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Objectives: Osteoporosis is a common skeletal disorder affecting postmenopausal women. Data suggest that postmenopausal women are at increased risk of periodontal diseases. Amino bisphosphonates are potent inhibitors of bone resorption and effectively used in the treatment of osteoporosis. Preliminary data indicate that there is a potential role for bisphosphonates in the management of periodontitis. Hence, this randomized placebo-controlled trial was designed to investigate the clinical efficacy of amino bisphosphonate on periodontal disease status among postmenopausal women. Materials and Methods: Thirty patients were randomly allocated to two treatment groups: Group A, which received scaling and root debridement and 70 mg weekly single oral dose of alendronate drug, and Group B, which received scaling and root debridement and placebo drug for 6 months. Clinical periodontal measurements were carried out for all patients at the baseline and 6 months later. Mandibular bone mineral density (BMD) was measured using a dual energy X-ray absorptiometer at the beginning of the study and the end of 6 months. Results: A weekly single oral dose of 70 mg alendronate was well-tolerated. The intragroup comparison showed significant improvement in periodontal parameters in both groups. The intergroup comparison showed a significant increase in BMD after 6 months in Group A when compared with Group B (P = 0.0179). Conclusion: Single oral dose of 70 mg alendronate per week is well-tolerable, gastro-intestinally safe, and improves the clinical outcome of nonsurgical periodontal therapy.

Objective Periodontitis initiation and progression are a result of host immune inflammatory response to oral pathogens. Several pharmacological agents are being delivered locally, to improve periodontal health. Hence, the present randomized placebo controlled clinical trial is designed to check the clinical and antimicrobial efficacy of locally delivered 1.2% rosuvastatin (RSV) in intrabony defects (IBD) in periodontitis patients. Materials and Methods One-hundred patients were randomly allotted into two treatment groups: group A received 1. 2% RSV gel, scaling and root debridement and group B received placebo gel, scaling and root debridement. Clinical parameters, including modified sulcus bleeding index (mSBI), probing depth (PD), clinical attachment level (CAL), and plaque index (PI), were recorded at baseline before phase 1 and after 6 months. Radiographic assessment of IBD was done by cone beam computed tomography at baseline and after 6 months. Anaerobic colony count was done at baseline and after 180 days. Results On intragroup comparison, there is a significant improvement in periodontal parameters in both the groups. On intergroup comparison, there is significant gain in CAL in group A than group B (p = 0.04). There is significant decrease in PD in group A, compared to group B. There is significant bone fill in group A (p = 0.034), compared to group B. With respect to mSBI, PI, and anaerobic colony count, there is no significant difference between the two groups after 6 months. No adverse effect was noticed in any subjects. Conclusion The author concludes that 1.2% RSV gel when delivered locally into IBD improved periodontal clinical parameters such as PD and CAL and showed significant bone fill.

Previously, we showed that Rab5a and Rab5b differentially regulate fluid-phase and receptor-mediated endocytosis in Leishmania, respectively. To unequivocally demonstrate the role of Rab5b in hemoglobin endocytosis in Leishmania, we generated null-mutants of Rab5b parasites by sequentially replacing both copies of LdRab5b with the hygromycin and neomycin resistance gene cassettes. LdRab5b−/− null-mutant parasite was confirmed by qPCR analysis of genomic DNA using LdRab5b specific primers. LdRab5b−/− cells showed severe growth defect indicating essential function of LdRab5b in parasite. To characterize the role of Rab5b in Hb endocytosis in parasites, LdRab5b−/− cells were rescued by exogenous addition of hemin in growth medium. Our results showed that LdRab5b−/− cells are relatively smaller in size. Ultrastructural analysis revealed the presence of relatively enlarged flagellar pocket and bigger intracellular vesicles in these cells in comparison to control cells. Both promastigotes and amastigotes of Rab5b null-mutant parasites were unable to internalize Hb but fluid phase endocytosis of different markers was not affected. However, complementation of LdRab5b:WT in LdRab5b−/− cells (LdRab5b−/−:pRab5b:WT) rescued Hb internalization in these cells. Interestingly, LdRab5b−/− cells showed significantly less Hb-receptor on cell surface in comparison to control cells indicating a block in HbR trafficking. Finally, we showed that LdRab5b−/− parasites can infect the macrophages but are unable to survive after 96 h of infection in comparison to control cells. However, supplementation of hemin in the growth medium significantly rescued LdRab5b−/− Leishmania survival in macrophage indicating that LdRab5b function is essential for the acquisition of heme from internalized Hb for the survival of Leishmania.

Intracellular pathogens can modulate host Rabs and SNAREs to support their replication and immune evasion. Singh et al. show that the Salmonella effector SipA functionally mimics an R-SNARE and recruits host Q-SNAREs to promote membrane fusion. Thus, SNARE mimicry by this intracellular pathogen effector modulates the host trafficking machinery for Salmonella survival., SipA is a major effector of Salmonella, which causes gastroenteritis and enteric fever. Caspase-3 cleaves SipA into two domains: the C-terminal domain regulates actin polymerization, whereas the function of the N terminus is unknown. We show that the cleaved SipA N terminus binds and recruits host Syntaxin8 (Syn8) to Salmonella-containing vacuoles (SCVs). The SipA N terminus contains a SNARE motif with a conserved arginine residue like mammalian R-SNAREs. SipAR204Q and SipA1–435R204Q do not bind Syn8, demonstrating that SipA mimics a cognate R-SNARE for Syn8. Consequently, Salmonella lacking SipA or that express the SipA1–435R204Q SNARE mutant are unable to recruit Syn8 to SCVs. Finally, we show that SipA mimicking an R-SNARE recruits Syn8, Syn13, and Syn7 to the SCV and promotes its fusion with early endosomes to potentially arrest its maturation. Our results reveal that SipA functionally substitutes endogenous SNAREs in order to hijack the host trafficking pathway and promote Salmonella survival.

Differential functions of Rab5 isoforms in endocytosis are not well characterized. Here, we cloned, expressed, and characterized Rab5a and Rab5b from Leishmania and found that both of them are localized in the early endosome. To understand the role of LdRab5 isoforms in different modes of endocytosis in Leishmania, we generated transgenic parasites overexpressing LdRab5a, LdRab5b, or their dominant-positive (LdRab5a:Q93L and LdRab5b:Q80L) or dominant-negative mutants (LdRab5a:N146I and LdRab5b:N133I). Using LdRab5a or its mutants overexpressing parasites, we found that LdRab5a specifically regulates the fluid-phase endocytosis of horseradish peroxidase and also specifically induced the transport of dextran-Texas Red to the lysosomes. In contrast, cells overexpressing LdRab5b or its mutants showed that LdRab5b explicitly controls receptor-mediated endocytosis of hemoglobin, and overexpression of LdRab5b:WT enhanced the transport of internalized Hb to the lysosomes in comparison with control cells. To unequivocally demonstrate the role of Rab5 isoforms in endocytosis in Leishmania, we tried to generate null-mutants of LdRab5a and LdRab5b parasites, but both were lethal indicating their essential functions in parasites. Therefore, we used heterozygous LdRab5a(+/-) and LdRab5b(+/-) cells. LdRab5a(+/-) Leishmania showed 50% inhibition of HRP uptake, but hemoglobin endocytosis was uninterrupted. In contrast, about 50% inhibition of Hb endocytosis was observed in LdRab5b(+/-) cells without any significant effect on HRP uptake. Finally, we tried to identify putative LdRab5a and LdRab5b effectors. We found that LdRab5b interacts with clathrin heavy chain and hemoglobin receptor. However, LdRab5a failed to interact with the clathrin heavy chain, and interaction with hemoglobin receptor was significantly less. Thus, our results showed that LdRab5a and LdRab5b differentially regulate fluid phase and receptor-mediated endocytosis in Leishmania.