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Background: There has been an increasing trend for the development of natural formulations for plaque control using medicinal plants as an adjunct, which can be a feasible alternative as these are widely available, cost-effective, and have fewer side effects. Aim: The evaluation of the effects of medicinal plant extracts in chronic periodontitis (CP). Materials and Methods: This study was carried out in two phases; first the antibacterial activity of two medicinal plant extracts was tested on periodontal pathogens, thereafter, a clinical assessment was carried out on subjects with CP. Forty-five individuals suffering from CP were randomized into three different groups; Group A: Scaling and root planing (SRP) along with Piper longum rinse, Group B: SRP along with mixture of Tinospora cordifolia and P. longum rinse, Group C: SRP along with chlorhexidine (CHX) (control group). The clinical parameters (gingival index [GI], plaque index, gingival bleeding index [BI], probing pocket depth [PPD], and clinical attachment level [CAL]) were recorded at baseline and months 1 and 3. The intra- and intergroup comparison of clinical parameters for all groups at different time intervals was performed. Results: At the end of the trial, all the three groups showed a statistically significant reduction when compared to baseline for all the clinical parameters. In intergroup comparison, statistically significant reduction in GI, PPD, and CAL for both Group A and Group C was seen at 3 months as compared to Group B. Comparable reduction was seen between Group A and C for all the clinical parameters. Reduction in plaque and gingival BI was seen to be highest in Group A. Conclusion: P. longum can be effectively utilized as an additive to mechanical periodontal treatment in comparison to CHX mouthwash for CP patients.

Purpose: To highlight the importance of histopathological evaluation of a lid mass to prognosticate the disease. We report a case of ulcerative squamous cell papilloma with clinical features suggesting malignancy. Case report: A 65-year-old man presented with a rapidly enlarging mass in the left upper eyelid, with clinical features suggesting a squamous cell carcinoma. However, a repeat histopathological examination showed no malignant cells. The patient was diagnosed with squamous cell papilloma. He was followed-up for 30 months and no recurrence was observed. No such case has previously been reported in the literature. Conclusion: This report highlights the need for histopathological examination of all eyelid lesions to enable surgeons to prognosticate the disease.

The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.

The Third Pole (TP) is a high mountain region in the world, and is well-known for its pristine environment, but recent development activities in the region have degraded its air quality. Here, we investigate the spatial and temporal changes of the air pollutants ammonia (NH₃), sulphur dioxide (SO₂) and carbon monoxide (CO) in TP, and reveal their sources using satellite measurements and emission inventory. We observe a clear seasonal cycle of NH 3 in TP, with high values in summer and low values in winter. The intense agriculture activities in the southern TP are the cause of high NH₃ (6-8 × 10 16 molec./cm 2 ) there. Similarly, CO shows a distinct seasonal cycle with high values in spring in the southeast TP due to biomass burning. In addition, the eastern boundary of TP in the Sichuan and Qinghai provinces also show high values of CO (about 1.5 × 10 18  mol/cm 2 ), primarily owing to the industrial activities. There is no seasonal cycle found for SO₂ distribution in TP, but relatively high values (8-10 mg/m 2 ) are observed in its eastern boundary. The high-altitude pristine regions of inner TP are also getting polluted because of increased human activities in and around TP, as we estimate positive trends in CO (0.5-1.5 × 10 16  mol/cm 2 /yr) there. In addition, positive trends are also found in NH₃ (0.025 × 10 16 molec./cm 2 /yr) during 2008-2020 in most regions of TP and SO₂ (about 0.25-0.75 mg/m 2 /yr) in the Sichuan and Qinghai region during 2000-2020. As revealed by the emission inventory, there are high anthropogenic emissions of NH 3 , SO 2 and CO within TP. There are emissions of pollutants from energy sectors, oil and refinery, agriculture waste burning and manure management within TP. These anthropogenic activities accelerate the ongoing development in TP, but severely erode its environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Innate immunity provides the first line of defense through multiple mechanisms, including pyrogen production and cell death. While elevated body temperature during infection is beneficial to clear pathogens, heat stress (HS) can lead to inflammation and pathology. Links between pathogen exposure, HS, cytokine release, and inflammation have been observed, but fundamental innate immune mechanisms driving pathology during pathogen exposure and HS remain unclear. Here, we use multiple genetic approaches to elucidate innate immune pathways in infection or LPS and HS models. Our results show that bacteria and LPS robustly increase inflammatory cell death during HS that is dependent on caspase-1, caspase-11, caspase-8, and RIPK3 through the PANoptosis pathway. Caspase-7 also contributes to PANoptosis in this context. Furthermore, NINJ1 is an important executioner of this cell death to release inflammatory molecules, independent of other pore-forming executioner proteins, gasdermin D, gasdermin E, and MLKL. In an in vivo HS model, mortality is reduced by deleting NINJ1 and fully rescued by deleting key PANoptosis molecules. Our findings suggest that therapeutic strategies blocking NINJ1 or its upstream regulators to prevent PANoptosis may reduce the release of inflammatory mediators and benefit patients., (© 2024. The Author(s).)

The earth is warming, and the frequency of extreme weather events have been rapidly growing globally with unprecedented consequences to farming communities. In principle, weather and climate information services (WCIS) can help farmers better manage their activities and farm level outcomes by supporting their decision-making with relevant and usable information to address the potential impacts of expected changing climate conditions. But, in practice, can the availability and use of WCIS help improve agricultural outcomes given the weather and climate related uncertainties? To understand the use and impact of WCIS in the cotton-wheat cropping areas of Pakistan, we conducted a multistage stratified clustered random sample of 612 farm households in the provinces of Punjab and Sindh. Over 55% of the farm households in the sample indicated that they used WCIS provided by the Pakistan Meteorological Department and other sources for making their agricultural decisions. Our analysis, however, suggests that the impact of using WCIS on major farm outcomes (i.e. farm revenue, costs, profits, and input usage) is not statistically significant when compared with those farm households not using WCIS (null result). This result is robust to different estimation techniques (i.e. ordinary least squares, instrumental variable approach, and propensity score matching method). From the focus group discussions, we gathered that farmers perceived WCIS as less reliable, often unclear, and difficult to understand as this information is not translated and transmitted in local languages. Addressing these issues can help reduce the impact of climate and weather variability on farm outcomes in those provinces as well as in Pakistan more generally. Our study suggests that, under uncertainty, emphasis should be on WCIS that farmers can rely on for making farming related decisions., (© 2024. The Author(s).)

We analyse the long-term (1980-2020) changes in aerosols over the Third Pole (TP) and assess the changes in radiative forcing (RF) using satellite, ground-based and reanalysis data. The annual mean aerosol optical depth (AOD) varies from 0.06 to 0.24, with the highest values of around 0.2 in the north and southwest TP, which are dominated by dust from Taklimakan and Thar deserts, respectively. However, Organic Carbon (OC), Black Carbon (BC) and sulphate aerosols have significant contributions to the total AOD in the south and east TP. High amounts of dust are observed in spring and summer, but BC in winter. Trajectory analysis reveals that the air mass originated from East and South Asia carries BC and OC, whereas the air from South Asia, Central Asia and Middle East brings dust to TP. Significant positive trends in AOD is found in TP, with high values of about 0.002/yr in the eastern and southern TP. There is a gradual increase in BC and OC concentrations during 1980-2020, but the change from 2000 is phenomenal. The RF at the top of the atmosphere varies from -10 to 2 W/m 2 in TP, and high positive RF of about 2 W/m 2 is estimated in Pamir, Karakoram and Nyainquentanglha mountains, where the massive glacier mass exists. The RF has increased in much of TP during recent decades (2001-2020) with respect to previous decades (1981-2000), which can be due to the rise in BC and dust during the latter period. Therefore, the positive trend in BC and its associated change in RF can amplify the regional warming, and thus, the melting of glaciers or ice in TP. This is a great concern as it is directly connected to the water security of many South Asian countries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Influenza A virus (IAV) continues to pose a significant global health threat, causing severe respiratory infections that result in substantial annual morbidity and mortality. Recent research highlights the pivotal role of innate immunity, cell death, and inflammation in exacerbating the severity of respiratory viral diseases. One key molecule in this process is ZBP1, a well-recognized innate immune sensor for IAV infection. Upon activation, ZBP1 triggers the formation of a PANoptosome complex containing ASC, caspase-8, and RIPK3, among other molecules, leading to inflammatory cell death, PANoptosis, and NLRP3 inflammasome activation for the maturation of IL-1β and IL-18. However, the role for other molecules in this process requires further evaluation. In this study, we investigated the role of MLKL in regulating IAV-induced cell death and NLRP3 inflammasome activation. Our data indicate IAV induced inflammatory cell death through the ZBP1-PANoptosome, where caspases and RIPKs serve as core components. However, IAV-induced lytic cell death was only partially dependent on RIPK3 at later timepoints and was fully independent of MLKL throughout all timepoints tested. Additionally, NLRP3 inflammasome activation was unaffected in MLKL-deficient cells, establishing that MLKL and MLKL-dependent necroptosis do not act upstream of NLRP3 inflammasome activation, IL-1β maturation, and lytic cell death during IAV infection.

The innate immune system provides the first line of defense against pathogens and cellular insults and is activated by pattern recognition receptors sensing pathogen- or damage-associated molecular patterns. This activation can result in inflammation via cytokine release as well as the induction of lytic regulated cell death (RCD). Innate immune signaling can also induce the expression of interferon regulatory factor 1 (IRF1), an important molecule in regulating downstream inflammation and cell death. While IRF1 has been shown to modulate some RCD pathways, a comprehensive evaluation of its role in inflammatory cell death pathways is lacking. Here, we examined the role of IRF1 in cell death during inflammasome and PANoptosome activation using live cell imaging, Western blotting, and ELISA in primary murine macrophages. IRF1 contributed to the induction of ZBP1- (Z-DNA binding protein 1), AIM2- (absent in melanoma-2), RIPK1- (receptor interacting protein kinase 1), and NLRP12 (NOD-like receptor family, pyrin domain-containing 12)-PANoptosome activation and PANoptosis. Furthermore, IRF1 regulated the cell death under conditions where inflammasomes, along with caspase-8 and RIPK3, act as integral components of PANoptosomes to drive PANoptosis. However, it was dispensable for other inflammasomes that form independent of the PANoptosome to drive pyroptosis. Overall, these findings define IRF1 as an upstream regulator of PANoptosis and suggest that modulating the activation of molecules in the IRF1 pathway could be used as a strategy to treat inflammatory and infectious diseases associated with aberrant inflammatory cell death., Competing Interests: Conflict of interest T.-D. K. was a consultant for Pfizer. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the world. Inflammation is often an underlying risk factor for developing CRC. Maintaining gut homeostasis and balancing inflammation is therefore critical to prevent CRC development. One key class of molecular complexes that impact gut homeostasis are inflammasomes, cytosolic multiprotein immune complexes that assemble upon sensing various intracellular alterations. Inflammasomes regulate inflammation, cell death, cytokine release, signaling cascades, and other cellular processes. Roles for inflammasomes in colitis and colitis-associated CRC have been shown in multiple animal models. The activation of inflammasomes leads to the release of the bioactive forms of interleukin (IL)-1β and IL-18, the inflammasome effector cytokines. These cytokines ensure an optimal inflammatory immune response during colitis and colitis-associated CRC. The activation of some inflammasome sensors, including NLRP3, NLRP1, NLRP6, and Pyrin, provides protection from colitis-associated CRC via effector cytokine-dependent mechanisms. Additionally, activation of other inflammasome sensors, such as AIM2, NLRC4, and NAIPs, provides mostly effector cytokine-independent protection. Inflammasomes can also act as integral components of PANoptosomes, which are multifaceted complexes that integrate components from other cell death pathways and regulate a unique form of innate immune inflammatory cell death called PANoptosis. Furthermore, IRF1, a key regulator of some inflammasomes and PANoptosomes, has been implicated in CRC. It is therefore critical to consider the role of inflammasomes in effector cytokine-dependent and -independent protection as well as their role in PANoptosis to modulate CRC for therapeutic targeting. Here, we discuss the mechanisms of inflammasome activation, the functions of inflammasomes in CRC, and current obstacles and future perspectives in inflammasome and CRC research., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Interleukin 1α (IL-1α) and IL-1β are the founding members of the IL-1 cytokine family, and these innate immune inflammatory mediators are critically important in health and disease. Early studies on these molecules suggested that their expression was interdependent, with an initial genetic model of IL-1α depletion, the IL-1α KO mouse ( Il1a -KO line1 ), showing reduced IL-1β expression. However, studies using this line in models of infection and inflammation resulted in contrasting observations. To overcome the limitations of this genetic model, we have generated and characterized a new line of IL-1α KO mice ( Il1a -KO line2 ) using CRISPR-Cas9 technology. In contrast to cells from Il1a -KO line1 , where IL-1β expression was drastically reduced, bone marrow-derived macrophages (BMDMs) from Il1a -KO line2 mice showed normal induction and activation of IL-1β. Additionally, Il1a -KO line2 BMDMs showed normal inflammasome activation and IL-1β expression in response to multiple innate immune triggers, including both pathogen-associated molecular patterns and pathogens. Moreover, using Il1a -KO line2 cells, we confirmed that IL-1α, independent of IL-1β, is critical for the expression of the neutrophil chemoattractant KC/CXCL1. Overall, we report the generation of a new line of IL-1α KO mice and confirm functions for IL-1α independent of IL-1β. Future studies on the unique functions of IL-1α and IL-1β using these mice will be critical to identify new roles for these molecules in health and disease and develop therapeutic strategies., Competing Interests: T-DK is a consultant for Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Malireddi, Bynigeri, Kancharana, Sharma, Burton, Pelletier and Kanneganti.)

Resistance to programmed cell death (PCD) is a hallmark of cancer. While some PCD components are prognostic in cancer, the roles of many molecules can be masked by redundancies and crosstalks between PCD pathways, impeding the development of targeted therapeutics. Recent studies characterizing these redundancies have identified PANoptosis, a unique innate immune-mediated inflammatory PCD pathway that integrates components from other PCD pathways. Here, we designed a systematic computational framework to determine the pancancer clinical significance of PANoptosis and identify targetable biomarkers. We found that high expression of PANoptosis genes was detrimental in low grade glioma (LGG) and kidney renal cell carcinoma (KIRC). ZBP1, ADAR, CASP2, CASP3, CASP4, CASP8 and GSDMD expression consistently had negative effects on prognosis in LGG across multiple survival models, while AIM2, CASP3, CASP4 and TNFRSF10 expression had negative effects for KIRC. Conversely, high expression of PANoptosis genes was beneficial in skin cutaneous melanoma (SKCM), with ZBP1, NLRP1, CASP8 and GSDMD expression consistently having positive prognostic effects. As a therapeutic proof-of-concept, we treated melanoma cells with combination therapy that activates ZBP1 and showed that this treatment induced PANoptosis. Overall, through our systematic framework, we identified and validated key innate immune biomarkers from PANoptosis which can be targeted to improve patient outcomes in cancers., (© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Cancer.)

Type I interferons (IFNs) are essential innate immune proteins that maintain tissue homeostasis through tonic expression and can be upregulated to drive antiviral resistance and inflammation upon stimulation. However, the mechanisms that inhibit aberrant IFN upregulation in homeostasis and the impacts of tonic IFN production on health and disease remain enigmatic. Here, we report that caspase-8 negatively regulates type I IFN production by inhibiting the RIPK1-TBK1 axis during homeostasis across multiple cell types and tissues. When caspase-8 is deleted or inhibited, RIPK1 interacts with TBK1 to drive elevated IFN production, leading to heightened resistance to norovirus infection in macrophages but also early onset lymphadenopathy in mice. Combined deletion of caspase-8 and RIPK1 reduces the type I IFN signaling and lymphadenopathy, highlighting the critical role of RIPK1 in this process. Overall, our study identifies a mechanism to constrain tonic type I IFN during homeostasis which could be targeted for infectious and inflammatory diseases., Competing Interests: Declaration of interests T.-D.K. is a consultant for Pfizer., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), continues to cause substantial morbidity and mortality in the ongoing global pandemic. Understanding the fundamental mechanisms that govern innate immune and inflammatory responses during SARS-CoV-2 infection is critical for developing effective therapeutic strategies. Whereas interferon (IFN)-based therapies are generally expected to be beneficial during viral infection, clinical trials in COVID-19 have shown limited efficacy and potential detrimental effects of IFN treatment during SARS-CoV-2 infection. However, the underlying mechanisms responsible for this failure remain unknown. In this study, we found that IFN induced Z-DNA-binding protein 1 (ZBP1)-mediated inflammatory cell death, PANoptosis, in human and murine macrophages and in the lungs of mice infected with β-coronaviruses, including SARS-CoV-2 and mouse hepatitis virus (MHV). In patients with COVID-19, expression of the innate immune sensor ZBP1 was increased in immune cells from those who succumbed to the disease compared with those who recovered, further suggesting a link between ZBP1 and pathology. In mice, IFN-β treatment after β-coronavirus infection increased lethality, and genetic deletion of Zbp1 or its Zα domain suppressed cell death and protected the mice from IFN-mediated lethality during β-coronavirus infection. Overall, our results identify that ZBP1 induced during coronavirus infection limits the efficacy of IFN therapy by driving inflammatory cell death and lethality. Therefore, inhibiting ZBP1 activity may improve the efficacy of IFN therapy, paving the way for the development of new and critically needed therapeutics for COVID-19 as well as other infections and inflammatory conditions where IFN-mediated cell death and pathology occur.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia and insulin resistance. Gut microbiota (GM) are specific groups of microbes colonized in the gastrointestinal (GI) tract. They profoundly influence health, disease protection, and associated with metabolic activities, and play a vital role in the production of functional metabolites from dietary substances. Dysbiosis of GM has been linked to the onset of T2DM and can be altered to attain eubiosis by intervention with various nutritional bioactive compounds such as polyphenols, prebiotics, and probiotics. This review presents an overview of the evidence and underlying mechanisms by which bioactive compounds modulate the GM for the prevention and management of T2DM., (Copyright © 2022. Published by Elsevier Masson SAS.)

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, and innate immune responses and inflammation are known to affect the course of disease. Interferon (IFN) signaling in particular is critical for modulating inflammation-associated diseases including CRC. While the effects of IFN signaling in CRC have been studied, results have been conflicting. Furthermore, individual molecules in the IFN pathway that could be therapeutically targeted have distinct functions, with many of their diverse roles in CRC remaining unclear. Here, we found that IRF9 had an oncogenic effect in CRC; loss of IRF9 reduced tumorigenesis in both azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced and spontaneous CRC models. IRF9 also reduced DSS-induced colitis and inflammation in the colon, but it had no effect on the NF-κB and MAPK signaling activation. Instead, IRF9 enhanced the transcription and production of the inflammatory cytokine IL-6. By promoting IL-6 release, IRF9 drove the activation of pro-oncogenic STAT3 signaling in the colon. Overall, our study found that IRF9 promoted the development of CRC via modulation of the IL-6/STAT3 signaling axis, identifying multiple potential targets and suggesting new therapeutic strategies for the treatment of CRC.

We report here two genome-wide CRISPR screens performed to identify genes that, when knocked out, alter levels of lysosomal cholesterol or bis(monoacylglycero)phosphate. In addition, these screens were also performed under conditions of NPC1 inhibition to identify modifiers of NPC1 function in lysosomal cholesterol export. The screens confirm tight coregulation of cholesterol and bis(monoacylglycero)phosphate in cells and reveal an unexpected role for the ER-localized SNX13 protein as a negative regulator of lysosomal cholesterol export and contributor to ER-lysosome membrane contact sites. In the absence of NPC1 function, SNX13 knockdown redistributes lysosomal cholesterol and is accompanied by triacylglycerol-rich lipid droplet accumulation and increased lysosomal bis(monoacylglycero)phosphate. These experiments provide unexpected insight into the regulation of lysosomal lipids and modification of these processes by novel gene products., (© 2021 Lu et al.)

Ethnic fermented foods are known for their unique aroma, flavour, taste, texture and other sensory properties preferred by every ethnic community in this world culturally as parts of their eatables. Some beneficial microorganisms associated with fermented foods have several functional properties and health-promoting benefits. Bacteriocins are the secondary metabolites produced by the microorganisms mostly lactic acid bacteria present in the fermented foods which can act as lantibiotics against the pathogen bacteria. Several studies have been conducted regarding the isolation and characterization of potent strains as well as their association with different types of bacteriocins. Collective information regarding the gene organizations responsible for the potent effect of bacteriocins as lantibiotics, mode of action on pathogen bacterial cells is not yet available. This review focuses on the gene organizations, pathways include for bacteriocin and their mode of action for various classes of bacteriocins produced by lactic acid bacteria in some ethnic fermented foods., Competing Interests: Conflict of interestThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© The Korean Society of Food Science and Technology 2021.)

Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. Z-DNA binding protein 1 (ZBP1) activates inflammatory cell death, PANoptosis, whereas adenosine deaminase acting on RNA 1 (ADAR1) serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1's interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining interferons (IFNs) and nuclear export inhibitors (NEIs) activates ZBP1-dependent PANoptosis. ADAR1 suppresses this PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1 fl/fl LysM cre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wild-type mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1-dependent manner. Our findings suggest that ADAR1 suppresses ZBP1-mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to informing therapeutic strategies for cancer and other diseases., Competing Interests: Declaration of interests St. Jude Children’s Research hospital filed a provisional patent application on the IFN and NEI treatment strategy described in this study, listing R.K. and T.-D.K. as inventors (serial no. 63/196,986)., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

An attempt was made, to characterize natural antibiotics or lantibiotics from unconventional sources and its antibacterial spectrum against food borne pathogens and drug resistant bacteria. Six different traditional fermented foods i.e., fermented fish, fermented soybeans, Soibum (fermented bamboo shoots), milk, idly and dosa batter were used for the isolation of bacteriocin producing Lactic acid bacteria (LAB). Among all bacterial cultures isolated from the various sources, 129 cultures have found to produce antimicrobial compounds. Nisin specific reporter bacteria was utilized as biosensor to identify the Nisin like bacteriocin, where 10 cultures found to be positive Nisin producer. Identified Nisin like bacteriocin was partially concentrated by using ammonium sulphate followed by butanol extraction. Minimum inhibitory concentration (MIC) was analyzed against food borne pathogen and drug resistant bacteria. MIC of partially purified Nisin (pp-Nisin) of all the LAB isolates against food-borne pathogens are ranged between 0.5 and 92 µg/ml respected to various Gram-positive bacteria. Similarly, the drug resistant bacteria were also inhibited by pp-Nisin (MIC ranged between 15 and 175 µg/ml). All samples of ppnisin exhibited auto induction ability. Taxonomic identification of the nisin producers was done by whole genome sequencing which reveals that cultures belongs to Lactococcus lactis ssp. lactis. Also it was found that Lactococcus lactis ssp. lactis C2d and Lactococcus lactis ssp. lactis SP2C4 harbor nisA gene and Lactococcus lactis ssp. lactis FS2 (L. lactis FS2) harbor nisQ gene. The finding of this study highlights the first case of L. lactis FS2 isolated from fermented fish harbor nisQ gene. Antibacterial activity of pp-Nisin against drug resistant LAB is also reported., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The NLRP3 inflammasome is a multimeric cytosolic protein complex that assembles in response to cellular perturbations. This assembly leads to the activation of caspase-1, which promotes maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18, as well as inflammatory cell death (pyroptosis). The inflammatory cytokines contribute to the development of systemic low-grade inflammation, and aberrant NLRP3 activation can drive a chronic inflammatory state in the body to modulate the pathogenesis of inflammation-associated diseases. Therefore, targeting NLRP3 or other signaling molecules downstream, such as caspase-1, IL-1β or IL-18, has the potential for great therapeutic benefit. However, NLRP3 inflammasome-mediated inflammatory cytokines play dual roles in mediating human disease. While they are detrimental in the pathogenesis of inflammatory and metabolic diseases, they have a beneficial role in numerous infectious diseases and some cancers. Therefore, fine tuning of NLRP3 inflammasome activity is essential for maintaining proper cellular homeostasis and health. In this Review, we will cover the mechanisms of NLRP3 inflammasome activation and its divergent roles in the pathogenesis of inflammation-associated diseases such as cancer, atherosclerosis, diabetes and obesity, highlighting the therapeutic potential of targeting this pathway.

COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by inflammatory cell death, PANoptosis. Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation., Competing Interests: Declaration of Interests St. Jude Children’s Research hospital filed a provisional patent application on TNF-α and IFN-γ signaling described in this study, listing R.K. and T.-D.K. as inventors (serial no. 63/106,012)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Viruses and hosts have coevolved for millions of years, leading to the development of complex host-pathogen interactions. Influenza A virus (IAV) causes severe pulmonary pathology and is a recurrent threat to human health. Innate immune sensing of IAV triggers a complex chain of host responses. IAV has adapted to evade host defense mechanisms, and the host has coevolved to counteract these evasion strategies. However, the molecular mechanisms governing the balance between host defense and viral immune evasion is poorly understood. Here, we show that the host protein DEAD-box helicase 3 X-linked (DDX3X) is critical to orchestrate a multifaceted antiviral innate response during IAV infection, coordinating the activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, assembly of stress granules, and type I interferon (IFN) responses. DDX3X activated the NLRP3 inflammasome in response to WT IAV, which carries the immune evasive nonstructural protein 1 (NS1). However, in the absence of NS1, DDX3X promoted the formation of stress granules that facilitated efficient activation of type I IFN signaling. Moreover, induction of DDX3X-containing stress granules by external stimuli after IAV infection led to increased type I IFN signaling, suggesting that NS1 actively inhibits stress granule-mediated host responses and DDX3X-mediated NLRP3 activation counteracts this action. Furthermore, the loss of DDX3X expression in myeloid cells caused severe pulmonary pathogenesis and morbidity in IAV-infected mice. Together, our findings show that DDX3X orchestrates alternate modes of innate host defense which are critical to fight against NS1-mediated immune evasion strategies during IAV infection., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)