The Effect of Recombinant Human Erythropoietin on Bacterial Growth: A Dual-Edged Sword.

BACKGROUND: Hypererythropoietinemia is associated with common diseases like non-uremic anaemia where infection burden is high. Erythropoietin (EPO) is also given as therapy for anaemia associated with chronic kidney disease and cancer and in those who are at a higher risk of infections. EPO is known to have an effect on macrophages by which it helps in the growth of some intracellular pathogens. However, its direct role on bacterial growth is currently unknown. SUMMARY: Here, we investigated the direct effect of recombinant human erythropoietin (rhuEPO) on the growth of pathogenic Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. In silico experiments were designed to gain insight into the mechanisms. We found that 30 IU/L rhuEPO promoted the growth of E. coli and S. aureus and inhibited the growth of P. aeruginosa. In silico observations suggest that bacterial cell surface proteins may interact with the EPO and may cause the observed effects. KEY MESSAGE: It appears that some pathogens can explore EPO to proliferate and growth of others are inhibited by the same. The consequence of such observation is a matter of widespread concern for future research.

Inhalational supplementation of metformin butyrate: A strategy for prevention and cure of various pulmonary disorders.

The management of chronic lung diseases such as cancer, asthma, COPD and pulmonary hypertension remains unsatisfactory till date, and several strategies are being tried to control the same. Metformin, a popular anti-diabetic drug has shown promising effects in pre-clinical studies and has been subject to several trials in patients with debilitating pulmonary diseases. However, the clinical evidence for the use of metformin in these conditions is disappointing. Recent observations suggest that metformin use in diabetic patients is associated with an increase in butyrate-producing bacteria in the gut microbiome. Butyrate, similar to metformin, shows beneficial effects in pathological conditions found in pulmonary diseases. Further, the pharmacokinetic data of metformin suggests that metformin is predominantly concentrated in the gut, even after absorption. Butyrate, on the other hand, has a short half-life and thus oral supplementation of butyrate and metformin is unlikely to result in high concentrations of these drugs in the lung. In this paper, we review the pre-clinical studies of metformin and butyrate pertaining to pathologies commonly encountered in chronic lung diseases and underscore the need to administer these drugs directly to the lung via the inhalational route.

A novel insight in favor of structure-function relationship for 16S rRNA.

Sequences in the stem-loop part of 16S ribosomal RNA (rRNA) are considered to be crucial for predicting antibiotic resistance. Mutant sequences have been reported to be helpful in the prediction of spectinomycin resistance. It is expected that such mutations alter the 16S rRNA stem-loop conformation, which affects antibiotic binding. Metagenomic database provides 16S ribosomal DNA sequences isolated from environmental samples. Using in silico tools, we observed that the existence of specific mutation does not alter the stem-loop structure of 16S rRNA along with its three-dimensional conformation. Our observation suggests that the three-dimensional structure is a better guide to understand whether a specific mutation can cause spectinomycin resistance.

High dose targeted delivery on cancer sites and the importance of short-chain fatty acids for metformin's action: Two crucial aspects of the wonder drug.

Metformin is a popular anti-diabetic drug currently being explored for its role in cancer and gut microbiome amongst other areas. Recently, Adak T et al. explicatively reviewed metformin's effects as an anti-cancer drug and a gut microbiome modulator. We feel that the authors have not adequately addressed some of the key concerns around metformin in their report and in this correspondence, we seek to add some of the issues that need to be addressed by researchers.

Metformin exerts anti-obesity effect via gut microbiome modulation in prediabetics: A hypothesis.

Prediabetic individuals are characterized by high levels of insulin, an anabolic hormone having an important role in the maintenance of glucose homeostasis. However, insulin has also been found to increase the growth of certain bacteria which form the non-butyrate producing part of the gut microbiome. The gut microbiome is recently in focus for its strong association with many chronic diseases such as type 2 diabetes mellitus and obesity. Metformin, a widely popular anti-diabetic medication has been shown to prevent weight gain in many trials. There are many studies postulating the mechanisms of the anti-obesity effect of metformin including improvement in insulin sensitivity (and consequently a reduction in insulin levels). Recently, however, it is becoming evident that metformin's action is likely to be primarily mediated by the gut. Further, metformin has also shown to affect the growth characteristics of certain bacteria which form the part of the human gut microbiome. With this frame of reference in mind, we hypothesize that metformin is likely to exert its anti-obesity effect by altering the composition of the gut microbiome. If proved, this has the potential to contribute to the management of obesity and pave the way for the development of novel anti-obesity drugs.

A story of metformin-butyrate synergism to control various pathological conditions as a consequence of gut microbiome modification: Genesis of a wonder drug?

The most widely prescribed oral anti-diabetic agent today in the world today is a member of the biguanide class of drugs called metformin. Apart from its use in diabetes, it is currently being investigated for its potential use in many diseases such as cancer, cardiovascular diseases, Alzheimer's disease, obesity, comorbidities of diabetes such as retinopathy, nephropathy to name a few. Numerous in-vitro and in-vivo studies as well as clinical trials have been and are being conducted with a vast amount of literature being published every day. Numerous mechanisms for this drug have been proposed, but they have been unable to explain all the actions observed clinically. It is of interest that insulin has a stimulatory effect on cellular growth. Metformin sensitizes the insulin action but believed to be beneficial in cancer. Like -wise metformin is shown to have beneficial effects in opposite sets of pathological scenario looking from insulin sensitization point of view. This requires a comprehensive review of the disease conditions which are claimed to be affected by metformin therapy. Such a comprehensive review is presently lacking. In this review, we begin by examining the history of metformin before it became the most popular anti-diabetic medication today followed by a review of its relevant molecular mechanisms and important clinical trials in all areas where metformin has been studied and investigated till today. We also review novel mechanistic insight in metformin action in relation to microbiome and elaborate implications of such aspect in various disease states. Finally, we highlight the quandaries and suggest potential solutions which will help the researchers and physicians to channel their research and put this drug to better use.