions. On the other hand, adding benzethonium chloride (BzCl; a chemical that mimics the effects of myosuppressins), H-89 or Rp-cAMPS (inhibitors of protein kinase A, PKA), or carbenoxolone (an inhibitor of gap junctions) reduced the frequency of the unstimulated, spontaneous and/or 5-HT-stimulated crop contractions. Adding aedeskinin III did not detectably alter crop contraction rates. In addition to pharmacological evidence of gap junctions, we demonstrated that the crop expressed several mRNAs encoding gap junctional proteins (i.e. innexins). Furthermore, we localized immunoreactivity for innexin 2 and innexin 3 to muscle and epithelial cells of the crop, respectively. Our results 1) suggest that 5-HT and myosupressins oppositely regulate contractile activity of the mosquito crop, and 2) provide the first evidence for putative roles of cAMP, PKA, and gap junctions in modulating contractile activity of the dipteran crop.