Discovery of lysosomal

The lysosomal acid phosphatase enzyme played a key role in the discovery of lysosomes by de Duve in 1963 and is widely used as a lysosomal marker. This enzyme shows a high degree of sequence similarity (ca. 49 % identity) with prostatic acid phosphatase [9] and both are inhibited by L-(+)-tartrate ion [10]. 

There have been few discoveries of lysosomal storage diseases being related to a deficiency of a protease. Efficient lysosomal proteolysis could be such a crucial metabolic process that any defects in this system would be developmentally lethal and therefore never observed medically. For example, mice deficient in cathepsin D were generated by targeted disruption of the gene and the animals died in a state of anorexia by day 26 due to widespread intestinal necroses [42]. Since bulk lysosomal... 

In the very rare and fatal Niemann-Pick Cl disease lysosomes in cells of the central nervous system and the viscera accumulate LDL-derived cholesterol. Study of the DNA of patients led to discovery of a 1278-residue integral membrane protein, which may be required for the Golgi-mediated transport of unest-erified cholesterol from lysosomes to the ER.189/232 234c... 

Sphingolipids were first described in a remarkable treatise on the chemical constitution of the brain by Johann L. W. Thudichum, a physician-scientist in London, who published his findings more than 100 years ago. A major impetus for the study of the chemistry and metabolism of the sphingolipids was the discovery of several rare human diseases that could be attributed to the abnormal accumulation of sphingolipids. This accumulation has been shown to result from a defect in catabolism that normally occurs in lysosomes. It is now known that many different kinds of sphingolipids exist, and more than 300 structures have been reported to occur in nature. 

Soon after the discovery of the ability of SPG to complex homopolynucleotides, it was demonstrated that schizophyllan complexes with poly(A) or poly(C) will dissociate at pH 4—6 [45]. This property is important as SPG polyplexes could potentially release their polynucleotide cargo in the acidic pH environment of endosomes and/or lysosomes. However, since these polyplexes possess a net negative charge and lack targeting groups, they are inefficient in terms of cellular internalization. 

It may be asked whether the study of a substance s effects on the lysosomal membrane is of therapeutic interest The discovery that lysosomes play a role in inflammatory processes is in itself sufficient to justify such an investigation. Indeed some symptoms of inflammation probably result from an increase in fragility of the lysosomal membrane and the release of the granular content leading to cellular and extracellular injuries. Hence a compound able to stabilize the lysosomal membrane may possess anti-inflammatory properties. Many well-known anti-inflammatory drugs do indeed stabilize the lysosomal membrane... 

Most polymer-based carriers for the delivery of nucleic acid drugs must escape the endosomes before complete acidification, which activates lysosomal digestion. After the discovery of the powerful endosomal destabilization activity of PEI [66], many polymer-based carriers have mimicked the structure of PEI for endosomal escape. As explained in Sect. 3.2, the proton-sponge effect of xmprotonated tertiary amines and direct contact of protonated polyamines with the endosomal membrane are two possible mechanisms of endosomal disruption by PEI. Because pH-dependent protonation is critical in both mechanisms, polymers with a high density of protonable amines during the early endosomal acidification firom pH 7.4 to 5.5 are one of the main kinds of polymer-based carriers with an endosomal escape function. Like tertiary amines in PEI, protonable moieties with low p Ta values have been frequently introduced into the polymer-based carriers. An imidazole moiety with pA"a of around 6.0 was one such candidate. The introduction of polyhistidine with an imidazole moiety on a PLL backbone showed significant increase in endosomal escape efficiency [169]. 

The IGF-II /CI-MPR has also been found in the circulation as a result of proteolytic release from the cell surface. The soluble receptor has been postulated to sequester IGF-II, thereby controlling the proliferative effects of this mitogen [166]. Consequently, the ability of the IGF-IFCI-MPR to target lysosomal enzymes, to bind TGF-b, and to bind IGF-II has implicated it in a role in tumor suppression. The discovery that there are a variety of mutations in the IGF-IFCI-MPR in human cancers have provided further evidence of this association [167,168,169,170]. 

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