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1.
Hrushikesh S. Chaudhari Omkar S. Palkar KM Abha Mishra Kalyan K. Sethi 《Journal of biochemical and molecular toxicology》2023,37(9):e23417
During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B ( 1 ) and isavuconazole ( 2 ) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole ( 3 ) and deferasirox ( 4 ) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 ( 5 ) and APX001A ( 6 ), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis. 相似文献
2.
V KW Wong T Li B YK Law E DL Ma N C Yip F Michelangeli C KM Law M M Zhang K YC Lam P L Chan L Liu 《Cell death & disease》2013,4(7):e720
Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump, leading to autophagy induction through the activation of the Ca2+/calmodulin-dependent kinase kinase–AMP-activated protein kinase–mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells. 相似文献
3.
The effects of the trichothecene mycotoxins (acetyl T-2 toxin, T-2 toxin, HT-2 toxin, palmityl T-2 toxin, diacetoxyscirpenol (DAS), deoxynivalenol (DON), and T-2 tetraol) on bovine platelet function were examined in homologous plasma stimulated with platelet activating factor (PAF). The mycotoxins inhibited platelet function with the following order of potency: acetyl T-2 toxin > palmityl T-2 toxin = DAS > HT-2 toxin = T-2 toxin. While T-2 tetraol was completely ineffective as an inhibitor, DON exhibited minimal inhibitory activity at concentrations above 10×10?4M. The stability of the platelet aggregates formed was significantly reduced in all mycotoxin treated platelets compared to that of the untreated PAF controls. It is suggested that the increased sensitivity of PAF stimulated bovine platelets to the more lipophilic mycotoxins may be related to their more efficient partitioning into the platelet membrane compared to the more hydrophilic compounds. 相似文献
4.
Cytochrome P-448 (mol wt 55,000 Daltons) from rabbit liver was purified to a specific content of 16.6 nmol/mg. Mice were immunised with this preparation, their spleens removed and dissociated lymphocytes hybridised with myeloma cells. Four monoclonal antibodies against cytochrome P-448 were raised and partially characterised. All four antibodies interacted with cytochrome P-448 in intact microsomal fractions and selectively immunoadsorbed cytochrome P-448 from solubilised microsomal preparations. One of the antibodies inhibited benzo[a] pyrene hydroxylase activity in a reconstituted system, one had no effect on activity and two increased activity. The possible applications of such antibodies are discussed. 相似文献
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6.
α(1)-Antitrypsin (α1AT) deficiency is a disease with multiple manifestations, including cirrhosis and emphysema, caused by the accumulation of stable polymers of mutant protein in the endoplasmic reticulum of hepatocytes. However, the molecular basis of misfolding and polymerization remain unknown. We produced and crystallized a trimeric form of α1AT that is recognized by an antibody specific for the pathological polymer. Unexpectedly, this structure reveals a polymeric linkage mediated by domain swapping the carboxy-terminal 34 residues. Disulphide-trapping and antibody-binding studies further demonstrate that runaway C-terminal domain swapping, rather than the s4A/s5A domain swap previously proposed, underlies polymerization of the common Z-mutant of α1AT in vivo. 相似文献
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8.
We recently solved the crystallographic structure of a dimeric form of the serpin antithrombin which has fundamentally changed the way we think about serpin polymerization. Like for other diseases that have protein deposition as a hallmark, the serpinopathies are associated with discrete inter-protomer linkage followed by subsequent association into larger fibrils and aggregates. Polymerization of the serpins is an off-pathway event that occurs during folding in the endoplasmic reticulum. Our structure reveals the nature of the polymerogenic folding intermediate, the reason that the inter-protomer linkage is hyperstable, and suggests a mechanism of lateral association of polymers into soluble fibrils and insoluble aggregates. While the basis of cellular toxicity is still unclear, novel therapeutic approaches targeting the folding intermediate or the lateral association event are now conceivable.Key words: aggregation, conformation, folding, polymerization, serpin, structure, toxicityThe serpins are serine protease inhibitors that utilize a unique and well characterized β-sheet expansion event as a necessary part of their mechanism.1–3 This conformational/topological change from a five-stranded (N in Fig. 1) to a six-stranded β-sheet A (L in Fig. 1) results in a doubling of the protein''s stability, and is driven by a free-energy term of around −32 kcal/mol.4 Thus, the native form of serpins is metastable in defiance of the Anfinsen principle,5 requiring a folding pathway that kinetically traps the five-stranded state. This unusual protein folding requirement allows for an off-pathway event known as polymerization, where one protomer completes the A sheet of another.6 For secreted serpins, this occurs in the endoplasmic reticulum (ER) where polymers are seen to accumulate as insoluble proteinaceous inclusions. Polymerization has been described for several serpins and is always associated with a loss of functional levels due to accumulation within the cell, and occasionally it is associated with the death of the secretory cells through a poorly understood mechanism.7–9 The best examples of the latter are provided by the Z variant of α1-antitrypsin (α1AT) leading to liver disease and the Syracuse variant of neuroserpin that causes early onset dementia.Open in a separate windowFigure 1Serpin folding and polymerization. The pathway of serpin folding proceeds from the unfolded state (U) to the native state (N) via a stable intermediate (M*). The native conformation is the only active state, and is composed of a five-stranded A sheet (red) and a 20 residue reactive centre loop (RCL, yellow). Serpin inhibitory function requires the native conformation to be a kinetically trapped metastable state. Completion of sheet A by incorporation of the RCL as strand 4, to form the latent (L) state, results in the doubling of the serpin''s thermodynamic stability (the six strands are labelled on L). Folding and unfolding of native serpins is known to proceed via a stable intermediate denoted M*, which also corresponds to the polymerogenic form.24–26 The key feature of the M* state is that strand 5 is not yet incorporated into sheet A, and can thus insert in an intermolecular fashion to form off-pathway polymers (P, each protomer of the pentamer is in a different colour). The polymers have complete A sheets and are thus hyperstable. As a consequence of polymerization, the linker region (cyan), containing helix I, remains unfolded. We hypothesize that the hydrophobic linker (indicated by the oval) is responsible for the lateral association of polymers into insoluble aggregates.We recently solved a crystal structure of a self-terminating (closed) serpin dimer that revealed a large domain swap including the fourth and fifth strands of β-sheet A.10 We then modelled an open polymerization competent polymer based on the structure (P in Fig. 1) that explained their facile propagation, the hyperstability and flexibility of the inter-protomer linkage, and also suggested a structure for the polymerogenic folding intermediate (M* in Fig. 1). We proposed that the final step in folding to the native state is the insertion of strand 5 into β-sheet A and the association of the coiled linker domain to the ‘bottom’ of the molecule. This event would leave the fourth strand (the reactive centre loop) accessible to serve as bait for proteolytic attack, necessary for the functioning of the serpin mechanism. While many details are yet to be confirmed, the position of certain polymerogenic mutations on and underlying strand 5A supports the proposal.10One unexpected implication of our model is the requisite unfolding and exposure of helix I and the following coiled region in linear serpin polymers. Exposure of this ‘linker region’ was verified in linear polymers of serpins antithrombin and α1AT through limited proteolysis and fluorescence studies, and explains the observation that polymers are hydrophobic and exhibit an increased propensity towards aggregation. Unglycosylated serpins typically aggregate when polymerized in vitro (with heat or low concentrations of chaotrophes), even at vanishingly low concentrations, whereas high concentrations are required to observe aggregation of glycosylated serpin polymers. We hypothesized that aggregation/precipitation occurs via lateral association of linear polymers, either through specific β-strand linkage or non-specific hydrophobic interactions involving the linker region. Sequence analysis of helix I suggest that it is a ‘frustrated’ β-strand11 for several serpins including α1AT, supporting the idea that aggregates of serpin polymers form through an extended β-sheet mechanism akin to other ‘conformational diseases.’12While there are clear parallels between the ‘serpinopathies’ and conformational diseases such as Alzheimer, Huntington and the prion encephalopathies (e.g., ordered intermolecular linkage, β-sheet expansion, cell death, dementia, accumulation of insoluble aggregates, domain-swapping),12,13 the detailed molecular mechanism revealed by our crystal structure is unique to the serpins. Domain swaps in other proteins are generally characterized by normal activity and stability, and may not play a role in the secondary association event that leads to the toxic species.14,15 For serpins the domain swap leads to hyperstability and the exposure of hydrophobic regions not seen in the monomeric state. Another key difference is the manner of cellular toxicity and the nature of the toxic species. It is becoming clear that for Alzheimer, Huntington and other conformational diseases the toxic fragments are likely to be the soluble (proto)-fibrils, not the insoluble aggregates (inclusions).16,17 Serpin polymerization generally leads to disease through loss of secretion of the active species, and only in two special cases is it through gain-of-function cellular toxicity, and although the toxic mechanisms are incompletely resolved, they appear to involve the insoluble aggregates.The most common cause of cirrhosis among children is the homozygous Z mutation in α1AT.18 Antitrypsin is expressed at high levels by hepatocytes (1.3–3.5 g/l in blood plasma) and its expression can increase in response to infection and other stimuli.19 However, only about one-third of the homozygous carriers ever manifest liver disease18 and it never occurs in carriers of a single Z allele, indicating that hepatocytes are generally well equipped to deal with the mutant protein. Soluble Z α1AT in the ER binds to chaperones and is subsequently targeted to the ERAD pathway for clearance by the proteosome, and insoluble polymers and aggregates are thought to activate autophagy for degradation in the lysosomes.20,21 In such a model, accumulation of polymers and cellular toxicity only occur when the proteosomal and autophagic pathways have been saturated by the high level of expression of mutant α1AT in the liver.21 In contrast, neuroserpin is expressed at low levels in neurons and mutation leads to polymerization and dementia in an autosomal dominant fashion.22,23 However, cell death and disease are still associated with accumulation of inclusion bodies within the ER, and the toxic mechanisms are likely to be similar.9In summary, we have elucidated a novel mechanism of serpin polymerization that involves a hyperstable domain swap of a folding intermediate. Formation of linear polymers exposes hydrophobic regions that mediate lateral polymer association and eventually leads to intra ER accretion and cellular toxicity. Our proposal suggests new avenues for the rational design of compounds to combat the diseases caused by serpin polymerization, either through targeting the folding intermediate or the lateral association of soluble polymers. 相似文献
9.
This study addressed whether competition under different light environments was reflected by changes in leaf absorbed light energy partitioning, photosynthetic efficiency, relative growth rate and biomass allocation in invasive and native competitors. Additionally, a potential allelopathic effect of mulching with invasive Prunus serotina leaves on native Quercus petraea growth and photosynthesis was tested. The effect of light environment on leaf absorbed light energy partitioning and photosynthetic characteristics was more pronounced than the effects of interspecific competition and allelopathy. The quantum yield of PSII of invasive P. serotina increased in the presence of a competitor, indicating a higher plasticity in energy partitioning for the invasive over the native Q. petraea, giving it a competitive advantage. The most striking difference between the two study species was the higher crown-level net CO2 assimilation rates (Acrown) of P. serotina compared with Q. petraea. At the juvenile life stage, higher relative growth rate and higher biomass allocation to foliage allowed P. serotina to absorb and use light energy for photosynthesis more efficiently than Q. petraea. Species-specific strategies of growth, biomass allocation, light energy partitioning and photosynthetic efficiency varied with the light environment and gave an advantage to the invader over its native competitor in competition for light. However, higher biomass allocation to roots in Q. petraea allows for greater belowground competition for water and nutrients as compared to P. serotina. This niche differentiation may compensate for the lower aboveground competitiveness of the native species and explain its ability to co-occur with the invasive competitor in natural forest settings. 相似文献
10.