Current Pharmaceutical Design - Volume 28, Issue 27, 2022

The toll-like receptor (TLR) signaling pathway plays a key role in inducing immune responses and is shown to be expressed in immune cells and tumor cells and is involved in the progression of several malignancies, including breast cancer. These findings provide proof of the concept of targeting this pathway as a potential therapeutic option in the treatment of breast cancer. Moreover, there is a growing body of data showing the activation of TLRs in the tumor microenvironment and its dual function as anti-tumoral (dendritic T and natural killer cells activation) or pro-tumoral activity (cell proliferation, and drug resistance). Several agents have been developed for targeting this pathway, and one of these inhibitors, called Bacillus Calmette-Guerin (an agonist of TLR2 and TLR4), is recently being approved by FDA for immunotherapy of bladder cancer. This review summarizes the current knowledge of the mechanisms of action of TLR pathways in the development/progression of cancer for better management of this disease.

COVID-19, a dreaded and highly contagious pandemic, is flagrantly known for its rapid prevalence across the world. Till date, none of the treatments are distinctly accessible for this life-threatening disease. Under the prevailing conditions of a medical emergency, one creative strategy for the identification of novel and potential antiviral agents gaining momentum in research institutions and progressively being leveraged by pharmaceutical companies is target-based drug repositioning/repurposing. Continuous monitoring and recording of results offer anticipation that this strategy may help to reveal new medications for viral infections. This review recapitulates the neoteric illation of COVID-19, its genomic dispensation, molecular evolution via phylogenetic assessment, drug targets, the most frequently worldwide used repurposed drugs and their therapeutic applications, and a recent update on vaccine management strategies. The available data from solidarity trials exposed that the treatment with several known drugs, viz. lopinavir-ritonavir, chloroquine, hydroxychloroquine, etc. had displayed various antagonistic effects along with no impactful result in the diminution of mortality rate. The drugs, like remdesivir, favipiravir, and ribavirin, have proved to be quite safer therapeutic options for treatment against COVID-19. Similarly, dexamethasone, convalescent plasma therapy and oral administration of 2DG are expected to reduce the mortality rate of COVID-19 patients.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a serious clinical common disease caused by various pathological factors and can induce serious complications. There is still no specific and effective method for the treatment of ALI/ARDS. Mesenchymal stem cells (MSCs) have been one of the treatment methods for ALI, which can regulate related signal pathways such as PI3K/AKT, Wnt, and NF-ΚB to reduce inflammation. MSCs exist in various tissues and can self-renewal and differentiation, which can be activated by specific substances or environments and home to the site of tissue damage, where they differentiate into new tissue cells and repair the damage. Both exosomes and cytokines involving the paracrine mechanism of MSCs have benefits in treating ALI. Lung organoids produced by 3D culture technology can simulate the lung's characteristics and help research the pathophysiological process of ALI. This review summarizes the mechanisms by which MSCs treat ALI/ARDS and expects to use 3D models for future challenges in this field.

Background: Concurrent disorder or dual diagnosis refers to a combination of substance use disorders and mental disorders that occur in the same patient simultaneously. These conditions pose significant clinical and healthcare impacts and are often underdiagnosed, undertreated, and complex to manage. Objective: We assessed the quality of current pharmacological recommendations for the management of dual diagnosis, particularly by evaluating the use of second-generation antipsychotics (SGA). Methods: A literature search was performed using the PubMed and Scopus databases for publications up to September 21, 2021, without any time restrictions. The following search strings were used: (aripiprazole OR brexpiprazole OR cariprazine OR paliperidone OR risperidone OR quetiapine OR clozapine OR olanzapine) AND (psychosis OR schizophrenia OR schizoaffective) AND (“substance use disorder” OR cocaine OR alcohol OR cannabis OR heroin OR “double diagnosis” OR “dual diagnosis”)) NOT (animal OR rat OR mouse) NOT (review or meta-analysis). Results: The search produced a final set of 41 articles. Most patients were males and were affected by schizophrenia, with cannabis the most abused substance, followed by alcohol. Aripiprazole was the most used drug, either orally or by long-acting formulations, followed by risperidone with oral and long-acting formulations, clozapine, olanzapine, and quetiapine. Conclusion: The findings highlight the use of SGA for the treatment of psychotic symptoms in comorbidity with substance use. Future studies on people with dual diagnosis and focused on long-term evaluations are warranted and need to investigate the efficacy of newly introduced molecules, such as partial D2 agonists and longacting injectable antipsychotics.

Background: Pentraxin 3 (PTX3), a soluble pattern recognition molecule, not only acts as a promising indicator reflecting the disease activity of rheumatoid arthritis (RA) patients but exerts essential pathogenic roles in the progression of RA and serves as a potential therapeutic target for RA patients. Our study intends to systematically evaluate the circulating PTX3 levels and their potential influencing factors in RA patients. Methods: Articles regarding the circulating PTX3 levels of RA patients were identified in Pubmed, Embase, China National Knowledge Infrastructure (CNKI), and Cochrane databases. Standardized mean difference (SMD) and corresponding 95% confidence intervals (95% CI) were calculated and further illustrated by the forest plot. Egger’s regression test and sensitivity analysis were conducted to assess the publication bias and stability of the results, respectively. Results: Twenty articles with 21 individual studies were recruited in our meta-analysis. The overall results revealed that compared to healthy controls, RA patients had significantly higher circulating PTX3 levels (pooled SMD = 0.97, 95% CI: 0.48 to 1.45). Subgroup analyses further demonstrated that compared to healthy controls, RA patients of age ≤ 50 years, 2.6 < disease activity score in 28 joints (DAS28) ≤ 3.2, 3.2 < DAS28 ≤ 5.1, DAS28 > 5.1, C-reactive protein (CRP) levels > 10 mg/L, erythrocyte sedimentation rate (ESR) > 20 mm/h, and disease duration > 5 years had significantly higher circulating PTX3 levels, respectively; whereas RA patients of age > 50 years, DAS28 ≤ 2.6, CRP levels ≤ 10 mg/L, ESR ≤ 20 mm/h and disease duration ≤ 5 years had no significantly altered circulating PTX3 levels, respectively. Additionally, no matter whether the patients were of Caucasian ethnicity or not, circulating PTX3 levels were significantly increased in RA patients. Conclusion: Compared to healthy controls, circulating PTX3 levels are significantly increased in RA patients, which are influenced by age, disease activity, CRP levels, ESR, and disease duration.

Background: N6-methyladenosine (m6A) modification is widespread in eukaryotic mRNA, regulated by m6A demethylase, AlkB homolog 5 (ALKBH5). However, the role of m6A in systemic lupus erythematosus (SLE) is still obscure. We explored ALKBH5 expression in SLE patients and its effects on T cells. Methods: 100 SLE patients and 110 healthy controls were recruited to investigate the expression of ALKBH5 in peripheral blood mononuclear cells (PBMCs). An additional 32 SLE patients and 32 health controls were enrolled to explore the expression of ALKBH5 in T cells. Then we explored the function of ALKBH5 in T cells by lentivirus. Results: The expressions of ALKBH5 were downregulated in both PBMCs and T cells in SLE patients (all P<0.05). In PBMCs: ALKBH5 mRNA levels were associated with a complement C4 level in plasma (P<0.05). In T cells: ALKBH5 mRNA levels were downregulated in SLE patients with low complement levels, high antidsDNA, anti-Sm, anti-RNP, and proteinuria compared with those without, respectively (all P<0.05); ALKBH5 mRNA levels were negatively related with SLE disease activity index score, erythrocyte sedimentation rate, and anti-dsDNA levels (all P<0.05), and positively correlated with complement C3 and C4 level (all P<0.05). Functionally, the overexpression of ALKBH5 promoted apoptosis and inhibited the proliferation of T cells (all P<0.05). Conclusion: ALKBH5 expression is downregulated in SLE patients and could affect the apoptosis and proliferation of T cells, but the exact mechanism still needs to be further explored.