Significance: Although it has long been known that inflammatory immune responses are associated with death of cells through necrosis, the mechanisms controlling this process are not yet well understood. Recently a type of programmed inflammatory cell death, necroptosis, has been discovered. In this paper we reveal previously unidentified molecular mechanisms that operate to induce this form of cell death. Our results indicate that in order to undergo necroptosis, immune cells must produce and receive signals from the key immune regulator, interferon. Such interferon-dependent necroptosis of immune cells drives acute inflammatory pathology in a mouse model of sepsis. This work highlights the intimate connection between cell death and inflammation, and may lead to new understanding and treatment of inflammatory pathologies.

Checkpoint proteins are an integral part of the immune system and are used by the tumor cells to evade immune response, which helps them grow uncontrollably. By blocking these proteins, immune checkpoint inhibitors can restore the capability of the immune system to attack cancer cells and stop their growth. These findings are backed by adequate clinical trial data and presently, several FDA-approved immune checkpoint inhibitors exist in the market for treating various types of cancers, including melanoma, hepatocellular, endometrial, lung, kidney and others. Their mode of action is inhibition by targeting the checkpoint proteins CTLA-4, PD-1, PD-L1, etc. They can be used alone as well as in amalgamation with other cancer treatments, like surgery, radiation or chemotherapy. Since these drugs target only specific immune system proteins, their side effects are reduced in comparison with the traditional chemotherapy drugs, but may still cause a few affects like fatigue, skin rashes, and fever. In rare cases, these inhibitors are known to have caused more serious side effects, such as cardiotoxicity, and inflammation in the intestines or lungs. Herein, we provide an overview of these inhibitors and their role as biomarkers, immune-related adverse outcomes and clinical studies in the treatment of various cancers, as well as present some future perspectives.

For the last few years, the world has been going through a difficult time, and the reason behind this is severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), one of the significant members of the Coronaviridae family. The major research groups have shifted their focus towards finding a vaccine and drugs against SARS-CoV-2 to reduce the infection rate and save the life of human beings. Even the WHO has permitted using certain vaccines for an emergency attempt to cut the infection curve down. However, the virus has a great sense of mutation, and the vaccine’s effectiveness remains questionable. No natural medicine is available at the community level to cure the patients for now. In this study, we have screened the vast library of experimental drugs of Drug Bank with Schrodinger’s maestro by using three algorithms: high-throughput virtual screening (HTVS), standard precision, and extra precise docking followed by Molecular Mechanics/Generalized Born Surface Area (MMGBSA). We have identified 3-(7-diaminomethyl-naphthalen-2-YL)-propionic acid ethyl ester and Thymidine-5′-thiophosphate as potent inhibitors against the SARS-CoV-2, and both drugs performed impeccably and showed stability during the 100 ns molecular dynamics simulation. Both of the drugs are among the category of small molecules and have an acceptable range of ADME properties. They can be used after their validation in in-vitro and in-vivo conditions.

Increasing rates of serious multi-drug resistant (MDR) Pseudomonas aeruginosa infections have been reported globally, including in Saudi Arabia. This retrospective study investigates the epidemiological, microbiological, and clinical characteristics of multi-resistant P. aeruginosa (n3579 clinical isolates) in King Fahad Medical City, Riyadh, Saudi Arabia (2019–2021). Information on antimicrobial susceptibility and medical history was collected from the hospital database. P. aeruginosa infections occurred in 55.6% of males and 44.4% of females, and P. aeruginosa was more prevalent in children than in adults. Our analysis showed that P. aeruginosa had the highest sensitivity to amikacin (92.6%) and greatest resistance to aztreonam (29.8%), imipenem (29.5%), ceftazidime (26.1%), meropenem (25.6%), and cefepime (24.3%). MDR and extensively drug resistant (XDR) strains were more prevalent in male than female patients. Female patients showed higher rates of infection with pan-drug resistant (PDR) strains. Respiratory samples contained the majority of resistant isolates. Septic shock and liver disease were strongly correlated with mortality in the ICU patient group after analysing the relative risk associated with mortality. Our study emphasises the threat of multi-resistant P. aeruginosa in Saudi Arabia (and potentially the Middle East) and highlights important sources and contexts of infection that inhibit its effective control and clinical management.

Asthma is a significant health-care burden that has great impact on the quality of life of patients and their families. The limited amount of previously reported data and complicated pathophysiology of asthma make it a difficult to treat and significant economic burden on public healthcare systems. Ferula asafoetida is an herbaceous, monoecious, perennial plant of the Umbelliferae family. In Asia, F. asafoetida is used to treat a range of diseases and disorders, including asthma. Several in vitro studies demonstrated the therapeutic efficacy of F. asafoetida against asthma. Nevertheless, the precise molecular mechanism is yet to be discovered. In the framework of current study, network pharmacology approach was used to identify the bioactive compounds of F. asafoetida in order to better understand its molecular mechanism for the treatment of asthma. In present work, we explored a compound-target-pathway network and discovered that assafoetidin, cynaroside, farnesiferol-B, farnesiferol-C, galbanic-acid, and luteolin significantly influenced the development of asthma by targeting MAPK3, AKT1 and TNF genes. Later, docking analysis revealed that active constituents of F. asafoetida bind stably with three target proteins and function as asthma repressor by regulating the expression of MAPK3, AKT1 and TNF genes. Thus, integration of network pharmacology with molecular docking revealed that F. asafoetida prevent asthma by modulating asthma-related signaling pathways. This study lays the basis for establishing the efficacy of multi-component, multi-target compound formulae, as well as investigating new therapeutic targets for asthma.