Current Pharmaceutical Design - Online First

Sepsis, like neutropenic sepsis, is a medical condition in which our body overreacts to infectious agents. It is associated with damage to normal tissues and organs by the immune system, which leads to the spread of inflammation throughout our body. Of note, microRNAs (miRNAs) have been found to have a critical role in the sepsis progression. Such miRNAs are registered in the miRNA databases, such as Gene Expression Omnibus (GEO), with a specific identifier and unique characteristics. There is also computational software, such as TargetScan, that are broadly employed for the analysis of miRNAs, including their identification, target prediction, and functional analysis.

The current in-silico study aimed to predict miRNAs involved in sepsis progression. To this end, the GEO database was employed to find the sepsis-related genome profile. Afterward, down-regulated genes were selected for further bioinformatics analysis with the assumption that their decreased expression is associated with an increased sepsis progression. The miRNAs complementary to the selected genes were then predicted using TargetScan software. Based on the current in-silico analysis, seven miRNAs, including hsa-miR-325-3p, hsa-miR-146a-3p, hsa-miR-126-5p, hsa-miR-22-3p, hsa-miR-223-3p, hsa-miR-145-5p, and has-miR-181 family, were predicted to participate in sepsis pathogenesis. Among the predicted miRNAs, hsa-miR-325-3p has not been previously predicted or validated to be involved in septic conditions.

Our prediction results showed that hsa-miR-325-3p may target genes implicating in both anti-(ETFB gene) and pro-inflammatory (TCEA1 and PTPN1 genes) responses, suggesting it is an immune hemostasis regulator during sepsis inflammation. Although the role of other predicted miRNAs has been already validated in the sepsis pathogenesis, the current study predicted new targets of these miRNAs, which have not been reported by previous in-silico or experimental studies on sepsis and other pathogenic conditions. Notably, other miRNAs, including hsa-miR-146a-3p, hsa-miR-126-5p, hsa-miR-22-3p, hsa-miR-223-3p, and hsa-miR-145-5p were predicted to target genes participating in inflammatory responses, including BLOC1S1, POLR2G, PTPN1, TCEA1, and CCT3.

In conclusion, the results of the present study can provide promising targets as therapeutic and diagnostic tools to treat and manage inflammation sepsis, such as neutropenic sepsis. However, these findings should be further evaluated in experimental studies to find their exact effects and underlying mechanisms.

Psychosis, marked by detachment from reality, includes symptoms like hallucinations and delusions. Traditional herbal remedies like kratom are gaining attention for psychiatric conditions. This was aimed at comprehending the molecular mechanisms of Kratom's antipsychotic effects utilizing a multi-modal computational approach.

This study employed network pharmacology followed by molecular docking and molecular dynamics simulation study to investigate the potential antipsychotic properties of kratom compounds by identifying their key molecular targets and interactions.

Compounds present in kratom interact with a variety of receptors and proteins that play a pivotal role in neurotransmission, neurodevelopment, and cellular signaling. These interactions, particularly with dopamine and serotonin receptors, various proteins, and pathways, suggest a complex influence on psychiatric conditions. Both mitragynine and zotepine (an atypical antipsychotic drug) display significant binding affinities for 5HTR2A receptors, suggesting their potential for modulating related physiological pathways. Mitragynine displayed higher flexibility in binding compared to zotepine, which showed a more stable interaction. Hydrogen bond analysis revealed a more variable interaction profile for mitragynine than zotepine.

The research findings suggest that the interaction between kratom compounds and essential brain receptors could influence psychiatric conditions. Notably, both mitragynine (a key kratom component) and zotepine (an antipsychotic) bind to the 5HTR2A receptor, suggesting the potential for kratom to modulate similar pathways. Interestingly, mitragynine's flexible binding mode compared to zotepine might indicate a more diverse range of effects. Overall, the findings suggest complex interactions between kratom and the brain's signaling system, warranting further investigation into its potential therapeutic effects.

Non-Small-Cell Lung Cancer (NSCLC) represents the leading cause of cancer deaths in the world. We previously found that daidzein, one of the key bioactivators in soy isoflavone, can inhibit NSCLC cell proliferation and migration, while the molecular mechanisms of daidzein in NSCLC remain unclear.

We developed an NSCLC nude mouse model using H1299 cells and treated the mice with daidzein (30 mg/kg/day). Mass spectrometry analysis of tumor tissues from daidzein-treated mice identified 601 differentially expressed proteins (DEPs) compared to the vehicle-treated group. Gene enrichment analysis revealed that these DEPs were primarily associated with immune regulatory functions, including B cell receptor and chemokine pathways, as well as natural killer cell-mediated cytotoxicity. Notably, the NOD-like receptor signaling pathway, which is closely linked to pyroptosis, was significantly enriched.

Further analysis of key pyroptosis-related molecules, such as ASC, CASP1, GSDMD, and IL-1β, revealed differential expression in NSCLC versus normal tissues. High levels of ASC and CASP1 were associated with a favorable prognosis in NSCLC, suggesting that they may be critical effectors of daidzein's action. In NSCLC-bearing mice treated with daidzein, RT-qPCR and Western blot analyses showed elevated mRNA and protein levels of ASC, CASP1, and IL-1β but not GSDMD, which was consistent with the proteomic data.

In summary, this study demonstrated that daidzein inhibits NSCLC growth by inducing pyroptosis. Key pathway modulators ASC, CASP1, and IL-1β were identified as primary targets of daidzein. These findings offer insights into the molecular mechanisms underlying the anti-NSCLC effects of daidzein and could offer dietary recommendations for managing NSCLC.

The COVID-19 pandemic has spurred significant endeavors to devise treatments to combat SARS-CoV-2. A limited array of small-molecule antiviral drugs, specifically monoclonal antibodies and interferon therapy, have been sanctioned to treat COVID-19. These treatments typically necessitate administration within ten days of symptom onset. There have been reported reductions in the effectiveness of these medications due to mutations in non-structural protein genes, particularly against Omicron subvariants. This underscores the pressing requirement for healthcare systems to continually monitor pathogen variability and its impact on the efficacy of prevention and treatments.

This review aimed to comprehend the therapeutic benefits and recent progress of nMAbs for preventing and treating the Omicron variant of SARS-CoV-2.

Neutralizing monoclonal antibodies (nMAbs) provide a treatment avenue for severely affected individuals, especially those at high risk for whom vaccination is not viable. With their specific epitope affinity, they pose no significant risk of severe adverse effects. The degree of reduction in neutralization varies significantly across different monoclonal antibodies and variant combinations. For instance, Sotrovimab maintained its neutralization effectiveness against Omicron BA.1, but exhibited diminished efficacy against BA.2, BA.4, BA.5, and BA.2.12.1.

Bebtelovimab has been observed to preserve its efficacy against all subtypes of the Omicron variant. Subsequently, WKS13, mAb-39, 19n01, F61-d2 cocktail, etc., have become effective. This review has highlighted the therapeutic implications of nMAbs in SARS-CoV-2 Omicron treatment and the progress of COVID-19 drug discovery.