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Cholestasis/cirrhosis is a multifaceted clinical complication that influences many organs, including the liver, kidney, heart, skeletal muscle, and lung. Cirrhosis-associated lung injury could lead to severe and lethal consequences, including acute respiratory syndrome and patient dearth. Unfortunately, there is no specific pharmacological intervention to manage cholestasis-induced lung injury. It has been revealed that severe inflammation and its associated complications, such as oxidative stress, are involved in the pathogenesis of cholestasis-associated pulmonary damage. The current study was designed to evaluate the role of dexamethasone (DXM) on lung inflammation in cholestatic mice. For this purpose, bile duct ligated (BDL) mice received DXM (1 and 2.5 mg/kg, i.p, 2 times/week) for 14 days. On day 15, the bronchoalveolar lavage fluid (BALF) was prepared. Several markers, including inflammatory cell infiltration, TNF-α, and IgG, were assessed in the BALF of BDL animals. Significant infiltration of inflammatory cells along with increased TNF-α and IgG were detected in the BALF of BDL mice (14 days after surgery). Moreover, significant ROS formation, glutathione depletion, lipid peroxidation, and protein carbonylation were evident in the lung tissue of the BDL group. It was found that DXM (1 and 2.5 mg/kg) significantly blunted inflammation and oxidative stress in the lung of cholestatic mice. Moreover, lung tissue histopathological changes, including inflammatory cell infiltration, were significantly mitigated in DXM-treated mice. These data offer the potential therapeutic effects of DXM against cholestasis-related complications. Therefore, patients with cholestasis-induced lung injury might benefit from repurposing DXM in clinical settings. [ABSTRACT FROM AUTHOR]

L-asparaginase from Escherichia coli is an important therapeutic agent in the treatment of childhood acute lymphoblastic leukemia. In this study, the secretory production of a recombinant form of L-asparaginase enzyme was investigated in E. coli cells immobilized in calcium alginate beads. The protein expression was determined for the immobilized cells with two different initial cell concentrations and compared with the free cells. The maximum enzyme activity of the released asparaginase was achieved in the culture medium of the alginate beads with the lower cell density at 3 days after immobilization. Total asparaginase activity of the enzymes released into the culture medium or entrapped in the alginate beads was 315.8 U, which exhibited about 2-fold higher activity than the extracellular asparaginase activity of the conventional free cells (162.3 U). A maximum plasmid stability of 49%, which was 25-fold higher than the free cells, was obtained by the immobilized cells. [ABSTRACT FROM AUTHOR]

Aim of the study: Cholestasis is the stoppage of bile flow that primarily affects liver function. On the other hand, kidneys are also severely influenced during cholestasis. Cholestasis-induced kidney injury is known as cholemic nephropathy (CN). There is no precise pharmacological option in CN. Previous studies revealed that oxidative stress plays a crucial role in the pathogenesis of CN. On the other hand, the positive effects of pentoxifylline (PTX) against renal injury with different etiologies have been frequently reported. In the current study, the potential nephroprotective role of PTX in cholestasis-induced renal injury is investigated. Material and methods: Bile duct ligated (BDL) rats were treated with PTX (10, 50, and 100 mg/kg), and renal markers of oxidative stress, urine level of inflammatory cytokines, as well as renal histopathological alterations were monitored. Results: Significant changes in oxidative stress markers were detected in the BDL group. On the other hand, it was found that PTX (10, 50, and 100 mg/kg) significantly ameliorated cholestasis-induced oxidative stress in renal tissue. Renal histopathological changes, including interstitial inflammation, tubular atrophy, fibrosis, and cast formation, were detected in the BDL rats. Moreover, urine pro-inflammatory cytokines [interleukin (IL)-1, IL-9, IL-18, tumor necrosis factor α (TNF-α), and interferon γ (INF-γ)] were significantly increased in the cholestatic animals. PTX (10, 50, and 100 mg/kg, 14 days) significantly ameliorated renal histopathological alterations and urine levels of inflammatory cytokines. Conclusions: These data indicate a potential nephroprotective role for PTX in cholestasis. The effects of PTX on oxidative stress parameters and the inflammatory response could play a primary role in its renoprotective mechanisms. [ABSTRACT FROM AUTHOR]

Hyperpigmentation disorders negatively influence an individual's quality of life and may cause emotional distress. Over the years, various melanogenesis inhibitors (mainly tyrosinase inhibitors) have been developed, most of which with low efficacy or high toxicity. Although metabolic engineering by deviation in the flux of substrate is of considerable interest, trials to develop a melanogenesis inhibitor based on L‐tyrosine (L‐Tyr) restriction are missing. We propose a novel proteinaceous melanogenesis inhibitor called tyrosine ammonia‐lyase (TAL), an enzyme that catalyzes the conversion of L‐Tyr to p‐coumaric acid and ammonia. Since the cell membrane can act as a barrier for intracellular protein delivery, we have covalently conjugated a recombinant TAL enzyme from Rhodobacter sphaeroides (RsTAL) to a trans‐activator of transcription (TAT) cell‐penetrating peptide (CPP) to afford the intracellular delivery. The heterologously expressed TAT‐RsTAL fusion protein was delivered successfully into B16F10 melanocytes as confirmed by the direct fluorescence microscopy with increased intensity from 30 to 180 min. TAT‐RsTAL showed sufficient intracellular activity of about 0.83 ± 0.04 and 0.34 ± 0.03 nmol•mg−1•s−1 for the native and inclusion body‐extracted conjugates, respectively. The conjugate inhibited melanin biosynthesis in B16F10 cells in a time‐dependent manner. Melanin accumulation was inhibited by 12.7 ± 6.2%, 28.2 ± 5.7%, and 33.9 ± 2.9% compared to the nontreated control groups after 24, 48, and 72 hr of incubation, respectively. L‐Tyr restriction had no significant effect on the cell viability up to a concentration of 100 μgml−1 even after 72 hr. According to the observed hypopigmentary effect of the conjugate in this study, TAT‐RsTAL can be suggested as a melanogenesis inhibitor for further investigations. [ABSTRACT FROM AUTHOR]