Small heat shock proteins (sHsps) belong to the family of heat shock proteins (Hsps): some are induced in response to multiple stressful events to protect the cells while others are constitutively expressed. Until now, it was believed that Hsps, including sHsps, are present inside the cells and perform intracellular functions. Interestingly, several groups recently reported the extracellular presence of Hsps, and sHsps have also been detected in sera/cerebrospinal fluids in various pathological conditions. Secretion into the extracellular milieu during many pathological conditions suggests additional or novel functions of sHsps in addition to their intracellular properties. Extracellular sHsps are implicated in cell-cell communication, activation of immune cells, and promoting anti-inflammatory and anti-platelet responses. Interestingly, exogenous administration of sHsps showed therapeutic effects in multiple disease models implying that extracellular sHsps are beneficial in pathological conditions. sHsps do not possess signal sequence and, hence, are not exported through the classical Endoplasmic reticulum-Golgi complex (ER-Golgi) secretory pathway. Further, export of sHsps is not inhibited by ER-Golgi secretory pathway inhibitors implying the involvement of a nonclassical secretory pathway in sHsp export. In lieu, lysoendosomal and exosomal pathways have been proposed for the export of sHsps. Heat shock protein 27 (Hsp27), αB-crystallin (αBC), and Hsp20 are shown to be exported by exosomes. Exosomes packaged with sHsps have beneficial effects in in vivo disease models. However, secretion mechanisms and therapeutic use of sHsps have not been elucidated in detail. Therefore, this review aimed at highlighting the current understanding of sHsps (Hsp27, αBC, and Hsp20) in the extracellular medium.

Inhibition of the 26S proteasome is an attractive approach for anticancer therapy. Proteasome inhibitors are known to selectively target cancer cells and make them more sensitive to chemotherapeutic agents. Murraya koenigii is a medicinally important herb of Asian origin and a rich source of bioactive compounds such as flavonoids and alkaloids. In the present study, we investigated the proteasome inhibitory and apoptotic effect of M. koenigii leaf extract in vivo in a xenograft tumor mouse model, and also assessed the toxicity if any in normal mice. M. koenigii extract did not lead to any toxicity in mice. Analysis of extract revealed the presence of flavonoid compounds which act as proteasome inhibitors. Quercetin treatment led to the decrease in the cell viability and arrest of cells in G2/M phase. Quercetin, Apigenin, Kaempferol and Rutin; flavonoids present in the leaf extract, dose-dependently inhibited the endogenous 26S proteasome activity in MDA-MB-231 cells. Reduction in tumor growth was associated with a decrease in proteasomal enzyme activities in the treated groups. Increased caspase-3 activity and TUNEL-positive cells indicated enhanced apoptosis with Murraya leaf extract treatment. Decreased expression of angiogenic and anti-apoptotic gene markers is indicative of inhibition of angiogenesis and promotion of apoptosis in the leaf extract treated tumors.

HSPB5 or αB-crystallin (αBC) is a major protein of the vertebrate eye lens belonging to the small heat-shock protein family of proteins that respond to various stressful conditions. αBC also is found outside the lens in various non-ocular tissues and acts as a molecular chaperone by preventing aggregation of proteins, inhibits apoptosis and inflammation, and maintains cytoskeletal architecture. The αBC protein is phosphorylated on three serine residues S59, S45, and S19, and several functions of αBC are modulated by phosphorylation. Numerous studies have revealed the upregulation of αBC in pathological conditions such as neurodegenerative diseases, cancers, diabetes, retinal diseases, cataracts, ischemia/repurfusion, aging, and others. However, it is unknown whether the up-regulation of αBC is causative or protective for these pathological conditions. Although αBC has been shown to provide a protective effect in neurodegenerative diseases, inflammation, diabetes, and retinal diseases, other studies have described a deleterious role of αBC in cancers and pulmonary fibrosis. The therapeutic potential of αBC alone or in combination with αA-crystallin has been reported. Acetylated αBC peptides have been shown to be more potent than native αBC for chaperone as well as therapeutic activities using both in vitro and in vivo models. Further, for efficient delivery of α BC into cells, carrier molecules such as polylacticcoglycolic acid, polycaprolactone and cell penetration peptides have been used. In this review, we have summarized current data from emerging and exciting studies of the therapeutic strategies of α BC and α BC peptides and the efficient delivery strategies of these proteins in various disease models, including neurodegenerative diseases, retinal diseases, platelet aggregation, inflammation, and ischemia.