Infected Diabetic Mice Research Articles

Application of self-assembled antibacterial nanofiber loaded oriented artificial skin in infected diabetic-related wound regeneration

Diabetic patients develop wounds that exhibit delayed healing, prolonged inflammatory responses, and slower epithelialization kinetics compared to non-diabetic patients. Diabetic foot ulcers(DFUs) affect approximately 18.6 million people worldwide. The presence of a high glucose microenvironment in DFUs results in the significant accumulation of bacterial infection and advanced glycation end products (AGEs). To solve this, a self-assemble antibacterial nanofiber(ANF) loaded oriential artificial skin (ANF@OAS) was introduced in this research, which is consisted of L/D-phenylalanine derivatives coupled the natural antimicrobial peptides. The ANF@OAS can effectively reduce AGEs production and suppress multiple resistant bacteria. Additionally, the ANF@OAS can suppress infection and stimulate wound healing in infected diabetic mice.

Application of self-assembled antibacterial nanofiber loaded oriented artificial skin in infected diabetic-related wound regeneration.

Diabetic patients develop wounds that exhibit delayed healing, prolonged inflammatory responses, and slower epithelialization kinetics compared to non-diabetic patients. Diabetic foot ulcers(DFUs) affect approximately 18.6 million people worldwide. The presence of a high glucose microenvironment in DFUs results in the significant accumulation of bacterial infection and advanced glycation end products (AGEs). To solve this, a self-assemble antibacterial nanofiber(ANF) loaded oriential artificial skin (ANF@OAS) was introduced in this research, which is consisted of L/D-phenylalanine derivatives coupled the natural antimicrobial peptides.The ANF@OAS can effectively reduce AGEs production and suppress multiple resistant bacteria. Additionally, the ANF@OAS can suppress infection and stimulate wound healing in infected diabetic mice.

Aggravated pneumonia and diabetes in SARS-CoV-2 infected diabetic mice

ABSTRACT Multiple clinical and epidemiological studies have shown an interconnection between coronavirus disease 2019 (COVID-19) and diabetes, but experimental evidence is still lacking. Understanding the interplay between them is important because of the global health burden of COVID-19 and diabetes. We found that C57BL/6J mice were susceptible to the alpha strain of SARS-CoV-2. Moreover, diabetic C57BL/6J mice with leptin receptor gene deficiency (db/db mice) showed a higher viral load in the throat and lung and slower virus clearance in the throat after infection than C57BL/6J mice. Histological and multifactor analysis revealed more advanced pulmonary injury and serum inflammation in SARS-CoV-2 infected diabetic mice. Moreover, SARS-CoV-2 infected diabetic mice exhibited more severe insulin resistance and islet cell loss than uninfected diabetic mice. By RNA sequencing analysis, we found that diabetes may reduce the collagen level, suppress the immune response and aggravate inflammation in the lung after infection, which may account for the greater susceptibility of diabetic mice and their more severe lung damage after infection. In summary, we successfully established a SARS-CoV-2 infected diabetic mice model and demonstrated that diabetes and COVID-19 were risk factors for one another.

HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients

Infections are common in patients with diabetes, but increasing antibiotic resistance hampers successful bacterial clearance and calls for alternative treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is known to influence the innate immune defense and could therefore serve as a possible target. However, the impact of high glucose on HIF-1 has received little attention and merits closer investigation. Here, we show that higher levels of proinflammatory cytokines and CAMP, encoding for the antimicrobial peptide cathelicidin, LL-37, correlate with HIF-1 in type 2 diabetic patients. Chemical activation of HIF-1 further enhanced LL-37, IL-1β, and IL-8 in human uroepithelial cells exposed to high glucose. Moreover, HIF-1 activation of transurethrally infected diabetic mice resulted in lower bacterial load. Drugs activating HIF-1 could therefore in the future potentially have a therapeutic role in clearing bacteria in diabetic patients with infections where antibiotic treatment failed.Key messages• Mohanty et al. “HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients.”• Our study highlights induction of the antimicrobial peptide, LL-37, and strengthening of the innate immunity through hypoxia-inducible factor 1 (HIF-1) in diabetes.• Our key observations are:1. HIF-1 activation increased LL-37 expression in human urothelial cells treated with high glucose. In line with that, we demonstrated that patients with type 2 diabetes living at high altitude had increased levels of the LL-37.2. HIF-1 activation increased IL-1β and IL-8 in human uroepithelial cells treated with high glucose concentration.3. Pharmacological activation of HIF-1 decreased bacterial load in the urinary bladder of mice with hereditary diabetes.• We conclude that enhancing HIF-1 may along with antibiotics in the future contribute to the treatment in selected patient groups where traditional therapy is not possible.

Type I Diabetes Mellitus Increases the Cardiovascular Complications of Influenza Virus Infection

People with diabetes mellitus are susceptible to both cardiovascular disease and severe influenza A virus infection. We hypothesized that diabetes also increases risks of influenza-associated cardiac complications. A murine type 1 (streptozotocin-induced) diabetes model was employed to investigate influenza-induced cardiac distress. Lung histopathology and viral titres revealed no difference in respiratory severity between infected control and diabetic mice. However, compared with infected control mice, infected diabetic mice had increased serum cardiac troponin I and creatine-kinase MB, left ventricular structural changes and right ventricular functional alterations, providing the first experimental evidence of type I diabetes increasing risks of influenza-induced cardiovascular complications.

Strategy for Treatment of Infected Diabetic Foot Ulcers.

Diabetic foot ulcers (DFUs) are chronic wounds that develop in 30% of diabetic patients. In DFUs, the normal wound healing process consisting of inflammation, angiogenesis, and extracellular matrix (ECM) remodeling is dysregulated and stalled. Upon injury, neutrophils and monocytes arrive at the wound and secrete matrix metalloproteinase (MMP)-8 and reactive oxygen species (ROS). ROS activates nuclear factor kappa beta (NF-κB), which upregulates MMP-9. Monocytes become macrophages, secreting tumor growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) for angiogenesis, resulting in remodeling of the ECM. MMP-9 cleaves laminin for keratinocyte migration. MMP-8 is beneficial for remodeling the ECM and healing the wound. In DFUs, the excess unregulated MMP-9 is detrimental, destroying the ECM and preventing the wound from healing. DFUs are typically infected, many with biofilm-producing bacteria that are resistant to antibiotics. Infection increases the time for wound healing and the likelihood for a lower-limb amputation. Despite the use of antibiotics, amputations occur in 24.5% of patients with DFUs. Clearly, new strategies for treatment of DFUs are needed. With the use of an affinity resin that binds exclusively to the active forms of MMPs and proteomics, we identified two proteinases, MMP-8 and MMP-9, in wounds of diabetic mice and diabetic humans. With the use of selective inhibitors, gene ablation of MMP-9, and exogenous application of MMP-8, we demonstrated that MMP-8 is beneficial to wound repair and that MMP-9 prevents the diabetic wound from healing. Our research has shown that infection increases active MMP-9, increasing inflammation and decreasing angiogenesis. As a result, infected diabetic wounds take a longer time to heal than uninfected ones. We found that active MMP-9 and NF-κB increased in human DFUs with wound severity and infection. The best strategy for treatment of DFUs is to selectively inhibit the detrimental proteinase MMP-9 without affecting the beneficial MMP-8 so that the body can repair the wound. Lead optimization of the thiirane class of inhibitors led to the discovery of (R)-ND-336, a potent (19 nM) and selective (450-fold) MMP-9 inhibitor. (R)-ND-336 accelerated wound healing in diabetic mice by decreasing ROS and NF-κB, lowering inflammation, and increasing angiogenesis. (R)-ND-336 in combination with the antibiotic linezolid improved wound healing in infected diabetic mice by inhibiting MMP-9, which mitigated macrophage infiltration and increased angiogenesis, thereby restoring the normal wound healing process.

Insulin Modulates Inflammatory Cytokine Release in Acute Stages and Augments Expression of Adhesion Molecules and Leukocytes in Lungs on Chronic Stages of Paracoccidioidomycosis.

Type 1 diabetes mellitus (T1D) is caused by partial destruction of the insulin-producing beta cells in the pancreas and is a major issue for public health care worldwide. Reduced or impaired immunological responses, which render patients more susceptible to infections, have been observed in T1D, and this dysfunction is often related to a lack of insulin in the blood. Paracoccidioidomycosis is an important systemic mycosis endemic in Latin America. To evaluate the effects of T1D on this fungal infection and the modulatory effects of insulin, we induced diabetes in C57Bl/6 male mice (alloxan, 60 mg/kg), infected the mice (Pb18, 1 x 106 cells), and treated the mice with neutral protamine Hagedorn (NPH) insulin (2 IU/600 mg/dL blood glucose). Twenty-four hours after infection, infected diabetic mice showed reduced secretion of interferon (IFN)-γ and interleukine (IL)-12 p70 compared to infected nondiabetic controls. On the 45th day of infection, infected diabetic mice presented higher IFN-γ levels, a higher tumor necrosis factor (TNF)-α:IL-10 ratio, and lower adhesion molecule expression levels than nondiabetic mice. In the in vitro experiments, alveolar macrophages from diabetic animals showed reduced phagocytic activity compared to those from control animals at 4, 12, and 24 h. In infected diabetic mice, treatment with insulin restored IL-12 p70 levels at 24 h of infection, reduced IFN-γ levels and the TNF-α:IL-10 ratio at 45 days, and restored vascular cell adhesion molecule (VCAM)-1 expression in pulmonary blood vessels, and this treatment reduced the diminished phosphorylation of extracellular signal-regulated kinases (ERK) and increased nuclear factor-kappa-B(iκb)-α and jun amino-terminal kinases (JNK) p46 levels in infected nondiabetic mice. In addition, insulin promoted increased phagocytic activity in the alveolar macrophages of diabetic mice. These data suggest that T1D mice are more susceptible to Pb18 infection and that insulin modulates this inflammation in diabetic mice by augmenting the expression of adhesion molecules and leukocytes in the lungs and by reducing chronic inflammation.

Selective MMP-9 Inhibitor (R)-ND-336 Alone or in Combination with Linezolid Accelerates Wound Healing in Infected Diabetic Mice.

Diabetic foot ulcers (DFUs) are a common complication of diabetes that are recalcitrant to healing due to persistent inflammation. The majority of DFUs have bacterial biofilms, with Staphylococcus epidermidis as a predominant bacterium, requiring infection control with antibiotics before treatment of the wound. Matrix metalloproteinases (MMPs) play roles in the pathology and repair of DFUs. However, defining the roles of the 24 human MMPs has been challenging due to the presence of three forms for each MMP, of which only one is catalytically competent, and the lack of convenient methods to distinguish among the three forms of MMPs. Using an affinity resin that binds only to the active forms of MMPs, with identification and quantification by mass spectrometry, we found that infected wounds in mice had increased levels of active MMP-9 compared to uninfected ones, paralleling infected human DFUs. MMP-9 activity prevents diabetic wounds from healing. We evaluated the efficacy of the selective small-molecule MMP-9 inhibitor, (R)-ND-336, in the infected diabetic mouse model of wound healing and showed that (R)-ND-336 alone or in combination with the antibiotic linezolid improves wound healing by inhibiting the detrimental MMP-9, mitigating macrophage infiltration to diminish inflammation, and increasing angiogenesis to restore the normal wound healing process. An advantage of this strategy is the ability to administer (R)-ND-336 concurrently with an antibiotic.

Sporulation on blood serum increases the virulence of Mucor circinelloides

Mucor circinelloides is an opportunistic human pathogen that is used to study mucormycosis, a rare but lethal infection in susceptible immunosuppressed patients. However, the virulence characteristics of this pathogen have not been fully elucidated. In this study, sporangiospores (spores) produced on YPG medium supplemented with native blood serum increased the virulence of M. circinelloides compared with spores produced on YPG supplemented with denatured blood serum or on YPG alone. The spores produced from YPG supplemented with native blood serum increased nematode death and led to significant increases in interleukin (IL)-6, IL-1β, macrophage inhibitory protein-2, and tumour necrosis factor α mRNA levels in liver and lung tissues from infected diabetic mice compared with those in tissues from animals infected with spores produced in the presence of YPG supplemented with denatured blood serum or of YPG alone. Moreover, spores produced from cultures supplemented with native blood serum showed increased germination rates and longer hyphae compared with other spores. The spores produced in YPG supplemented with native blood serum also enhanced resistance to stress factors and H2O2 and increased thermotolerance compared with spores produced under other conditions. In addition, spores produced in presence of blood serum increased the ability of the pathogen to survive in the presence of macrophages. Taken together, our results showed that these factors were important features for fungal virulence in humans and suggested that thermolabile components in the blood serum may induce M. circinelloides virulence.

Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice

Diabetic individuals are at considerable risk for invasive infection by Staphylococcus aureus, however, the mechanisms underlying this enhanced susceptibility to infection are unclear. We observed increased mortality following i.v. S. aureus infection in diabetic mice compared with nondiabetic controls, correlating with increased numbers of low-density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDNs have been implicated in the inflammatory pathology of diseases such as lupus, given their release of large amounts of NETs. Our goal was to describe what drives LDN increases during S. aureus infection in the diabetic host and mechanisms that promote increased NET production by LDNs. LDN development is dependent on TGF-β, which we found to be more activated in the diabetic host. Neutralization of TGF-β, or the TGF-β-activating integrin αvβ8, reduced LDN numbers and improved survival during S. aureus infection. Targeting S. aureus directly with MEDI4893*, an α toxin-neutralizing monoclonal antibody, blocked TGF-β activation, reduced LDNs and NETs, and significantly improved survival. A comparison of gene and protein expression in high-density neutrophils and LDNs identified increased GPCRs and elevated phosphatase and tensin homolog (PTEN) in the LDN subset. Inhibition of PTEN improved the survival of infected diabetic mice. Our data identify a population of neutrophils in infected diabetic mice that correlated with decreased survival and increased NET production and describe 3 therapeutic targets, a bacterial target and 2 host proteins, that prevented NET production and improved survival.

Insulin Treatment Rescues Alterations in the Lung following H1N1 Influenza Virus Infection in Diabetic Mice

Hyperglycemia has recently been identified as a major risk factor for the development and worsening severity of viral respiratory infections. However, the regulation of glucose homeostasis in the diabetic lung and during influenza infection is currently under‐investigated. We hypothesized that hyperglycemia would predispose diabetic mice to alterations in pulmonary glucose homeostasis following influenza A infection, which would be rescued by in vivo insulin treatment. To test this hypothesis, we used a streptozotocin‐induced type 1 diabetic mouse model (n=8–12/group). A subset of diabetic mice was treated with insulin via a subcutaneous insulin pump. After 8 weeks, mice were intranasally infected with influenza A H1N1 (A/PR/8/34; 250 PFU) and sacrificed 3 days post infection. Glucose concentration in BAL fluid was measured spectrophotometrically. Glucose transporter (GLUT) protein location was determined via immunohistochemistry, and GLUT protein content was quantified by Western blotting. As expected, diabetic (non‐infected and influenza‐infected) mice displayed hyperglycemia while insulin‐treated diabetic mice remained euglycemic. In addition, H&E‐stained lungs revealed that infection with H1N1 induced hemorrhage, inflammatory cell infiltration, and vasculitis in the lungs of both diabetic and control mice. Interestingly, infected diabetic mice displayed significant upregulation of non‐insulin‐sensitive GLUT protein (−1, −12) versus their control counterparts, with a concurrent significant downregulation of the insulin‐sensitive GLUT4 protein (p<0.05). In contrast, non‐infected diabetic mice demonstrated a significant downregulation of GLUT1 protein in the lung (p<0.001). These alterations in GLUT protein expression in the lung were rescued when diabetic mice were treated with insulin for 8 weeks. Both infected and non‐infected diabetic mice had a higher concentration of glucose in BAL fluid than their control counterparts, which was rescued following in vivo insulin treatment (p<0.05). Interestingly, infected mice of both the control and diabetic groups had a significantly higher glucose concentrations than their non‐infected counterparts (p=0.0032 and p=0.0299, respectively), while both non‐infected and infected insulin‐treated mice possessed similar BAL glucose concentrations. BAL glucose concentration was significantly correlated with blood glucose in both non‐infected and infected groups (p=0.045 and p=0.07, respectively). In addition, in vivo insulin treatment partially rescued the neutrophilic response in BALF of infected diabetic mice (p<0.05). These novel findings suggest that 1) the regulation of glucose transport is altered in the lungs of diabetic mice, potentially worsening response to H1N1 influenza infection, and 2) in vivo insulin treatment rescues the significant pathological alterations found in the diabetic lung following influenza infection.Support or Funding InformationThis study was funded by the Oklahoma Center for Respiratory and Infectious Disease (OCRID – CoBRE, NIH 1P20 GM103648), the Harold Hamm Diabetes Center, and Oklahoma State University Center for Veterinary Health Sciences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Therapeutic potential of thymoquinone liposomes against the systemic infection of Candida albicans in diabetic mice.

The present study was aimed to develop a liposomal formulation of thymoquinone (Lip-TQ) to treat Candida albicans infection in diabetic mice. Streptozotocin (STZ) was injected to induce hyperglycemia and on day 3 post STZ administration, mice were intravenously infected with C. albicans. Various doses (2, 5 and 10 mg/kg) of Free or Lip-TQ were administered in C. albicans infected diabetic mice. The effect of Lip-TQ was also determined on the organ indices, liver and kidney function parameters. Lip-TQ at a dose of 10 mg/kg significantly reduced the level of the blood glucose and alleviated the systemic C. albicans infection in diabetic mice. C. albicans infected diabetic mice treated with Lip-TQ at a dose of 10 mg/kg showed the survival rate of 70% as compared to that of 20% in the group treated with free TQ. The treatment with Lip-TQ resulted in the recovery of the organ indices, liver inflammation, kidney functioning and pancreas regeneration in diabetic mice. Moreover, TQ formulations also showed the direct therapeutic effect against candidiasis in the untreated or metformin-treated diabetic mice. Therefore, the findings of the present study support the use of Lip-TQ in the treatment of candidiasis in the diabetic patients.

Insulin Modulates Paracoccidioides brasiliensis-Induced Inflammation by Restoring the Populations of NK Cells, Dendritic Cells, and B Lymphocytes in Lungs.

Paracoccidioidomycosis, a key issue for Brazilian health service, can be aggravated in patients with impaired immunological responses, such as diabetic patients. We evaluated the role of insulin in inflammatory parameters in diabetic and nondiabetic mice using a systemic mycosis Paracoccidioides brasiliensis (Pb) model. Diabetic C57BL-6 mice and controls were infected with Pb18 and treated with insulin for 12 days prior to experiments. After 55 days, infected diabetic mice exhibited fewer leukocytes in both peritoneal lavage fluid (PeLF) and bronchoalveolar lavage fluid and reduced secretion of interleukin- (IL-) 6 in lungs. In addition, diabetic mice presented a reduced influx of TCD4+ cells, TCD8+ cells, B lymphocytes, NK cells, and dendritic cells compared to control infected groups. Insulin treatment restored the leukocyte number in PeLF and restored the presence of B lymphocytes, dendritic cells, and NK cells in lungs of diabetic animals. The data suggest that diabetic mice present impaired immunological response to Pb18 infection and insulin modulates inflammation by reducing IL-6 levels in lung and CINC-1 levels in spleen and liver homogenates, restoring leukocyte concentrations in PeLF and also restoring populations of dendritic cells and B lymphocytes in lungs of diabetic mice, permitting the host to better control the infection.

Prostaglandin E2 threshold dictates susceptibility to skin infection in diabetic mice

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) is the primary cause of skin infection in people with diabetes. MRSA skin infection is characterized by the migration of phagocytes and abscess formation to prevent deeper tissue infections. However, the events that drive poor host defense in diabetes is poorly understood. Here, we examined the role of the lipid mediator prostaglandin E2 (PGE2) and its impact on host defense during MRSA skin infection in diabetes. We have shown that diabetic mice are unable to control MRSA skin infection, along with excessive cytokine production and neutrophil migration. Our data indicate that PGE2 production is lower in diabetic mice than nondiabetic mice at both days 1 and 9. Daily topical treatment with a PGE2 analog decreased lesion size and improved bacterial clearance in the skin of infected diabetic mice. Reduced lesion size in PGE2-treated diabetic mice correlated with decreased production of the cytokines TNF-, IL-1, and IL-6 and neutrophil migration. While we did observe a well-defined abscess in infected nondiabetic mice, infection in diabetic mice resulted in poor abscess formation; and topical PGE2 treatment restores abscess formation. Poor skin defense in diabetic mice also correlated with increased numbers of dead cells at days 1 and 9 post-infection suggesting that dead cells are not eliminated. When we studied the expression of molecules involved in dead cell ingestion, we observed an increased abundance of inhibitory receptor SIRPa in infected diabetic mice and PGE2 ointment restored SIRPa levels back to those observed in infected nondiabetic mice. These data indicate that the threshold of PGE2 drives the inflammatory milieu during infection and effects skin homeostasis in diabetes.

IL-6 regulates pro- and anti-inflammatory cytokine production and mortality of Mycobacterium tuberculosis infected type 2 diabetic mice (INC2P.418)

Abstract In this study, to determine whether diabetic (DM) mice are susceptible to Mycobacterium tuberculosis (Mtb) infection, we developed experimentally induced diabetes in wild type C57BL/6 mice with streptozotocin & nicotinamide. We then infected non-DM and DM mice with Mtb H37Rv by aerosol. Around 50% of Mtb infected DM (p=0.05) and 25% of uninfected DM (p=0.07) mice died in 5 to 6 months compared to no deaths in infected control mice. Six months after Mtb infection, there was a statistically significant but marginal increase in bacterial burden in the lungs of Mtb infected DM mice compared to non-DM infected mice (3.1 ± 0.4 x106 vs 0.9 ± 0.1 x 106, p=0.001) suggesting increased mortality was not due to increased bacterial burden. Real time PCR analysis of Mtb infected DM lungs indicated significantly increased pro- and anti-inflammatory cytokine gene expression compared to uninfected DM and infected control mice, including increased levels of IL-6 mRNA. Anti-IL-6 antibody treatment of Mtb infected DM mice enhanced the survival (100% vs 60% survival in isotype control antibody treated, p=0.02) and reduced pro- and anti-inflammatory cytokine production. Dendritic cells (DC), but not other immune cells were the major source for IL-6 in Mtb infected DM mice. NK cells of Mtb infected DM mice further enhanced IL-6 production by autologous DCs. Our results suggest NK-DC interaction enhance IL-6 production which drives the immune pathology and mortality of Mtb infected diabetic mice

Reduced Neutrophil Apoptosis in Diabetic Mice during Staphylococcal Infection Leads to Prolonged Tnfα Production and Reduced Neutrophil Clearance

Diabetes is a frequent underlying medical condition among individuals with Staphylococcus aureus infections, and diabetic patients often suffer from chronic inflammation and prolonged infections. Neutrophils are the most abundant inflammatory cells during the early stages of bacterial diseases, and previous studies have reported deficiencies in neutrophil function in diabetic hosts. We challenged age-matched hyperglycemic and normoglycemic NOD mice intraperitoneally with S. aureus and evaluated the fate of neutrophils recruited to the peritoneal cavity. Neutrophils were more abundant in the peritoneal fluids of infected diabetic mice by 48 h after bacterial inoculation, and they showed prolonged viability ex vivo compared to neutrophils from infected nondiabetic mice. These differences correlated with reduced apoptosis of neutrophils from diabetic mice and were dependent upon the presence of S. aureus and a functional neutrophil respiratory burst. Decreased apoptosis correlated with impaired clearance of neutrophils by macrophages both in vitro and in vivo and prolonged production of proinflammatory tumor necrosis factor alpha by neutrophils from diabetic mice. Our results suggest that defects in neutrophil apoptosis may contribute to the chronic inflammation and the inability to clear staphylococcal infections observed in diabetic patients.

Use of a low-dose steroid as an adjunct in the treatment, in mice, of severe sepsis caused byBurkholderia pseudomallei

Human melioidosis caused by Burkholderia pseudomallei is a severe septic disease that is associated with high mortality, even under appropriate antibiotic treatment. The therapeutic effects of low-dose hydrocortisone plus ceftazidime, and of ceftazidime alone, have recently been investigated in the treatment of acute, severe sepsis caused by B. pseudomallei, both in normal BALB/c mice and in BALB/c mice with streptozotocin-induced diabetes. The mice were infected and then treated intravenously, from day 1 or day 2 post-infection, with saline (as a control, given twice daily for 10 days), low-dose hydrocortisone (given in twice-daily doses of 5 mg/kg, for 5 days) plus ceftazidime (given in twice-daily doses of 1200 mg/kg, for 10 days), or the same doses of ceftazidime alone. Although the infected, untreated mice all died within 14 days, almost all of the treated animals were still alive at the end of the follow-up, 30 days post-infection. The addition of the steroid appeared to have no benefit, with bacterial loads and plasma concentrations of tumour necrosis factor, aspartate aminotransferase, alanine aminotransferase and creatinine decreasing similarly in all the treated groups. The infected diabetic mice given hydrocortisone-ceftazidime from day 1 (but not those given just ceftazidime from day 1) showed an increase in their blood glucose concentrations. When infected mice were treated with the low-dose steroid and lower doses of the antibiotic (in twice-daily doses of 120-600 mg/kg), the steroid not only offered no apparent benefit but seemed to reduce survival. It therefore appears that low-dose hydrocortisone, as an adjunct to antibiotic treatment, does not provide benefit in the treatment of murine melioidosis and may have negative effects on human cases of the disease who have diabetes mellitus.

On The Interaction between Induced Diabetes Mellitus and Schistosomiasis: Mechanism and Protection

In this study mice were percutaneously exposed to 50 S. mansoni cercariae. Seven weeks post infection (pi), infected mice were either injected i.p. a single dose of alloxan (200 mg kg -1 ) or treated with a single dose of alloxan followed, three days later, with daily i.p. treatment of ethanolic extract of Cleome droserifolia (0.31 g kg -1 ) for 18 days. Diabetes mellitus (DM) affected characteristics of Schistosoma infection as shown in alteration of oogram pattern, impairing of egg maturation and lowering of faecal egg output. However, extract treatment (EXT) affected the previously mentioned aspects in addition to its remarkable effect on worm load, diminishing of hepatic granulomas and suppressing the formation of involutional granulomas. Results indicated that DM increased the complications of schistosomiasis that was manifested by the augmented increase of serum glucose level, the severe decrease of serum thyroid hormones (tri-iodothyronine; T3 and tetra-iodo-thyronin; T4), insulin levels, liver glycogen content and hepatic DNA. In addition, a decrease in hepatic GSH that was accompanied by an increase in serum uric acid were observed in infected-DM mice. Serum total proteins concentrations were obviously decreased and some of protein fractions were also decreased or absent in both infected and infected-DM mice except for gamma globulin that was increased in both groups. EXT succeeded efficiently to alleviate these alterations in infecteddiabetic mice, to various extents. The beneficial effects of EXT on thyroid and pancreatic hormones status seem to be contradictory to its beneficial anti-schistosomiasis effects. This contradiction may suggest that EXT exerts its beneficial effects through its direct effects on the parasite, not secondary to its effect on the host. The current results showing differential effects of both diabetes and extract on schistosomiasis, though both are beneficial, serve to corroborate this hypothesis.