An extensive review on antifungal approaches in the treatment of mucormycosis

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.     

Comparative behavior of Pd and Ag deposition phenomenon on clean α-Al2O3 (001) surface—A first principle study

The nature of bonding at the interface between deposited silver/palladium and clean Al-terminated (001) surface of α-Al₂O₃ has been investigated using a periodic ab initio method. Substantial inter-planar relaxations within the alumina were found at both the interfaces and the bulk. The periodic calculation with both Ag and Pd deposition shows that 10% of loading on alumina results maximum stability. Surface energy and work function calculations were performed to propose the stability for the metals on the studied surfaces. The deposited Ag forms a three-dimensional (3-D) cluster on top of the alumina surface. The Pd cluster formed on the alumina surface is two-dimensional (2-D) and is distorted to accommodate the Ag cluster in its domain. A further low index calculation can explain the reason for a higher stability of the membrane generated over alumina support with silver and palladium. The results are discussed in view of the existing experimental data and models of metal-oxide interface and a reason for the difference of activity of the metal interaction with alumina surface is postulated.     

Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model

In a continuing study of our clinical candidate 5 VN/124-1 (TOK-001) and analogs as potential agents for prostate cancer therapy, putative metabolites (10, 15 and 18) of compound 5 were rationally designed and synthesized. However, none of these agents were as efficacious as 5 in several in vitro studies. Using western blot analysis, we have generated a preliminary structure–activity relationship (SAR) of 5 and related analogs as androgen receptor ablative agents (ARAAs). In vivo using the androgen-dependent LAPC-4 prostate cancer xenograft model, we demonstrated for the first time that 5 is more efficacious than the 17-lyase inhibitor 3 (abiraterone)/4 (abiraterone acetate) that is currently in phase III clinical trials. In our desire to optimize the potency of 5, compounds 6 (3ξ-fluoro-) and 9 (3β-sulfamate-) designed to increase the stability and oral bioavailability of 5, respectively were evaluated in vivo. We showed, that on equimolar basis, compound 6 was ∼2-fold more efficacious versus LAPC-4 xenografts than 5, but the toxicity observed with 6 is of concern. These studies further demonstrate the efficacy of 5 in a clinically relevant prostate cancer model and justify its current clinical development as a potential treatment of prostate cancer.     

Bt工程菌WG-001与化学杀虫剂复配最佳配方筛选及田间防效研究

为了延缓小菜蛾Plutella xylostella(L.)抗药性的产生和发展,筛选Bt工程菌WG-001与化学杀虫剂的最佳复配配方,本研究采用浸叶法分别测定了Bt工程菌WG-001与茚虫威、丁醚脲和巴丹复配对小菜蛾的增效作用。结果表明,当Bt工程菌WG-001与茚虫威以有效成分之比为100.10∶0.72复配时,增效作用最强,共毒系数为178.05。而Bt工程菌WG-001分别与丁醚脲和巴丹复配表现相加或拮抗作用。田间试验结果表明,Bt工程菌WG-001与茚虫威以100.10∶0.72的有效成分之比进行复配后,药后7d,500倍液对小菜蛾的平均防效为84.88%,显著优于Bt工程菌WG-001和茚虫威单用的平均防效。     

In vitro and in vivo pharmacokinetic and pharmacodynamic study of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent

MBRI-001 was demonstrated preliminary better pharmacokinetics and antitumor effects than that of plinabulin in vivo. In this approach, we further carried out systematic pharmacokinetic and pharmacodynamic study of MBRI-001 in vitro and in vivo. MBRI-001 was tested stable in rat plasma and more stable in liver microsomes than plinabulin in vitro. In vivo, MBRI-001 could be distributed rapidly and widely in various tissues, especially the concentration of MBRI-001 in lung was remarkably higher than other tissues. Excretion study indicated that MBRI-001 might been decomposed and excreted as metabolites. Additionally, the combination treatment of MBRI-001 and gefitinib revealed better antitumor inhibition rate than monotherapy in vivo. Therefore, we suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.     

The Tilapia collagen peptide mixture TY001 protects against LPS-induced inflammation,disruption of glucose metabolism,and aberrant expression of circadian clock genes in mice

The Tilapia collagen peptide mixture TY001 has been shown to accelerate wound healing in streptozotocin-induced diabetic mice and to protect against streptozotocin-induced inflammation and elevation in blood glucose. The goals of the present study are to further study TY001 effects on lipopolysaccharide (LPS)-induced inflammation and metabolic syndrome. LPS is known to disrupt circadian clock to produce toxic effects, the effects of TY001 on rhythmic alterations of serum cytokines and hepatic clock gene expressions were examined. Mice were given TY001 (30 g/L, ≈ 40 g/kg) through the drinking water for 30 days, and on the 21^st day of TY001 supplementation, LPS (0.25 mg/kg, ip, daily) was given for 9 days to establish the inflammation model. Repeated LPS injections produced inflammation, impaired glucose metabolism, and suppressed the expression of circadian clock core genes Bmal1 and Clock; clock feedback gene Cry1, Cry2, Per1, and Per2; clock target gene Rev-erbα and RORα. TY001 prevented LPS-induced elevations of TNFα, IL-1β, IL-6, and IL-10 in the liver, along with improved histopathology. TY001 reduced LPS-elevated fasting blood glucose and increased LPS-reduced serum insulin levels, probably via increased glucose transporter GLUT2, enhanced insulin signaling p-Akt and p-IRS-1^Try612. Importantly, LPS-induced circadian elevations of serum TNFα and IL-1β and aberrant expression of circadian clock genes in the liver were ameliorated by TY001. Immunohistochemistry revealed that the LPS decreased Bmal1 and Clock protein in the liver, which was recovered by TY001. Taken together, TY001 is effective against LPS-induced inflammation, disruption of glucose metabolism and disruption of circadian clock gene expressions.

Abbreviations: TY001: Tilapia collagen peptide mixture; LPS: Lipopolysaccharide; TNFα: Tumor necrosis factor-α; IL-1β: Interleukin-1β; GLUT2: Glucose transporter 2     

RAD 001 (everolimus) prevents mTOR and Akt late re‐activation in response to imatinib in chronic myeloid leukemia

The mammalian target of rapamycin (mTOR) is one target of BCR‐ABL fusion gene of chronic myeloid leukemia (CML). Moreover, it drives a compensatory route to Imatinib mesylate (IM) possibly involved in the progression of leukemic progenitors towards a drug‐resistant phenotype. Accordingly, mTOR inhibitors are proposed for combined therapeutic strategies in CML. The major caveat in the use of mTOR inhibitors for cancer therapy comes from the induction of an mTOR‐phosphatidylinositol 3 kinase (PI3k) feedback loop driving the retrograde activation of Akt. Here we show that the rapamycin derivative RAD 001 (everolimus, Novartis Institutes for Biomedical Research) inhibits mTOR and, more importantly, revokes mTOR late re‐activation in response to IM. RAD 001 interferes with the assembly of both mTOR complexes: mTORC1 and mTORC2. The inhibition of mTORC2 results in the de‐phosphorylation of Akt at Ser⁴⁷³ in the hydrophobic motif of C‐terminal tail required for Akt full activation and precludes Akt re‐phosphorylation in response to IM. Moreover, RAD 001‐induced inhibition of Akt causes the de‐phosphorylation of tuberous sclerosis tumor suppressor protein TSC2 at 14‐3‐3 binding sites, TSC2 release from 14‐3‐3 sigma (restoring its inhibitory function on mTORC1) and nuclear import (promoting the nuclear translocation of cyclin‐dependent kinase [CDK] inhibitor p27^Kip1, the stabilization of p27^Kip1 ligand with CDK2, and the G₀/G₁ arrest). RAD 001 cytotoxicity on cells not expressing the BCR‐ABL fusion gene or its p210 protein tyrosine kinase (TK) activity suggests that the inhibition of normal hematopoiesis may represent a drug side effect. J. Cell. Biochem. 109: 320–328, 2010. © 2009 Wiley‐Liss, Inc.     

Development of chiral fluorinated alkyl derivatives of emixustat as drug candidates for the treatment of retinal degenerative diseases

The discovery of how a photon is converted into a chemical signal is one of the most important achievements in the field of vision. A key molecule in this process is the visual chromophore retinal. Several eye diseases are attributed to the abnormal metabolism of retinal in the retina and the retinal pigment epithelium. Also, the accumulation of two toxic retinal derivatives, N-retinylidene-N-retinylethanolamine and the retinal dimer, can damage the retina leading to blindness. RPE65 (Retinal pigment epithelium-specific 65 kDa protein) is one of the central enzymes that regulates the metabolism of retinal and the formation of its toxic metabolites. Its inhibition might decrease the rate of the retina’s degeneration by limiting the amount of retinal and its toxic byproducts. Two RPE65 inhibitors, (R)-emixustat and (R)-MB001, were recently developed for this purpose.     

HrpNCSDS001基因克隆及其表达产物诱导拟南芥基因表达谱变化的研究

Erwinia carotovora subsp.carotovora CSDS001菌株具有可直接诱导烟草过敏反应特征,从构建的CSDS001菌株基因组文库,鉴定、克隆到hrpNCSDS001基因,GenBank登录号AY939927;构建的重组hrpNCSDS001基因工程菌株经IPTG诱导培养,获得的高效表达HarpinCSDS001蛋白,可诱导烟草发生过敏反应。30μg/mLHarpinCSDS001蛋白喷施拟南芥后,分析第3h、12h、24h、36h和48h拟南芥全基因谱表达动态变化,结果显示发生显著表达差异(logratio≤?1或≥1)的基因数分别为912、1787、2393、1833和1755。对被诱导发生显著表达差异的转录因子基因分析表明,有13个转录因子家族:ZIM、BES1、TCP、C2C2、AP2/EREBP、WRKY、bHLH、bZIP、GARP、MYB、NAC、HB、C2H2与HarpinCSDS001蛋白作用相关,这些转录因子家族主要参与调控植物抗性、光合作用、生长发育、开花等相关功能基因表达。