Dysregulation of Macrophage-Secreted Cathepsin B Contributes to HIV-1-Linked Neuronal Apoptosis

Chronic HIV infection leads to the development of cognitive impairments, designated as HIV-associated neurocognitive disorders (HAND). The secretion of soluble neurotoxic factors by HIV-infected macrophages plays a central role in the neuronal dysfunction and cell death associated with HAND. One potentially neurotoxic protein secreted by HIV-1 infected macrophages is cathepsin B. To explore the potential role of cathepsin B in neuronal cell death after HIV infection, we cultured HIV-1ADA infected human monocyte-derived macrophages (MDM) and assayed them for expression and activity of cathepsin B and its inhibitors, cystatins B and C. The neurotoxic activity of the secreted cathepsin B was determined by incubating cells from the neuronal cell line SK-N-SH with MDM conditioned media (MCM) from HIV-1 infected cultures. We found that HIV-1 infected MDM secreted significantly higher levels of cathepsin B than did uninfected cells. Moreover, the activity of secreted cathepsin B was significantly increased in HIV-infected MDM at the peak of viral production. Incubation of neuronal cells with supernatants from HIV-infected MDM resulted in a significant increase in the numbers of apoptotic neurons, and this increase was reversed by the addition of either the cathepsin B inhibitor CA-074 or a monoclonal antibody to cathepsin B. In situ proximity ligation assays indicated that the increased neurotoxic activity of the cathepsin B secreted by HIV-infected MDM resulted from decreased interactions between the enzyme and its inhibitors, cystatins B and C. Furthermore, preliminary in vivo studies of human post-mortem brain tissue suggested an upregulation of cathepsin B immunoreactivity in the hippocampus and basal ganglia in individuals with HAND. Our results demonstrate that HIV-1 infection upregulates cathepsin B in macrophages, increases cathepsin B activity, and reduces cystatin-cathepsin interactions, contributing to neuronal apoptosis. These findings provide new evidence for the role of cathepsin B in neuronal cell death induced by HIV-infected macrophages

Effect of <i>Aegle marmelos </i>Correa. (Bael) fruit extract on tissue antioxidants in <span style="font-size:14.0pt;line-height:115%;font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman";color:#333333;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">streptozotocin <span style="font-size:14.0pt;line-height:115%;font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman";color:#1B1B1B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">diabetic rats</span></span>

1285-1288A study was undertaken to evaluate the anti -lipid peroxidative activity of an aqueous extract of A. marmelos fruits (AMFEt) in streptozotocin diabetic rats in heart and pancreas. Oral administration of AMFEt for 30 days (125 and 250 mg Kg-1 body weight twice daily) produced a significant decrease in the elevated levels of peroxidation products, viz.thiobarbituric acid reactive substances and hydroperoxides in the tissues of diabetic rats. The depressed activities of <span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#4B4B4B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">s<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#1B1B1B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">up<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#4B4B4B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">eroxide <span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#333333;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">dismutase, catalase and glutathione peroxidase and <span style="font-size:14.0pt; line-height:115%;font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">lowered <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">g<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">lutathion<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">e <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#333333;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">content <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">in th<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">e <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">heart <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">a<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">nd pancr<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">eas <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#333333;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">of diabetic <span style="font-size:14.0pt;line-height: 115%;font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">r<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">ats <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#333333;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">were found <span style="font-size:14.0pt;line-height: 115%;font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">t<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">o <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#333333;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">increase <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">on <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">tr<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">eatmen<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">t <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#333333;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">with AMFEt. AMFEt at <span style="font-size:14.0pt; line-height:115%;font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">a <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#333333;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">dose of 250 <span style="font-size:14.0pt;line-height: 115%;font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">mg <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#333333;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">kg<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#626262;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">-1<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#626262;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN"> <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#333333;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">was more <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">e<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">ffe<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">c<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#1B1B1B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">ti<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">ve <span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#333333;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">than glibenclamide <span style="font-size:14.0pt; line-height:115%;font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:&quot;Times New Roman&quot;; color:#4B4B4B;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">(300μ<span style="font-size:14.0pt;line-height:115%; font-family:&quot;Times New Roman&quot;;mso-fareast-font-family:HiddenHorzOCR;color:#4B4B4B; mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">g <span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#333333;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">kg<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#626262;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">-<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#1B1B1B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">l<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#4B4B4B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">) and <span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#333333;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">both rev<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#626262;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">e<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#333333;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">r<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#626262;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">se<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#333333;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">d <span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#4B4B4B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">a<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#1B1B1B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">ll th<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#626262;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">e va<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#333333;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">lue<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#626262;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">s s<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#333333;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">ignificantly. Thus AMFEt <span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#4B4B4B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">ex<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#1B1B1B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">hibit<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#4B4B4B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">s an<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#1B1B1B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">ti-<span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#4B4B4B;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">oxidative activity <span style="font-size:14.0pt;line-height:115%;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;color:#333333;mso-ansi-language:EN-IN; mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">in streptozotocin diabetic rats.</span