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The high temperature requirement factor A1 (HTRA1) is a serine protease which modulates an array of signalling pathways driving basal biological processes. HTRA1 plays a significant role in cell proliferation, migration and fate determination, in addition to controlling protein aggregates through refolding, translocation or degradation. The mutation of HTRA1 has been implicated in a plethora of disorders and this has also led to its growing interest as drug therapy target. This review details the involvement of HTRA1 in certain signalling pathways, namely the transforming growth factor beta (TGF-β), canonical Wingless/Integrated (WNT) and NOTCH signalling pathways during organogenesis and various disease pathogenesis such as preeclampsia, age-related macular degeneration (AMD), small vessel disease and cancer. We have also explored possible avenues of exploiting the serine proteases for therapeutic management of these disorders. [ABSTRACT FROM AUTHOR]

Wastewater-based epidemiology (WBE) has emerged as a valuable approach for forecasting disease outbreaks in developed countries with a centralized sewage infrastructure. On the other hand, due to the absence of well-defined and systematic sewage networks, WBE is challenging to implement in developing countries like Bangladesh where most people live in rural areas. Identification of appropriate locations for rural Hotspot Based Sampling (HBS) and urban Drain Based Sampling (DBS) are critical to enable WBE based monitoring system. We investigated the best sampling locations from both urban and rural areas in Bangladesh after evaluating the sanitation infrastructure for forecasting COVID-19 prevalence. A total of 168 wastewater samples were collected from 14 districts of Bangladesh during each of the two peak pandemic seasons. RT-qPCR commercial kits were used to target ORF1ab and N genes. The presence of SARS-CoV-2 genetic materials was found in 98% (165/168) and 95% (160/168) wastewater samples in the first and second round sampling, respectively. Although wastewater effluents from both the marketplace and isolation center drains were found with the highest amount of genetic materials according to the mixed model, quantifiable SARS-CoV-2 RNAs were also identified in the other four sampling sites. Hence, wastewater samples of the marketplace in rural areas and isolation centers in urban areas can be considered the appropriate sampling sites to detect contagion hotspots. This is the first complete study to detect SARS-CoV-2 genetic components in wastewater samples collected from rural and urban areas for monitoring the COVID-19 pandemic. The results based on the study revealed a correlation between viral copy numbers in wastewater samples and SARS-CoV-2 positive cases reported by the Directorate General of Health Services (DGHS) as part of the national surveillance program for COVID-19 prevention. The findings of this study will help in setting strategies and guidelines for the selection of appropriate sampling sites, which will facilitate in development of comprehensive wastewater-based epidemiological systems for surveillance of rural and urban areas of low-income countries with inadequate sewage infrastructure. [Display omitted] • Wastewater-based epidemiology (WBE) is a vital monitoring tool to track COVID-19 outbreaks. • Informal sewage networks present major challenges for WBE in the developing world. • The study demonstrates a novel WBE monitoring from rural hotspot and urban drain systems. • Genetic signals optimized from regional sampling sites. • WBE data correlated with clinically diagnosed cases of COVID-19. [ABSTRACT FROM AUTHOR]

Aluminum chloride induces neurodegenerative disease in animal model. Evidence suggests that aluminum intake results in the activation of glial cells and generation of reactive oxygen species. By contrast, astaxanthin is an antioxidant having potential neuroprotective activity. In this study, we investigate the effect of astaxanthin on aluminum chloride-exposed behavioral brain function and neuronal oxidative stress (OS). Male Swiss albino mice (4 months old) were divided into 4 groups: (i) control (distilled water), (ii) aluminum chloride, (iii) astaxanthin+aluminum chloride, and (iv) astaxanthin. Two behavioral tests; radial arm maze and open field test were conducted, and OS markers were assayed from the brain and liver tissues following 42 days of treatment. Aluminum exposed group showed a significant reduction in spatial memory performance and anxiety-like behavior. Moreover, aluminum group exhibited a marked deterioration of oxidative markers; lipid peroxidation (MDA), nitric oxide (NO), glutathione (GSH) and advanced oxidation of protein products (AOPP) in the brain. To the contrary, co-administration of astaxanthin and aluminum has shown improved spatial memory, locomotor activity, and OS. These results indicate that astaxanthin improves aluminum-induced impaired memory performances presumably by the reduction of OS in the distinct brain regions. We suggest a future study to determine the underlying mechanism of astaxanthin in improving aluminum-exposed behavioral deficits. [ABSTRACT FROM AUTHOR]

Dorso-ventral and proximo-distal axis formation of the optic cup is apparent from early stages of development. Pax6 is initially detectable in the optic vesicle and later shows a distal-high and proximal-low gradient of expression in the retina. To determine the early role of Pax6 in pattern formation of the optic cup, we expressed Pax6 ectopically in the optic vesicle of stages 9–10 chick embryos by in ovo electroporation, which resulted in a small eye-like phenotype. The signaling molecule fibroblast growth factor (FGF)8, which appears to be restricted to the central retina, was increased, whereas bone morphogenetic protein (BMP)4 and Tbx5, two dorsal markers, were down-regulated in Pax6-electroporated eye. Pax6 overexpression also decreased the expression of the ventral marker Vax. Electroporation with a dominant-negative form of Pax6 resulted in a decrease in FGF8 expression, but BMP4 expression was unaffected initially while it was diminished later. Our data suggest a new role for Pax6 in regulating FGF8 and BMP4 expression during pattern formation of the optic cup, and that a Pax6-regulated balance between FGF8 and BMP4 is critical for retinogenesis. [ABSTRACT FROM AUTHOR]

Organ formation requires spatio-temporal proliferation and differentiation of precursor cells. During lens development, placodal cells in the posterior lens vesicle exit from the cell cycle and enter into the process of differentiation. Cyclin-dependent kinase inhibitors play critical roles in cell cycle exit and promote differentiation in several tissues. We have found that p27kip1 is expressed in the posterior lens cells that undergo differentiation to form the differentiated fiber cells. The transcription factor L-Maf is expressed in these cells earlier than p27kip1. From in ovo gain- or loss-of-function experiments, we have found that L-Maf can, respectively, induce or inhibit the expression of p27kip1 in lens cells. Promoter assays using the 5′ upstream sequences of the human p27kip1 gene indicate that L-Maf can activate p27kip1 transcription through the basal regulatory region. We suggest that L-Maf regulates cell cycle exit of the posterior lens cells by activating p27kip1, and thus directs fiber cell differentiation during lens formation in chick. [ABSTRACT FROM AUTHOR]

During lens development in vertebrates, the orchestration of multiple transcriptional regulators is essential for fate determination and terminal differentiation. In early development, Pax6, Sox2 and Six3 are expressed in the head ectoderm, while L-maf, Prox1 and crystallin genes are expressed at a later stage in the lens placode in a more restricted fashion. To uncover the genetic interactions among these factors during lens development, we examined the effects of dominant-negative molecules of Pax6 and L-Maf, which play decisive roles in lens formation. The two dominant-negative isoforms of Pax6 repress L-maf, Prox1 and δ-crystallin expression, resulting in failure of lens formation. These effects of dominant-negative Pax6 are fully rescued by co-expression with wild-type L-Maf. In addition, dominant-negative L-Maf inhibits the expression of Prox1 and δ-crystallin, while misexpression of L-Maf causes ectopic induction of these genes in a Sox-2-dependent fashion. Our results demonstrate that L-Maf is a downstream target of Pax6 and mediates Pax6 activity in developing lens cells. [Copyright &y& Elsevier]

Lens development is regulated by a variety of transcription factors with distinct properties. The lens-specific transcription factor, L-Maf, is essential for lens formation and induces lens-specific markers, such as the crystallin genes. In this study, we analyzed the mechanism by which L-Maf regulates δ-crystallin expression. Misexpression of L-Maf in the head ectoderm of lens placode-forming embryos by in ovo electroporation induced δ-crystallin only in the region surrounding the lens. To define this restricted expression, we misexpressed L-Maf together with other transcription factors implicated in δ-crystallin expression. Sox2 plus L-Maf expanded the δ-crystallin-inducible domain to the entire head ectoderm and simultaneously increased the quantity of δ-crystallin mRNA expressed. In contrast, co-expression of L-Maf with other factors such as Pax6, Six3 and Prox1 had little or no effect on δ-crystallin. We also observed that L-Maf and Sox2 cooperatively enhanced the transactivation of a reporter gene bearing the δ-crystallin enhancer in ovo, implying that L-Maf and Sox2 can induce δ-crystallin through the same enhancer. In conclusion, we report here that L-Maf and Sox2 cooperatively regulate the expression of δ-crystallin during chick lens development. [Copyright &y& Elsevier]

Red spinach ( Amaranthus tricolor ) has been reported to possess many benefits and medicinal properties and used as a part of traditional medicine in Ayurveda and Siddha. The aim of the study was to investigate the effects of Amaranthus tricolor on isoproterenol-induced oxidative stress, fibrosis, and myocardial damage in ovariectomized rats. Ovariectomy surgery was conducted to remove both ovaries from the rats. After recovery, rats were administered with ISO subcutaneously (50 mg/kg) twice a week and were treated with ethanolic extracts of A. tricolor . This investigation showed that the level of oxidative stress markers was significantly increased while the superoxide dismutase (SOD) activity decreased in ISO administered ovariectomized rats. A. tricolor extract and atenolol treatment prevented the rise of malondialdehyde, nitric oxide and advanced protein oxidation product. Moreover, elevated activities of AST, ALT, and CK-MB enzymes were also lowered by both atenolol and A. tricolor treatment. Increased uric acid and creatinine levels were also normalized by atenolol, and A. Tricolor treatment in ISO administered ovariectomized rats. ISO-induced ovariectomized rats also showed massive inflammatory cell infiltration, fibrosis and iron deposition in heart compared to sham rats. Atenolol and A. tricolor treatment prevented the inflammatory cells infiltration, fibrosis, and iron deposition. These results suggest that A. tricolor treatment may protect against ISO administered myocardial infarction in ovariectomized rats probably by preventing inflammation, oxidative stress, and fibrosis. Further research is warranted to examine molecular mechanism of cardioprotective effect of A. tricolor . [ABSTRACT FROM AUTHOR]

The development of combined anticancer therapeutic techniques has drawn increased attention for enhanced therapeutic efficacy. In this work, we synthesized Near Infrared (NIR) responsive ICG (I) functionalized hexagonal boron-nitride (hBN) as photothermal therapeutic agent (hBNI) and Doxorubicin (Dox)-conjugated Hyaluronic acid (HA) as tumor targeted chemotherapeutic agent (d-HA-Dox). Using adhesion properties of Dopamine (d), the hBNI has been integrated with d-HA-Dox to make a tumor targeted photothermal chemotherapeutic agent (hBNI/d-HA-Dox). The nanostructure of hBNI/d-HA-Dox has been studied using 1H NMR, FTIR, UV–vis-NIR and AFM images. Our in vitro results have provided evidence that hBNI/d-HA-Dox can efficiently damage targeted cancer cells while healthy cells are less affected suggesting that the targeted hBNI/d-HA-Dox nanoparticles work as a complementary antitumor agent with its synergistic co-therapeutic power. [ABSTRACT FROM AUTHOR]

Background Liver fibrosis is a leading pathway to cirrhosis and a global clinical issue. Oxidative stress mediated tissue damage is one of the prime causes of hepatic dysfunction and fibrosis. Apocynin is one of many strong antioxidants. Objective To evaluate the effect of apocynin in the CCl 4 administered hepatic dysfunction in rats. Methods Female Long Evans rats were administered with CCl 4 orally (1 mL/kg) twice a week for 2 weeks and were treated with apocynin (100 mg/kg). Both plasma and liver tissues were analyzed for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase activities. Oxidative stress parameters were also measured by determining malondialdehyde (MDA), nitric oxide (NO), myeloperoxidase (MPO), advanced protein oxidation product (APOP). In addition, antioxidant enzyme activities such as superoxide dismutase (SOD) and catalase activities in plasma and liver tissues were analyzed. Moreover, inflammation and tissue fibrosis were confirmed by histological staining of liver tissue sections. Results Apocynin significantly reduced serum AST, ALT, and ALP activities in carbon tetrachloride treated rats. It also exhibited a considerable reduction of the oxidative stress markers (MDA, MPO, NO, and APOP level) which was elevated due to CCl 4 administration in rats. Apocynin treatment also restored the catalase and superoxide dismutase activity in CCl 4 treated rats. Histological analysis of liver sections revealed that apocynin prevented inflammatory cells infiltration and fibrosis in CCl 4 administered rats. Conclusion These results suggest that apocynin protects liver damage induced by CCl 4 by inhibiting lipid peroxidation and stimulating the cellular antioxidant system. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a common manifestation of certain cardiac diseases where oxidative stress and fibrosis aggravate the condition markedly. Investigation of L-carnitine's cardioprotective roles and mechanism of action in a rat model of MI. To develop a MI animal model, Isoproterenol (ISO) was administered in male Long Evans rats where animals were divided into five groups (six rats/group). The oxidative stress and antioxidant enzyme activities were determined by different biochemical tests. The real-time PCR was performed to determine the expression of TNF-α and Il-1β. Histopathological observations by hematoxylin-eosin and Masson trichrome were made to observe the tissue damage and fibrosis in heart and kidney. The ISO-treated rats showed increased levels of troponin I and lipid peroxidation and lower antioxidant enzyme activity in heart and kidney tissues. The levels of TNF-α and IL-1β were also increased in ISO-rats. Co-administration of L-carnitine with ISO reversed all these parameters. The elevated levels of uric acid and creatinine kinase and ALP, AST and ALT activities in ISO-rats were also significantly reduced by L-carnitine administration. L-carnitine markedly decreased the infiltration of inflammatory cells and improved the tissue architecture in heart and kidney. Control animals did not show any appreciable response upon L-carnitine administration. These results suggest that L-carnitine plays a defensive role against cardiac and renal damage in ISO-treated MI rat model via suppressing oxidative stress and increasing antioxidant enzyme functions through inhibition of TNF-α and IL-1β. [ABSTRACT FROM AUTHOR]