Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes.

BACKGROUND: We examined components of systemic and intestinal renin-angiotensin system on gut barrier permeability, glucose homeostasis, systemic inflammation, and progression of diabetic retinopathy (DR) in human subjects and mice with type 1 diabetes (T1D). METHODS: T1D individual with (n=18) and without (n=20) DR and controls (n=34) were examined for changes in gut-regulated components of the immune system, gut leakage markers (FABP2 [fatty acid binding protein 2] and peptidoglycan), and Ang II (angiotensin II); Akita mice were orally administered a Lactobacillus paracasei (LP) probiotic expressing humanized ACE2 (angiotensin-converting enzyme 2) protein (LP-ACE2) as either a prevention or an intervention. Akita mice with genetic overexpression of humanAce2 by small intestine epithelial cells (Vil-Cre.hAce2KI-Akita) were similarly examined. After 9 months of T1D, circulatory, enteral, and ocular end points were assessed. RESULTS: T1D subjects exhibit elevations in gut-derived circulating immune cells (ILC1 cells) and higher gut leakage markers, which were positively correlated with plasma Ang II and DR severity. The LP-ACE2 prevention cohort and genetic overexpression of intestinal ACE2 preserved barrier integrity, reduced inflammatory response, improved hyperglycemia, and delayed development of DR. Improvements in glucose homeostasis were due to intestinal MasR activation, resulting in a GSK-3ß (glycogen synthase kinase-3 beta)/c-Myc (cellular myelocytomatosis oncogene)-mediated decrease in intestinal glucose transporter expression. In the LP-ACE2 intervention cohort, gut barrier integrity was improved and DR reversed, but no improvement in hyperglycemia was observed. These data support that the beneficial effects of LP-ACE2 on DR are due to the action of ACE2, not improved glucose homeostasis. CONCLUSIONS: Dysregulated systemic and intestinal renin-angiotensin system was associated with worsening gut barrier permeability, gut-derived immune cell activation, systemic inflammation, and progression of DR in human subjects. In Akita mice, maintaining intestinal ACE2 expression prevented and reversed DR, emphasizing the multifaceted role of the intestinal renin-angiotensin system in diabetes and DR.

Effect of nonsteroidal anti-inflammatory drugs (aspirin and naproxen) on inflammation-associated proteomic profiles in mouse plasma and prostate during TMPRSS2-ERG (fusion)-driven prostate carcinogenesis.

Recent preclinical studies have shown that the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and naproxen could be an effective intervention strategy against TMPRSS2-ERG fusion-driven prostate tumorigenesis. Herein, as a follow-up mechanistic study, employing TMPRSS2-ERG (fusion) positive tumors and plasma from TMPRSS2-ERG. Ptenflox/flox mice, we profiled the stage specific proteomic changes (focused on inflammatory circulating and prostate tissue/tumor-specific cytokines, chemokines, and growth factors/growth signaling-associated molecules) that contribute to prostate cancer (PCa) growth and progression in the TMPRSS2-ERG fusion-driven mouse model of tumorigenesis. In addition, the association of the protective effects of NSAIDs (aspirin 1400 ppm and naproxen 400 ppm) with the modulation of these specific molecular pathways was determined. A sandwich Elisa based membrane array-proteome profiler identifying 111 distinct signaling molecules was employed. Overall, the plasma and prostate tissue sample analyses identified 54 significant and differentially expressed cytokines, chemokines, and growth factors/growth signaling-associated molecules between PCa afflicted mice (TMPRSS2-ERG. Ptenflox/flox, age-matched noncancerous controls, NSAIDs-supplemented and no-drug controls). Bioinformatic analysis of the array outcomes indicated that the protective effect of NSAIDs was associated with reduced expression of (a) tumor promoting inflammatory molecules (M-CSF, IL-33, CCL22, CCL12, CX3CL1, CHI3L1, and CD93), (b) growth factors- growth signaling-associated molecules (Chemerin, FGF acidic, Flt-3 ligand, IGFBP-5, and PEDF), and (c) tumor microenvironment/stromal remodeling proteins MMP2 and MMP9. Overall, our findings corroborate the pathological findings that protective effects of NSAIDs in TMPSS2-ERG fusion-driven prostate tumorigenesis are associated with antiproliferative and anti-inflammatory effects and possible modulation of the immune cell enriched microenvironment.

Putative Role of Anti-microbial Peptide Recovered from Lactiplantibacillus spp. in Biocontrol Activity.

Antimicrobial peptides (AMPs) stand as a promising alternative to conventional pesticides, leveraging a multifaceted approach to combat plant pathogens. This study focuses on identifying and characterizing the AMP produced by Lactiplantibacillus argentoratensis strain IT, demonstrating potent antibacterial activity against various harmful microorganisms. Evaluation of AMPs' antibacterial activity was conducted through an agar well diffusion assay, a reliable method for assessing secondary metabolite antimicrobial efficacy. The study unveils the antimicrobial potential of the purified extract obtained from Lactiplantibacillus argentoratensis IT, isolated from goat milk. Notably, the AMP exhibited robust antibacterial activity against phytopathogens affecting solanaceous crops, including the Gram-negative Ralstonia solanacearum. Expression conditions and purification methods were optimized to identify the peptide's mass and sequence, utilizing LC-MS and SDS-PAGE. This paper underscores the application potential of Lactiplantibacillus spp. IT as a biocontrol agent for managing bacterial infectious diseases in plants. Results indicate optimal AMP production at 37 °C, with a culture broth pH of 5 during fermentation. The obtained peptide sequence corresponded to peaks at 842.5 and 2866.4 m/z ratio, with a molecular weight of approximately 5 kDa according to tricine SDS-PAGE analysis. In conclusion, this study lays the foundation for utilizing Lactiplantibacillus spp. IT derived AMPs in plant biocontrol strategies, showcasing their efficacy against bacterial phytopathogens. These findings contribute valuable insights for advancing sustainable agricultural practices.

Leaching Approach for ß-Glucosidase Extraction from Fermented Rice Husk in Solid State Cultivation by Aspergillus protuberus.

Environmental problems are caused by the disposal of agrowastes in developing countries. It is imperative to convert such wastes into useful products, which require enzymes such as ß-glucosidase. ß-Glucosidase has variety of applications in biotechnology including food, textile, detergents, pulp and paper, pharmaceutical and biofuel industries. ß-Glucosidase production was performed using the locally isolated Aspergillus protuberus using best growth circumstances on rice husk in solid-state fermentation (SSF). Leaching of ß-glucosidase from fermented rice husk with number of solvents to evaluate their extraction efficacy. Among the different solvents examined, acetate buffer (0.02 M, pH 5.0) proved to be the best solvent. The subsequent parameters were optimized with acetate buffer. Two washes with acetate buffer each by shaking (30 min) in a ratio of 1 g of rice husk: 5 ml of acetate buffer together attained maximum recovery of ß-glucosidase with 41.95 U/g of rice husk.

Vibrational spectroscopy for decoding cancer microbiota interactions: Current evidence and future perspective.

The role of human microbiota in cancer initiation and progression is recognized in recent years. In order to investigate the interactions between cancer cells and microbes, a systematic analysis using various emerging techniques is required. Owing to the label-free, non-invasive and molecular fingerprinting characteristics, vibrational spectroscopy is uniquely suited to decode and understand the relationship and interactions between cancer and the microbiota at the molecular level. In this review, we first provide a quick overview of the fundamentals of vibrational spectroscopic techniques, namely Raman and infrared spectroscopy. Next, we discuss the emerging evidence underscoring utilities of these spectroscopic techniques to study cancer or microbes separately, and share our perspective on how vibrational spectroscopy can be employed at the intersection of the two fields. Finally, we envision the potential opportunities in exploiting vibrational spectroscopy not only in basic cancer-microbiome research but also in its clinical translation, and discuss the challenges in the bench to bedside translation.

SIRT3 Is a Critical Regulator of Mitochondrial Function of Fibroblasts in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a heterogeneous and life-threatening cardiopulmonary disorder in which mitochondrial dysfunction is believed to drive pathogenesis, although the underlying mechanisms remain unclear. To determine if abnormal SIRT3 (sirtuin 3) activity is related to mitochondrial dysfunction in adventitial fibroblasts from patients with idiopathic pulmonary arterial hypertension (IPAH) and hypoxic PH calves (PH-Fibs) and whether SIRT3 could be a potential therapeutic target to improve mitochondrial function, SIRT3 concentrations in control fibroblasts, PH-Fibs, and lung tissues were determined using quantitative real-time PCR and western blot. SIRT3 deacetylase activity in cells and lung tissues was determined using western blot, immunohistochemistry staining, and immunoprecipitation. Glycolysis and mitochondrial function in fibroblasts were measured using respiratory analysis and fluorescence-lifetime imaging microscopy. The effects of restoring SIRT3 activity (by overexpression of SIRT3 with plasmid, activation SIRT3 with honokiol, and supplementation with the SIRT3 cofactor nicotinamide adenine dinucleotide [NAD+]) on mitochondrial protein acetylation, mitochondrial function, cell proliferation, and gene expression in PH-Fibs were also investigated. We found that SIRT3 concentrations were decreased in PH-Fibs and PH lung tissues, and its cofactor, NAD+, was also decreased in PH-Fibs. Increased acetylation in overall mitochondrial proteins and SIRT3-specific targets (MPC1 [mitochondrial pyruvate carrier 1] and MnSOD2 [mitochondrial superoxide dismutase]), as well as decreased MnSOD2 activity, was identified in PH-Fibs and PH lung tissues. Normalization of SIRT3 activity, by increasing its expression with plasmid or with honokiol and supplementation with its cofactor NAD+, reduced mitochondrial protein acetylation, improved mitochondrial function, inhibited proliferation, and induced apoptosis in PH-Fibs. Thus, our study demonstrated that restoration of SIRT3 activity in PH-Fibs can reduce mitochondrial protein acetylation and restore mitochondrial function and PH-Fib phenotype in PH.

Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection.

Endothelial dysfunction and inflammation contribute to the vascular pathology of coronavirus disease (COVID-19). However, emerging evidence does not support direct infection of endothelial or other vascular wall cells, and thus inflammation may be better explained as a secondary response to epithelial cell infection. In this study, we sought to determine whether lung endothelial or other resident vascular cells are susceptible to productive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and how local complement activation contributes to endothelial dysfunction and inflammation in response to hypoxia and SARS-CoV-2-infected lung alveolar epithelial cells. We found that ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) mRNA expression in lung vascular cells, including primary human lung microvascular endothelial cells (HLMVECs), pericytes, smooth muscle cells, and fibroblasts, was 20- to 90-fold lower compared with primary human alveolar epithelial type II cells. Consistently, we found that HLMVECs and other resident vascular cells were not susceptible to productive SARS-CoV-2 infection under either normoxic or hypoxic conditions. However, viral uptake without replication (abortive infection) was observed in HLMVECs when exposed to conditioned medium from SARS-CoV-2-infected human ACE2 stably transfected A549 epithelial cells. Furthermore, we demonstrated that exposure of HLMVECs to conditioned medium from SARS-CoV-2-infected human ACE2 stably transfected A549 epithelial cells and hypoxia resulted in upregulation of inflammatory factors such as ICAM-1 (intercellular adhesion molecule 1), VCAM-1 (vascular cell adhesion molecule 1), and IL-6 (interleukin 6) as well as complement components such as C3 (complement C3), C3AR1 (complement C3a receptor 1), C1QA (complement C1q A chain), and CFB (complement factor B). Taken together, our data support a model in which lung endothelial and vascular dysfunction during COVID-19 involves the activation of complement and inflammatory signaling and does not involve productive viral infection of endothelial cells.

Deciphering the fertilizing and disease suppression potential of phytofabricated zinc oxide nanoparticles on Brassicajuncea.

Every year 30-50% of crops suffer from fungal and bacterial diseases. Use of various chemically synthesized fungicides and bactericides make the soil environment more toxic and harmful to the plant health. Therefore, there is need to find non-toxic and cost effective alternative against plant pathogen. In recent years, nanotechnology has got attention because of its wide application in different areas of agriculture. Various nanoparticles have been used in agriculture for their fertilizing and antimicrobial potential. Among them zinc oxide nanoparticles (ZnO NPs) have gained the attention of agriculturists as zinc is an essential micronutrient for plants. Antifungal activity of Tb-ZnO NPs (Terminalia bellerica synthesized zinc oxide nanoparticles) against Alternaria brassicae causative agent of blight disease in Brassica juncea has been reported in our previous study. To use Tb-ZnO NPs as nanofungicides and simultaneously as nanofertilizers, the doses of Tb-ZnO NPs beneficial to the Brassica juncea crop is need to be known. Therefore, experiment has been designed to see the protective and curative potential of Tb-ZnO NPs in alluvial and calcareous soil. Biochemical constituents and stress enzymes analysis has shown significant potential of Tb-ZnO NPs at 200 ppm concentration in alleviating the stress caused by A. brassicae by modulating the photosynthetic, biochemical and enzymatic characteristics. Growth parameter analysis confirmed the role of Tb-ZnO NPs in increasing root and shoot length of B. juncea. Yield component such as seed number, seed weight and oil content of B. juncea crop also has been increased. There was one-fold increase in oil content of B. juncea as compared to control. Maximum percent disease control was found to be 70% in alluvial soil (protective method) grown plants. Therefore, present study supports the hypothesis of a relationship between nutrients and disease suppression.

Improving the Growth and Productivity of Macrotyloma uniflorum Medicinal Plant by the Co-inoculation of P, Zn and K-Solubilizing Fungi Under Field Conditions.

The presence of small amount of soluble forms of Phosphorus (P), Potassium (K) and Zinc (Zn) in most soils is one of the limiting factors for agronomic crop production. The current study focuses on Macrotyloma uniflorum (horse gram or gahat), the most commonly cultivated crop in Uttarakhand. The current initiative and study were started, because there is a little information available on the impact of co-inoculation of beneficial fungi on crops in agricultural fields. Aspergillus niger K7 and Penicillium chrysogenum K4 were isolated and selected for the study on the basis of in vitro P, K and Zn-solubilizing activity. The solubilizing efficiency of K4 strain was 140% and K7 was 173.9% for P. However, the solubilizing efficiencies of K4 and K7 were 160% and 138.46% for Zn and 160% and 466% for K, respectively. The field trials were performed for two consecutive years, and growth and yield related parameters were measured for evaluation of the effect of P, K and Zn-solubilizing fungal strains on the crop. All the treatments showed a significant (P < 0.05) increase in growth and yield of M. uniflorum plants over uninoculated control; however, the best treatment was found to be soil inoculated with P. chrysogenum K4 + A. niger K7 in which the yield was enhanced by 71% over control. Thus, the co-inoculation of K4 and K7 strains showed a great potential to improve the growth and yield of plants. Both the fungal strains simultaneously solubilized three important nutritional elements in soil, which is a rare trait. Moreover, the capacity of these fungal strains to enhance the plant root nodulation and microbial count in soil makes the co-inoculation practice quite beneficial for sustainable agriculture.

Isolation and Characterization of a Novel Laccase-Producing Bacteria Bhargavaea beijingensis from Paper and Pulp Effluent-Treated Soil Using In Silico Approaches.

Laccases (EC 1.10.3.2) are considered one of the most prominent multicopper enzymes that exhibit the inherent properties of oxidizing a range of phenolic substrates. Mostly, reported laccases have been isolated from the plants and fungi species, whereas bacterial laccases are yet to be explored. Bacterial laccases have numerous distinctive properties over fungal laccases, including stability at high temperatures and high pH. This study includes the isolation of bacteria through the soil sample collected from the paper and pulp industry; the highest laccase-producing bacteria was identified as Bhargavaea bejingensis, using 16S rRNA gene sequencing. The extracellular and intracellular activities after 24 h incubation were 1.41 U/mL and 4.95 U/mL, respectively. The laccase-encoding gene of the bacteria was sequenced; moreover, the in vitro translated protein was bioinformatically characterized and asserted that the laccase produced by the bacteria Bhargavaea bejingensis was structurally and sequentially homologous to the CotA protein of Bacillus subtilis. The enzyme laccase produced from B. bejingensis was classified as three-domain laccase with several copper-binding residues, where a few crucial copper-binding residues of the laccase enzyme were also predicted.

Serendipita indica chitinase protects rice from the blast and bakanae diseases.

Serendipita indica, a multifunctional and useful endophyte fungus, has been intensively investigated in promoting plant growth and resistance towards biotic and abiotic stress. Multiple chitinases from microorganisms or plants have been identified to have a high antifungal activity as a biological control. However, chitinase of S. indica still needs to be characterized. We functionally characterized a chitinase (SiChi) in S. indica. The result showed that the purified SiChi protein confers high chitinase activity; importantly, SiChi inhibits the conidial germination of Magnaporthe oryzae and Fusarium moniliforme. After the successful colonization of rice roots by S. indica, both the rice blast disease and bakanae disease were significantly reduced. Interestingly, the purified SiChi could promptly induce rice disease resistance towards M. oryzae and F. moniliforme pathogens when sprayed on rice leaves. Like S. indica, SiChi could upregulate rice pathogen-resistant proteins and defense enzymes. In conclusion, chitinase of S. indica has direct antifungal activity and indirect induced resistance activity, implying an efficient and economic strategy for rice disease control by applying S. indica and SiChi.

Stage-specific differential expression of zinc transporter SLC30A and SLC39A family proteins during prostate tumorigenesis.

Prostate cancer (PCa) initiation and progression uniquely modify the prostate milieu to aid unrestrained cell proliferation. One salient modification is the loss of the ability of prostate epithelial cells to accumulate high concentrations of zinc; however, molecular alterations associated with loss of zinc accumulating capability in malignant prostate cells remain poorly understood. Herein, we assessed the stage-specific expression of zinc transporters (ZNTs) belonging to the ZNT (SLC30A) and Zrt- and Irt-like protein (ZIP) (SLC39A) solute-carrier family in the prostate tissues of different genetically engineered mouse models (GEMM) of PCa (TMPRSS2-ERG.Ptenflox/flox , Hi-Myc+/- , and transgenic adenocarcinoma of mouse prostate), their age-matched wild-type controls, and 104 prostate core biopsies from human patients with different pathological lesions. Employing immunohistochemistry, differences in the levels of protein expression and spatial distribution of ZNT were evaluated as a function of the tumor stage. Results indicated that the expression of zinc importers (ZIP1, ZIP2, and ZIP3), which function to sequester zinc from circulation and prostatic fluid, was low to negligible in the membranes of the malignant prostate cells in both GEMM and human prostate tissues. Regarding zinc exporters (ZNT1, ZNT2, ZNT9, and ZNT10) that export excess zinc into the extracellular spaces or intracellular organelles, their expression was low in normal prostate glands of mice and humans; however, it was significantly upregulated in prostate adenocarcinoma lesions in GEMM and PCa patients. Together, our findings provide new insights into altered expression of ZNTs during the progression of PCa and indicate that changes in zinc homeostasis could possibly be an early-initiation event during prostate tumorigenesis and a likely prevention/intervention target.

Characterization of stage-specific tumor progression in TMPRSS2-ERG (fusion)-driven and non-fusion-driven prostate cancer in GEM models.

In the present study, we performed a comparative stage-specific pathological and molecular marker evaluation of TMPRSS2-ERG fusion and PTEN loss-driven (TMPRSS2-ERG. Ptenflox/flox ) versus non-fusion-driven prostate tumorigenesis (Hi-Myc) in mice. Anterior, ventral, and dorsolateral prostates were collected from mice at different ages (or time points post-Cre induction). Results indicated that growth and progression of prostatic intraepithelial lesions to adenocarcinoma stages occurred in both mice models albeit at different rates. In the TMPRSS2-ERG. Ptenflox/flox mice, the initiation of tumorigenesis was slow, but subsequent progression through different stages became increasingly faster. Adenocarcinoma stage was reached early on; however, no high-grade undifferentiated tumors were observed. Conversely, in the Hi-Myc+/- mice, tumorigenesis initiation was rapid; however, progression through different stages was relatively slower and it took a while to reach the more aggressive phenotype stage. Nevertheless, at the advanced stages in the Hi-Myc+/- mice, high-grade undifferentiated tumors were observed compared to the later stage tumors observed in the fusion-driven TMPRSS2-ERG. Ptenflox/flox mice. These results were corroborated by the stage specific-pattern in the molecular expression of proliferation markers (PCNA and c-Myc); androgen receptor (AR); fusion-resultant overexpression of ERG; Prostein (SLC45-A3); and angiogenesis marker (CD-31). Importantly, there was a significant increase in immune cell infiltrations, which increased with the stage of tumorigenesis, in the TMPRSS2-ERG fusion-positive tumors relative to fusion negative tumors. Together, these findings are both novel and highly significant in establishing a working preclinical model for evaluating the efficacy of interventions during different stages of tumorigenesis in TMPRSS2-ERG fusion-driven PCa.

Bioprospecting uncultivable microbial diversity in tannery effluent contaminated soil using shotgun sequencing and bio-reduction of chromium by indigenous chromate reductase genes.

The tannery industry generates a consequential threat to the environment by producing a large amount of potentially toxic metal-containing waste. Bioremediation has been a promising approach for treating potentially toxic metals, but the efficiency of remediation in microbes is one of the factors limiting their application in tanneries waste treatment. The motivation behind the present work was to explore the microbial diversity and chromate reductase genes present in the tannery effluent-contaminated soil using metagenomics approach. The use of shotgun sequencing enabled the identification of operational parameters that influence microbiome composition and their ability to reduce Chromium (Cr) concentration. The Cr concentration in Kanpur tannery effluent contaminated soil sample was 700 ppm which is many folds than the approved permissible limit by World Health Organisation (WHO) for Cr is 100 ppm. Metagenomic Deoxyribo Nucleic Acid (DNA) was extracted to explore taxonomic community structure, phylogenetic linkages, and functional profile. With a Guanine-Cytosine (GC) abundance of 54%, total of 45,163,604 high-quality filtered reads were obtained. Bacteria (83%), Archaebacteria (14%), and Viruses (3%) were discovered in the structural biodiversity. Bacteria were classified to phylum level, with Proteobacteria (52%) being the dominant population, followed by Bacteriodetes (15%), Chloroflexi (15%), Spirochaetes (7%), Thermotogae (5%), Actinobacteria (4%), and Firmicutes (1%). The OXR genes were cloned and checked for their efficiency to reduce Cr concentration. Insitu validation of OXR8 gene showed a reduction of Cr concentration from 700 ppm to 24 ppm in 72 h (96.51% reduction). The results of this study suggests that there is a huge reservoir of microbes and chromate reductase genes which are unexplored yet.

Exploring the Impact of Bioformulated Copper Oxide Nanoparticles on Cytomorphology of Alternaria brassicicola.

Black leaf spot of Brassica species is caused by a foliar pathogen Alternaria brassicicola (A. brassicicola), the noxious killer of mustard, cabbage, and cauliflower crops. The current investigation involved the synthesis of copper oxide nanoparticles (CuO NPs) from potential strain of Trichoderma harzianum (T. harzianum). Characterization of CuO NPs was performed by UV-vis, FTIR, XRD, SEM-EDX, and HR-TEM studies. UV-visible spectra showed an absorption peak at 275 nm. FTIR study revealed the presence of N-H bonds which could be due to the presence of enzymes and secondary metabolites released in the filtrate of T. harzianum. SEM and HR-TEM revealed the cube shape CuO NPs formed and average particle size was in the range of 31-45 nm. Poisoned food technique was used to check the antifungal efficacy of CuO NPs against A. brassicicola at various concentrations (0.025, 0.050, 0.1, and 0.15 mg/mL). In vitro assays carried on potato dextrose agar showed maximum antifungal activity at 0.15 mg/mL. The control sample have cylindrical and oblong shape conidia, while transverse septation was 2-4 in untreated population. The lower concentrations of CuO NPs (0.025 and 0.050 mg/mL) caused malformed spherical shape conidia with excessive septation, while its higher concentrations (0.1 and 0.15 mg/mL) leads to viability loss in fungal culture. Results indicated that a higher concentration of CuO NPs serve as an effective biocidal concentration for the control of phytopathogens.

Bioactive Microbial Metabolites in Cancer Therapeutics: Mining, Repurposing, and Their Molecular Targets.

The persistence and resurgence of cancer, characterized by abnormal cell growth and differentiation, continues to be a serious public health concern critically affecting public health, social life, and the global economy. Hundreds of putative drug molecules of synthetic and natural origin were approved for anticancer therapy in the last few decades. Although conventional anticancer treatment strategies have promising aspects, several factors such as their limitations, drug resistance, and side effects associated with them demand more effort in repositioning or developing novel therapeutic regimens. The rich heritage of microbial bioactive components remains instrumental in providing novel avenues for cancer therapeutics. Actinobacteria, Firmicutes, and fungi have a plethora of bioactive compounds, which received attention for their efficacy in cancer treatment targeting different pathways responsible for abnormal cell growth and differentiation. Yet the full potential remains underexplored to date, and novel compounds from such microbes are reported regularly. In addition, the advent of computational tools has further augmented the mining of microbial secondary metabolites and identifying their molecular targets in cancer cells. Furthermore, the drug-repurposing strategy has facilitated the use of approved drugs of microbial origin in regulating cancer cell growth and progression. The wide diversity of microbial compounds, different mining approaches, and multiple modes of action warrant further investigations on the current status of microbial metabolites in cancer therapeutics. Hence, in this review, we have critically discussed the untapped potential of microbial products in mitigating cancer progression. The review also summarizes the impact of drug repurposing in cancer therapy and discusses the novel avenues for future therapeutic drug development against cancer.

Immobilization-Based Bio-formulation of Aspergillus awamori S29 and Evaluation of Its Shelf Life and Re-usability in the Soil-Plant Experiment.

The present study was an attempt to evaluate the bio-formulations of phosphate-solubilizing fungus Aspergillus awamori S29 using two economically viable carriers (calcium alginate and agar) in repeated batch fermentation. Further, the viable cell count under storage and response of these stored bio-formulations on the growth of wheat plants were studied at the end of 2, 4, and 6 months of incubation. Also, the response of these formulations in next season on pearl millet (bajra) was studied without further inoculation. In repeated batch fermentation assay, immobilized form performed significantly better than free form. The viability of fungal inoculant was 88.2% in calcium alginate-based bio-formulation after six months of storage. These bio-formulations showed not only a statistically significant increase in the growth of wheat crop in first season but also of pearl millet in next season. This work strengthens the re-usability potential of immobilized bio-formulations for next season crop.

Plasma Microbiome in COVID-19 Subjects: An Indicator of Gut Barrier Defects and Dysbiosis.

The gut is a well-established route of infection and target for viral damage by SARS-CoV-2. This is supported by the clinical observation that about half of COVID-19 patients exhibit gastrointestinal (GI) complications. We aimed to investigate whether the analysis of plasma could provide insight into gut barrier dysfunction in patients with COVID-19 infection. Plasma samples of COVID-19 patients (n = 146) and healthy individuals (n = 47) were collected during hospitalization and routine visits. Plasma microbiome was analyzed using 16S rRNA sequencing and gut permeability markers including fatty acid binding protein 2 (FABP2), peptidoglycan (PGN), and lipopolysaccharide (LPS) in both patient cohorts. Plasma samples of both cohorts contained predominately Proteobacteria, Firmicutes, Bacteroides, and Actinobacteria. COVID-19 subjects exhibit significant dysbiosis (p = 0.001) of the plasma microbiome with increased abundance of Actinobacteria spp. (p = 0.0332), decreased abundance of Bacteroides spp. (p = 0.0003), and an increased Firmicutes:Bacteroidetes ratio (p = 0.0003) compared to healthy subjects. The concentration of the plasma gut permeability marker FABP2 (p = 0.0013) and the gut microbial antigens PGN (p < 0.0001) and LPS (p = 0.0049) were significantly elevated in COVID-19 patients compared to healthy subjects. These findings support the notion that the intestine may represent a source for bacteremia and contribute to worsening COVID-19 outcomes. Therapies targeting the gut and prevention of gut barrier defects may represent a strategy to improve outcomes in COVID-19 patients.

Bone Marrow-Derived Cells Restore Functional Integrity of the Gut Epithelial and Vascular Barriers in a Model of Diabetes and ACE2 Deficiency.

RATIONALE: There is incomplete knowledge of the impact of bone marrow cells on the gut microbiome and gut barrier function. OBJECTIVE: We postulated that diabetes mellitus and systemic ACE2 (angiotensin-converting enzyme 2) deficiency would synergize to adversely impact both the microbiome and gut barrier function. METHODS AND RESULTS: Bacterial 16S rRNA sequencing and metatranscriptomic analysis were performed on fecal samples from wild-type, ACE2-/y, Akita (type 1 diabetes mellitus), and ACE2-/y-Akita mice. Gut barrier integrity was assessed by immunofluorescence, and bone marrow cell extravasation into the small intestine was evaluated by flow cytometry. In the ACE2-/y-Akita or Akita mice, the disrupted barrier was associated with reduced levels of myeloid angiogenic cells, but no increase in inflammatory monocytes was observed within the gut parenchyma. Genomic and metatranscriptomic analysis of the microbiome of ACE2-/y-Akita mice demonstrated a marked increase in peptidoglycan-producing bacteria. When compared with control cohorts treated with saline, intraperitoneal administration of myeloid angiogenic cells significantly decreased the microbiome gene expression associated with peptidoglycan biosynthesis and restored epithelial and endothelial gut barrier integrity. Also indicative of diabetic gut barrier dysfunction, increased levels of peptidoglycan and FABP-2 (intestinal fatty acid-binding protein 2) were observed in plasma of human subjects with type 1 diabetes mellitus (n=21) and type 2 diabetes mellitus (n=23) compared with nondiabetic controls (n=23). Using human retinal endothelial cells, we determined that peptidoglycan activates a noncanonical TLR-2 (Toll-like receptor 2) associated MyD88 (myeloid differentiation primary response protein 88)-ARNO (ADP-ribosylation factor nucleotide-binding site opener)-ARF6 (ADP-ribosylation factor 6) signaling cascade, resulting in destabilization of p120-catenin and internalization of VE-cadherin as a mechanism of deleterious impact of peptidoglycan on the endothelium. CONCLUSIONS: We demonstrate for the first time that the defect in gut barrier function and dysbiosis in ACE2-/y-Akita mice can be favorably impacted by exogenous administration of myeloid angiogenic cells.

Microbial biotechnological approaches: renewable bioprocessing for the future energy systems.

The accelerating energy demands of the increasing global population and industrialization has become a matter of great concern all over the globe. In the present scenario, the world is witnessing a considerably huge energy crisis owing to the limited availability of conventional energy resources and rapid depletion of non-renewable fossil fuels. Therefore, there is a dire need to explore the alternative renewable fuels that can fulfil the energy requirements of the growing population and overcome the intimidating environmental issues like greenhouse gas emissions, global warming, air pollution etc. The use of microorganisms such as bacteria has captured significant interest in the recent era for the conversion of the chemical energy reserved in organic compounds into electrical energy. The versatility of the microorganisms to generate renewable energy fuels from multifarious biological and biomass substrates can abate these ominous concerns to a great extent. For instance, most of the microorganisms can easily transform the carbohydrates into alcohol. Establishing the microbial fuel technology as an alternative source for the generation of renewable energy sources can be a state of art technology owing to its reliability, high efficiency, cleanliness and production of minimally toxic or inclusively non-toxic byproducts. This review paper aims to highlight the key points and techniques used for the employment of bacteria to generate, biofuels and bioenergy, and their foremost benefits.