UNVEILING THE COMPLEX ROLE OF NF-ΚB IN ALZHEIMER'S DISEASE: INSIGHTS INTO BRAIN INFLAMMATION AND POTENTIAL THERAPEUTIC TARGETS.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and dementia. One of the major pathologies underlying AD is chronic neuroinflammation mediated by microglia and astrocytes in the brain. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathway is a key regulator of inflammation and has been implicated in the neuroinflammatory processes associated with AD. This review comprehensively summarizes current findings on the complex role of NF-κB signalling in AD pathogenesis. The canonical and non-canonical NF-κB activation pathways are described, along with evidence from human studies and animal models demonstrating increased NF-κB activity in AD brains. The deleterious effects of NF-κB-mediated neuroinflammation are discussed, including the upregulation of inflammatory cytokines, chemokines, and enzymes that exacerbate neuronal damage over time. Targeting the NF-κB pathway is proposed as a promising therapeutic approach to dampen neuroinflammation in AD. Preclinical studies utilizing genetic or pharmacological inhibition of NF-κB are reviewed, and key challenges in translating these findings to clinical applications are analyzed. Overall, this review unveils the multifaceted contributions of NF-κB signalling to AD neuropathology and highlights anti-neuroinflammatory NF-κB modulation as a potential avenue for future AD treatments. Further research is warranted to fully elucidate the complex interactions between NF-κB and AD pathogenesis.

THE ROLE OF IMMUNOTHERAPY IN CANCER TREATMENT: CHECKPOINT INHIBITORS, CAR-T CELLS, AND VACCINES.

Immunotherapy causes cancer patients' immune systems to activate in search of and eliminate cancer cells. As a therapeutic area for cancer, it has expanded in importance and demonstrated promising results in treating many cancers. Checkpoint blockade (CPB) therapy may stimulate a suppressed immune response to provide long-lasting therapeutic results. However, the absence of a tumor-reactive immune infiltration is probably why response rates are still low. Using chimeric antigen receptor (CAR)-modified T cells to fight cancer may significantly impact immunology. This study explored using checkpoint inhibitors, car-T cells, and vaccines in immunotherapy to treat cancers. Drugs used for CPB aim to reduce immunological suppression, allowing for more effective CAR T cells and dendritic cell (DC) vaccines, providing some optimism that this may be increased, both of which have proven therapeutic efficacy in specific cancers. However, drug-induced side effects and the tumor microenvironment's propensity for immunosuppression mean treatment effectiveness is still inadequate. The outcomes of current preclinical tests suggest that novel therapies targeting lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin-domain containing-3 (TIM3), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and programmed cell death protein 1 (PD-1) could be used as adjuvant therapies to modify the tumor microenvironment.

Molecular detection of Salmonella isolated from commercial chicken.

Background: Salmonella in chicken, specially, the motile salmonellae, causes the food chain unsafe from farm to table and is considered a significant global threat to public health. Aims: The present study was carried out for molecular detection of Salmonellae in commercial poultry using PCR. Methods: The study was conducted for eight months, from July 2019 to February 2020, and a total of 26 poultry farms, including 15 broiler and 11-layer farms, were visited individually. Pooled faecal samples were obtained from the sheds. A total of 189 necropsy cases were examined for gastrointestinal lesions. Isolation and identification of the organism were done using microbe culture method, and the molecular characterization was performed via PCR targeting invA and ent genes. Results: The prevalence of salmonellosis in the broiler and layer farms was recorded at 20.0% and 45.4%, respectively, through the traditional gold standard culture method. From 189 necropsy birds, salmonellosis was recorded at 1.58% dead cases. Molecular detection of Salmonella isolates by PCR targeting invA gene was confirmed in 13.33% of the broiler farms and 36.3% of the layer farms. Further detection of Salmonella enteritidis was performed by PCR targeting ent gene by which 11.11% positivity was determined. Conclusion: This study, focused on the Salmonella prevalence, highlighted the zoonotic importance of the bacterium in the commercial poultry farms, which can subsequently be dispersed into the human food chain causing harmful health effects.

Descriptive epidemiology and high risk behavior of male prescription opioid abusers: Cross-sectional study from Sikkim, North East India.

BACKGROUND: Sikkim is emerging as an important area for prescription opioid abuse with frequent news of seizures and arrests due to possession of prescription opioids. However, till date there is a little information on descriptive epidemiology and high risk behavior of prescription opioid abusers from Sikkim. AIMS: The aim was to describe demographic (age, sex, religion, marital status, community, occupation, etc.); socioeconomic (income, education, family information etc.); and high risk behavior (e.g., injection sharing, visit to commercial sex workers [CSWs], homosexuality etc.) among treatment-seeking prescription opioid abusers in Sikkim. MATERIALS AND METHODS: Epidemiological data were collected by administering predevised questionnaires from n = 223 prescription opioid abusers (main problem prescription opioids) reporting for treatment at five different drug abuse treatment centers across Sikkim. RESULTS: The mean age of prescription opioid abusers in Sikkim was 27 years; all were male, of Nepalese ethnicity and single/never married, school dropout and/or illiterate, earning < Rs. 10,000/month with most spending almost Rs. 5000 a month on prescription opioids. Most (57.4%) prescription opioid abusers belonged to the urban community. Commonly abused prescription opioids were dextropropoxyphene and codeine. Injection sharing was more in urban areas whereas syringe exchange was observed equally among rural and urban prescription opioid abusers. Among urban injectors visits to CSWs, and multiple sex partners were also common in spite of knowledge about AIDS. Limited condom use was observed among rural respondents. Incidences of arrests, public intoxication, and violence under the influence of prescription opioids were also reported. CONCLUSION: Both the rural and urban areas of Sikkim show increasing rates of prescription opioid abuse among males. It is more prevalent among school dropouts and unemployed youth. Trends of injection drug use, unsafe injection, high risk behavior have also been observed.

Determination of in vivo estrogenic potential of Di-isobutyl phthalate (DIBP) and Di-isononyl phthalate (DINP) in rats.

Estrogenic potential of Di-isobutyl phthalate (DIBP) and Di-isononyl phthalate (DINP) was studied using two different test systems. Two different doses of DIBP (250 and 1250 mg/kg) and DINP (276 and 1380 mg/kg) were administered to immature female rats (20 days old) orally once daily for 3 and 20 days in uterotrophic and pubertal assay, respectively. The animals were sacrificed on day 4 and day 41 in case of 3-day uterotrophic and 20-day pubertal assay, respectively. The results indicated that non-significant alterations in uterine and ovarian wet weight were observed in both the DIBP- and DINP-treated groups while the uterus weight increased significantly (i.e., 4-6 times) in the Diethylstilbesterol (DES)-treated group in both the assays. In the present study, precocious vaginal opening occurred at 26 days of age in the DES-treated group with a mean body weight of 30.39 ± 1.08 g. However, no precocious vaginal opening was found in any of the DIBP- and DINP-treated groups. The results indicated that both the phthalate compounds were unable to induce elevation in the uterine weight in both the assays and unable to cause vaginal opening indicating non-estrogenic potential of both the phthalate compounds, i.e., DIBP and DINP in vivo.

Effects of in utero di-butyl phthalate and butyl benzyl phthalate exposure on offspring development and male reproduction of rat.

The study was conducted to assess the effects of in utero di-butyl phthalate (DBP) and butyl benzyl phthalate (BBP) exposure during late gestation on offspring's development and reproductive system of male rats. Pregnant rats were treated orally with DBP (2, 10, 50 mg/kg), BBP (4, 20, 100 mg/kg), and diethylstilbestrol (DES) 6 µg/kg (positive control) from GD14 to parturition. A significant reduction in dams' body weight on GD21 in DBP-, BBP-, and DES-treated groups was observed. The gestation length was considerably elevated in the treated groups. Decline in male pups' body weight was significant at PND75 in DBP- (50 mg/kg), BBP- (20,100 mg/kg), and DES-treated groups. The weight of most of the reproductive organs and sperm quality parameters was impaired significantly in DBP- (50 mg/kg) and BBP- (100 mg/kg) treated groups. Further, a non-significant decline in testicular spermatid count and daily sperm production was also monitored in treated groups. A significant reduction in serum testosterone level in BBP (100 mg/kg), whereas the testicular activity of 17ß-HSD was declined non-significantly in the treated groups with respect to control. The data suggests that DBP and BBP exposure during late gestation period might have adverse effects on offspring's development, spermatogenesis, and steroidogenesis in adult rats.

Population-based cancer incidence in Sikkim, India: report on ethnic variation.

BACKGROUND: A Population-Based Cancer Registry (PBCR) was set up in Sikkim (a state in the North Eastern India) in 2003. We examined incidence rates by ethnic groups from 2003-2008. METHODS: Age-adjusted incidence rates (AARs) per 100,000 person-years were calculated by direct method using the world standard population, and analysed by ethnic group (Bhutia, Rai and other). RESULT: There were a total of 1148 male and 1063 female cases of cancer between 2003 and 2008 on the Sikkim PBCR. The overall AARs were 89.4 and 99.4 per 100,000 person-years in males and females, respectively. Incidence rates were highest amongst the Bhutia group (AAR=172.4 and 147.4 per 100,000 person-years in males and females, respectively), and the largest difference in rates were observed for stomach cancers with AARs being 12.6 and 4.7 times higher in the Bhutia group compared with other ethnic groups in males and females, respectively. CONCLUSION: These observations call for further epidemiological investigations and the introduction of screening programmes.

Reproductive toxic potential of panmasala in male Swiss albino mice.

Some ingredients of panmasala have the ability to penetrate the blood-testis barrier but the reproductive toxic potential of panmasala has not been studied. This study is aimed to assess the possible damage caused by panmasala to male reproductive system in mice. Swiss albino male mice were randomly divided into 7 groups receiving either standard control diet or panmasala-containing diet. Three doses (0.5%, 1.5% and 3%) of panmasala plain (PMP) as well as panmasala with tobacco (PMT)-gutkha were given for a period of 6 months. Assessment of organ weight, sperm count and morphology, spermatid count, sperm production, testicular 17ß-hydroxysteroid dehydrogenase (17ß-HSD) activity and histology were conducted. A nonsignificant decrease in absolute and relative weight of testis and epididymis was observed. Spermatid count, sperm count and production were significantly decreased and 17ß-HSD activity was found considerably declined at 3% of both PMP- and PMT-treated groups as compared to control. The histological observations revealed panmasala induced testicular damage. Abnormal morphology of sperm head shape was significantly elevated in higher doses of both types of panmasala-treated groups than control. The results suggests that panmasala has reproductive toxic potential and more alteration is seen with gutkha as compared to panmasala plain, indicating that similar effects might also be possible in humans.

Cytogenetic alterations in buccal mucosa cells of chewers of areca nut and tobacco.

OBJECTIVE: the rationale of the study was to evaluate the cytological alterations especially micronucleus (MN) and other nuclear anomalies in buccal mucosa cells of chewers to understand the genotoxic and clastogenic potential of chewing mixture (containing areca nut and tobacco as main ingredients). METHODS: the buccal cytome assay involves the examination of epithelial smear to determine micronucleated cell and other nuclear anomalies after the Feulgen plus light green staining. The assay was applied to exfoliated buccal mucosa cells of 262 subjects [non-chewers - 161 and chewers - 101 (includes 20 subjects with OSMF)] and 1000 cells per individual were examined microscopically. Nuclear anomalies were compared among chewers, non-chewers and OSMF subjects and correlated with consumption of quids per day and duration of chewing in years. RESULTS: MN cells were found significantly (p<0.0001) higher among chewers and OSMF subjects as compared to non-chewers. Further analysis indicated that MN was significantly higher in OSMF subjects with respect to even chewers. Nuclear buds were significantly higher (p<0.0001) in OSMF subjects as compared to chewers as well as non-chewers. Nuclear anomalies viz. binucleated, karyorrhexis and karyolysis were also considerably higher in OSMF subjects as compared to non-chewers. CONCLUSION: the MN and other nuclear anomalies reflected genetic damage and cytotoxicity, associated with tobacco and areca nut consumption. Further, these data reveal a risk for development of OSMF among chewers of mixture containing areca nut and/or tobacco, as all the OSMF subjects were chewers.

Non-invasive assessment of healing of bacteria infected and uninfected wounds using optical coherence tomography.

BACKGROUND/PURPOSE: Bacterial infection is one of the main predisposing factors for the delay in wound healing. To facilitate a timely decision for correct therapy, it is important to accurately monitor the morphological changes in the infected wounds using noninvasive tools. In the present study, we have explored the use of optical coherence tomography (OCT) for monitoring the healing of superficial wounds infected with Staphylococcus aureus in mice under in vitro and in vivo conditions and studied the changes in collagen birefringence in the infected wounds. METHODS: The tape stripping method was used for generating superficial skin wounds in mice and wounds were infected with S. aureus. For in vitro studies, infected and uninfected wound tissues were resected, back scattered intensity and birefringence changes in collagen during wound healing were studied on the 2, 4 and 10th day of postinfection using polarization-sensitive (PS) OCT and images were compared with histology. Real-time OCT was used for studying the kinetics of healing of infected wounds under in vivo conditions. RESULTS: From the PS-OCT images, different phases of wound healing such as inflammation, reepithelialization and collagen remodeling could be identified. The edematic regions appeared prominent in infected wounds. Compared with uninfected wounds, reepithelization and collagen remodeling phases of wound healing were delayed significantly in the infected wounds. These changes were comparable with the different stages of wound healing observed under in vivo conditions. CONCLUSION: OCT imaging can provide a rapid assessment of the morphological changes associated with bacteria-infected and uninfected wounds and thereby aid in timely treatment planning.

Effect of helium-neon laser irradiation on hair follicle growth cycle of Swiss albino mice.

We report the results of a study carried out to investigate the effect of helium-neon (He-Ne) laser (632.8 nm) irradiation on the hair follicle growth cycle of testosterone-treated and untreated mice. Both histology and optical coherence tomography (OCT) were used for the measurement of hair follicle length and the relative percentage of hair follicles in different growth phases. A positive correlation (R = 0.96) was observed for the lengths of hair follicles measured by both methods. Further, the ratios of the lengths of hair follicles in the anagen and catagen phases obtained by both methods were nearly the same. However, the length of the hair follicles measured by both methods differed by a factor of 1.6, with histology showing smaller lengths. He-Ne laser irradiation (at approximately 1 J/cm(2)) of the skin of both the control and the testosterone-treated mice was observed to lead to a significant increase (p < 0.05) in % anagen, indicating stimulation of hair growth. The study also demonstrates that OCT can be used to monitor the hair follicle growth cycle, and thus hair follicle disorders or treatment efficacy during alopecia.

Evaluation of genotoxicity of pan masala employing chromosomal aberration and micronucleus assay in bone marrow cells of the mice.

Pan masala is commonly consumed in south-east Asian and other oriental countries as an alternate of tobacco chewing and smoking. Genotoxic potential of pan masala (pan masala plain and pan masala with tobacco known as gutkha) was evaluated employing chromosome aberration (CA) and micronucleus (MN) assay in vivo. Animals were exposed to three different doses (0.5%, 1.5% and 3%) of pan masala plain (PMP) and gutkha (PMT) through feed for a period of 6 months and micronucleus and chromosomal aberrations were studied in the bone marrow cells. Induction of mean micronuclei in polychromatic erythrocytes (MNPCE) and normochromatic erythrocyte (MNNCE) was higher in both types of pan masala treated groups with respect to control group. Both pan masala plain and gutkha treatment significantly induced the frequency of MNPCE and MNNCE in the bone marrow cells, indicating the genotoxic potential. Furthermore, slight decline in the ratio of polychromatic erythrocytes to normochromatic erythrocytes was also noticed, suggesting the cytotoxic potential even though the ratio was statistically non significant. A dose-dependent, significant increase in chromosome aberration was observed in both types of pan masala treated mice with respect to control. However, no significant difference in micronucleus and chromosomal aberration induction was noticed between two types of pan masala exposed (PMP and PMT) groups. Results suggest that both types of pan masala, i.e. plain and gutkha, have genotoxic potential.

Acute toxicity assessment of textile dyes and textile and dye industrial effluents using Daphnia magna bioassay.

Aquatic toxicity of textile dyes and textile and dye industrial effluents were evaluated in an acute toxicity study using Daphnia magna as an aquatic experimental animal model. The 48-h EC(50) value for the azo dyes, Remazol Parrot Green was 55.32 mg/L and for Remazol Golden Yellow was 46.84 mg/L. Whereas 48-h EC(50) values for three dye industrial effluents (D1, D2, and D3) were 14.12%, 15.52%, and 29.69%, respectively. Similarly, EC(50) value for three textile mill effluents (T1, T2, and T3) were >100%, 62.97%, and 63.04%, respectively. These results also showed linear relationship with high degree of confidence (r(2)A =A >0.84 to >0.99) between immobility and test concentrations. The ratio of 24 to 48-h EC(50) remains to be in between 1.1 and 1.2. The general criteria of toxicity classification showed that both dyes were minor acutely toxic having 48-h EC(50) in between 10 and 100 mg/L. Of the six textile and dye industrial effluents tested, one was not acutely toxic (48-h EC(50)A >A 100%) and five were minor acutely toxic (48-h EC(50)A >A 14.12-29.69%). The toxicity classification of effluent based on toxic unit (TU) showed that of the six effluents tested five were found toxic (TU = >1) and one was non-toxic (TU = <1). Thus, dye effluents showed highest toxicity and textile effluents lowest toxicity. The study also suggested that the assay with D.A magna was an excellent method for evaluation of aquatic toxicity of dyes and dyes containing industrial effluents.

A comparative profile of the prevalence and age distribution of human papillomavirus type 16/18 infections among three states of India with focus on northeast India.

Human papillomavirus (HPV) DNA in cervical scrape samples of married women from Manipur (n= 692) and Sikkim (n= 415) in northeast India was determined and compared with that of women from West Bengal (n= 1112) in eastern India by polymerase chain reaction. HPV prevalence was lower in Manipur (7.4%) than in Sikkim (12.5%), which was closely followed by West Bengal (12.9%). HPV18 was predominant in Manipur (2.03%) and strikingly lower (0.2%) in Sikkim and West Bengal (0.9%), while the reverse was true for HPV16. The proportion of HPV16/18 infections in Manipur (3.3%, 22/672) and Sikkim (3.89%, 14/359) were comparable and significantly lower compared to that in West Bengal (7.8%, 79/1007) among women having normal cervical cytology. Such prevalence was similar among all age groups in Manipur: increased with age for women in Sikkim and dropped with age for those in West Bengal similar to that reported previously. At age < or =30 years, HPV16/18 prevalence in Manipur (3.3%) and Sikkim (2.5%) was comparable but was significantly lower (P < 0.05) in contrast to that in West Bengal (8.8%). Among abnormal cytologic lesions, HPV16/18 infections were significantly higher than in normals (P= 0.000) both in Sikkim (14.3%) and West Bengal (20.9%) and absent in Manipur. Such prevalence was noted among women in Sikkim aged >30 years and equally among those in West Bengal aged < or =30 or >30 years. Thus, women from northeast India, particularly from Manipur, appear less susceptible to HPV16/18 infection and related cervical lesions compared to those from West Bengal, where such proneness was prominently evident at age < or =30 years.

Imaging growth dynamics of tumour spheroids using optical coherence tomography.

Optical coherence tomography (OCT) was used to monitor the dynamics of tumour spheroid formation by the hanging drop method. In contrast to microscopy, the estimates obtained using OCT for the volume of the spheroid, were consistent with the measured changes in cell number as a function of time. The OCT images also revealed heterogeneous structures in the spheroids of approximately 200 microm diameter. These corresponded to the necrotic regions identified by fluorescence of propidium iodide stained cells.

Cell death regulation by B-cell lymphoma protein.

Bcl-2 (B Cell Lymphoma) protein is an anti-apoptotic member of Bcl-2 family, which is comprised of pro- and anti-apoptotic members. It regulates cellular proliferation and death by inter- and intra-family interactions. It has a potential to suppress apoptotic cell death under variety of stress conditions by modulating mitochondrial transmembrane potential. However, prevalence of constitutively activated Bcl-2 cellular activity is not always required in cells; a mechanism likely exists in cells, which controls its activity. When expression of Bcl-2 is unregulated, it generates lymphoma like, follicular B-cell lymphoma. This article reviews the structural and functional regulation of Bcl-2 activity at transcriptional, translational, domain, structural and post-translational level, which also accounts for the effects of its deletion and site-directed mutants in the regulation of cellular proliferation and differentiation in vitro and in vivo. This concisely reviewed information on Bcl-2 helps us to update our understanding of cell death and its modulation by Bcl-2 and its mutant's interaction, which has gained therapeutic benefits in cell growth and proliferation, particularly for sensitive human hematopoietic stem cells.

Needle aspiration as a diagnostic tool and therapeutic modality in suppurative lymphadenitis following Bacillus Calmette Guerin vaccination.

OBJECTIVES: Outbreaks are known to occur after Bacillus Calmette Guerin (BCG) vaccination. An outbreak of suppurative lymphadenitis in 18 infants, following BCG vaccination is reported from Sikkim, with incidence of 8.6%. The outbreak occurred after a change of vaccine. METHODS: In a prospective study the cases of suppurative lymphadenitis were diagnosed by needle aspiration cytology and culture of the material aspirated and managed only with repeated needle aspiration and no antitubercular treatment was given. RESULTS: Cytomorphology revealed necrosis alone in 66.6% and necrotizing granulomas in 22.2%. Acid and alcohol fast bacilli were detected in 77.7% cases. Mycobacterium bovis was isolated in eight cases. One case of staphylococcal suppurative lymphadenitis was detected. Sixteen cases were managed with weekly aspiration with mean period of resolution in eight weeks. CONCLUSIONS: Needle aspiration is useful in the diagnosis and effective in the management of these cases. No antitubercular treatment is desired and required in the cases of suppurative lymphadenitis following BCG vaccination.