Aged garlic extract preserves beta-cell functioning via modulation of nuclear factor kappa-B (NF-κB)/Toll-like receptor (TLR)-4 and sarco endoplasmic reticulum calcium ATPase (SERCA)/Ca2+ in diabetes mellitus.

BACKGROUND: Peripheral insulin resistance and compromised insulin secretion from pancreatic ß-cells are significant factors and pathogenic hallmarks of diabetes mellitus (DM). NF-κß/TLR-4 and SERCA/Ca2+ pathways have been identified as potential pathways regulating insulin synthesis by preserving pancreatic ß-cell functioning. The current study aimed to evaluate the therapeutic effect of aged garlic extract (AGE) against DM in a streptozotocin (STZ)-induced rat model with particular emphasis on pancreatic ß-cell functioning. METHODS: AGE was characterized by gas chromatography-mass spectrometry (GC-MS), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) to evaluate its physio-chemical characteristics followed by in-vitro anti-diabetic and antioxidant potential. This was followed by the induction of DM in laboratory animals for investigating the therapeutic action of AGE by evaluating the role of NF-κß/TLR-4 and the SERCA/Ca2+ pathway. The parameters assessed in the present experimental setup encompassed antioxidant parameters, metabolic indicators, insulin concentration, intracellular calcium levels, apoptotic markers (CCK-8 and Caspase Glo-8), and protein expression (P-62 and APACHE-II). RESULTS: AGE characterization by SEM, GC-MS, and X-ray diffraction (XRD) revealed the presence of phenylalanine, alliin, S-allylmercaptocysteine (SAMC), tryptophan, 1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid as major bioactive constituents of AGE. Metabolic studies, including intraperitoneal glucose tolerance test (IPGTT), revealed significantly lower blood glucose levels in the AGE group compared to the disease control group. In contrast, the intraperitoneal insulin tolerance test (ITT) exhibited no significant difference in insulin sensitivity between the AGE supplementation group and the DM control group. Interestingly, AGE was found to have no significant effect on fasting glucose and serum insulin levels. In contrast, AGE supplementation was found to cause significant hypoglycaemia in postprandial blood glucose and insulin levels. Importantly, AGE causes restoration of intracellular Ca2+ levels by modulation of SERCA/Ca2 functioning and inhibition NF-κB/TLR-4 pathway. AGE was found to interact with and inhibit the DR-5/ caspase-8/3 apoptotic complex. Furthermore, microscopic studies revealed degeneration and apoptotic changes in pancreatic ß-cells of the DM control group, while supplementation of AGE resulted in inhibition of apoptotic pathway and regeneration of pancreatic ß-cells. CONCLUSION: The current study suggests that AGE enhance glucose homeostasis by exerting their effects on pancreatic ß-cells, without ameliorating peripheral sensitivity. Moreover, AGEs promote an increase in ß-cell mass by mitigating the apoptosis of pancreatic ß-cells. These findings suggest that AGE could aid in developing a viable alternative therapy for diabetes mellitus (DM).

Descriptive spectrum of thiamine deficiency in pregnancy: A potentially preventable condition.

OBJECTIVE: Pregnancy, a nutritionally demanding situation in terms of macro- and micronutrient supply owing to heightened maternal, placental, and fetal needs, significantly affects thiamine reserves. Thiamine deficiency during pregnancy and the postpartum period, presenting with varied manifestations and outcomes, is a relatively common condition in our population. The study aimed to understand the various manifestations and outcomes of acute thiamine deficiency in pregnant and postpartum women, emphasizing the significance of early recognition and thiamine therapy to prevent serious complications during pregnancy and after childbirth. METHODS: This prospective study conducted in a tertiary care center in North India enrolled consecutive pregnant and postpartum women presenting with clinical features consistent with thiamine deficiency disorders, such as thiamine deficiency-related neuropathy, high-output heart failure, heart failure with reduced ejection fraction, Wernicke's encephalopathy, gastric beriberi, and thiamine-responsive acute pulmonary hypertension. In addition to capturing medical history including drug intake, dietary consumption, and comorbidities, women underwent brief relevant clinical examinations and laboratory assessments, including whole-blood thiamine levels. Response to intravenous thiamine supplementation was also monitored. RESULTS: Data of 31 women (12 pregnant, 19 postpartum) with a diagnosis of acute thiamine deficiency and a mean age of 28.88 ± 2.69 years were analyzed. The mean thiamine level was 1.28 ± 0.44 µg/dL with mean blood lactate of 3.46 ± 3.33. The most common presentation was gastric beriberi (n = 10), followed by paraparesis (n = 6), high-output heart failure (n = 6), acute pulmonary hypertension, heart failure with reduced ejection fraction (n = 3 each), and an acute confusional state (n = 2). All patients responded to thiamine challenge. CONCLUSION: In the context of borderline thiamine status, particularly in our population with endemic thiamine deficiency and heightened demand for thiamine during pregnancy and the peripartum period, the deficiency can have varied and serious manifestations of dry and wet beriberi. Early recognition of the clinical features and thiamine therapy can be life-saving. There is a need for validated clinical criteria owing to the non-availability of thiamine testing in resource-limited settings.

Thiamine deficiency-related neuropathy: A reversible entity from an endemic area.

BACKGROUND AND PURPOSE: Despite thiamine deficiency being a lesser-known entity in modern times, beriberi in various forms, including thiamine deficiency-related neuropathy, remains endemic in Kashmir due to the consumption of polished rice as a staple food. This observational study investigates cases of peripheral neuropathy of unknown etiology and their potential responsiveness to thiamine administration. METHODS: This prospective study enrolled adult patients presenting to the emergency department with weakness consistent with thiamine deficiency-related neuropathy and conducted a therapeutic challenge with thiamine on 41 patients. Response to thiamine therapy was monitored based on subjective and objective improvements in weakness and power. Patients were divided into thiamine responders (n = 25) and nonresponders (n = 16) based on their response to thiamine therapy and nerve conduction studies. RESULTS: Most of the baseline characteristics were similar between responders and nonresponders, except the responders exhibited lower thiamine levels and higher partial pressure of oxygen and lactate levels compared to nonresponders. All patients had a history of consuming polished rice and traditional salt tea. Although weakness in the lower limbs was present in both groups, nonresponders were more likely to exhibit weakness in all four limbs. Clinical improvement was observed within 24 h, but proximal muscle weakness persisted for an extended period of time. CONCLUSIONS: Thiamine deficiency-related neuropathy presents with predominant lower limb weakness, exacerbated by vomiting, poor food intake, psychiatric illness, and pregnancy. Thiamine challenge should be followed by observation of clinical and biochemical response.

Thiamine deficiency in pregnancy and lactation: implications and present perspectives.

During pregnancy, many physiologic changes occur in order to accommodate fetal growth. These changes require an increase in many of the nutritional needs to prevent long-term consequences for both mother and the offspring. One of the main vitamins that are needed throughout the pregnancy is thiamine (vitamin B1) which is a water-soluble vitamin that plays an important role in many metabolic and physiologic processes in the human body. Thiamine deficiency during pregnancy can cause can have many cardiac, neurologic, and psychological effects on the mother. It can also dispose the fetus to gastrointestinal, pulmonological, cardiac, and neurologic conditions. This paper reviews the recently published literature about thiamine and its physiologic roles, thiamine deficiency in pregnancy, its prevalence, its impact on infants and subsequent consequences in them. This review also highlights the knowledge gaps within these topics.

Prevalence of Thiamine Deficiency in Pregnancy and its impact on fetal outcome in an area endemic for thiamine deficiency.

BACKGROUND: Pregnancy is a metabolically challenging state with increased nutritional demand. Thiamine is an important cofactor in various metabolic pathways and thus its deficiency could have a serious impact on both maternal and fetal outcomes. Kashmir has thiamine deficiency in endemic proportions, with multiple reports of infantile beriberi, postpartum neuropathy, and gastric beriberi. This prompted us to assess the extent of the burden of thiamine deficiency during pregnancy. METHODS: This cross-sectional study was conducted for a period of two years in pregnant women attending the antenatal clinic. A demographic, clinical, biochemical, and dietary assessment was done in all participants. The whole blood thiamine levels were assessed by high-performance liquid chromatography. RESULTS: A total of 492 participants were included in the study with a mean age of 30.30±4.57 years and a mean BMI of 24.25±3.32 Kg/m2. The mean whole blood thiamine level of all participants was 133.29±14.32 nmol/L. Low thiamine status was present in 38.2% (n = 188) of participants. Participants with low thiamine had poor perinatal outcomes, with 3.1% (n = 6) reporting early infant death. CONCLUSION: A high prevalence of thiamine deficiency occurs in pregnant women of Kashmir. Low thiamine is associated with poor nutritional status as well as poor perinatal outcomes. TRIAL REGISTRATION: CTRI/2022/07/044217.

Thiamine responsive high output heart failure of adults: an under-recognized entity.

Thiamine deficiency, commonly presenting as dry and wet beriberi, a lesser-known entity in the present era, is increasingly being reported from Kashmir, a north Indian state. The present study aims to present the clinical profile of patients presenting with high-output heart failure (HOHF). Subjects with a primary diagnosis of denovo heart failure and features suggestive of HOHF were recruited; those who responded to intravenous administration of thiamine alone (responders) were adults with no co-morbidities and those who required other medications particularly diuretics (non-responders) were elderly with co-morbidities and underlying heart disease. Responders showed considerably lower mean thiamine pyrophosphate (TPP) levels and higher mean lactate and venous oxygen saturation than non-responders. More importantly, the mean drop in lactate and SVO2 following thiamine therapy was more in responders. In a setting of high risk for thiamine deficiency, features suggestive of HOHF along with elevated lactate and higher venous oxygen saturation, a response to thiamine challenge may serve as surrogate marker of thiamine deficiency.

Insight into Oncogenic Viral Pathways as Drivers of Viral Cancers: Implication for Effective Therapy.

As per a recent study conducted by the WHO, 15.4% of all cancers are caused by infectious agents of various categories, and more than 10% of them are attributed to viruses. The emergence of COVID-19 has once again diverted the scientific community's attention toward viral diseases. Some researchers have postulated that SARS-CoV-2 will add its name to the growing list of oncogenic viruses in the long run. However, owing to the complexities in carcinogenesis of viral origin, researchers across the world are struggling to identify the common thread that runs across different oncogenic viruses. Classical pathways of viral oncogenesis have identified oncogenic mediators in oncogenic viruses, but these mediators have been reported to act on diverse cellular and multiple omics pathways. In addition to viral mediators of carcinogenesis, researchers have identified various host factors responsible for viral carcinogenesis. Henceforth owing to viral and host complexities in viral carcinogenesis, a singular mechanistic pathway remains yet to be established; hence there is an urgent need to integrate concepts from system biology, cancer microenvironment, evolutionary perspective, and thermodynamics to understand the role of viruses as drivers of cancer. In the present manuscript, we provide a holistic view of the pathogenic pathways involved in viral oncogenesis with special emphasis on alteration in the tumor microenvironment, genomic alteration, biological entropy, evolutionary selection, and host determinants involved in the pathogenesis of viral tumor genesis. These concepts can provide important insight into viral cancers, which can have an important implication for developing novel, effective, and personalized therapeutic options for treating viral cancers.

Clinical profile of patients presenting with thiamine-responsive upper-gastrointestinal upset: A pointer toward gastric beriberi.

OBJECTIVES: Although beriberi is considered a forgotten disease in the West, Kashmir has a rice-eating population that has beriberi in endemic proportions. Patients with a thiamine deficiency (TD) occasionally present with gastrointestinal (GI) symptoms, including nausea, recurrent vomiting, loss of appetite, and abdominal discomfort. Together these often respond to thiamine, which points to gastric beriberi. METHODS: Patients with GI symptoms suggestive of TD were recruited from the Department of Medicine at the Government Medical College and its associated hospital, SMHS, in Srinagar, India. Patients were evaluated for serum thiamine levels, serum lactate, biochemical parameters, and transabdominal ultrasonography after ruling out the usual causes of acute abdominal pain and vomiting. RESULTS: A total of 27 patients were recruited with a mean age of 47.28 ± 20.84 y. The mean lactate of patients at the time of admission was 6.43 ± 5.22 mmol/L, and the mean lactate at the time of discharge was 1.23 ± 0.50 mmol/L. All patients had a history of consuming polished rice, washed two to three times before cooking, as the staple diet. The most common GI symptoms were recurrent vomiting, nausea, and loss of appetite. All of the patients responded to the thiamine treatment, and showed improvement in their GI symptoms and decreased serum lactate levels within 2 to 6 h of their hospital stay. CONCLUSIONS: Gastric beriberi is a rare presentation of TD that can lead to severe GI symptoms and lactic acidosis. Given the rapid response to thiamine, it is the standard-of-care treatment in such cases. Thus, clinicians should suspect TD when patients present with either mild or moderate-to-severe GI symptoms and raised blood lactate.

Protective effect of Juglans regia L., against ultraviolet-B induced photoaging in human epidermal keratinocytes.

Solar ultraviolet-B radiation (UVB) has severe adverse effects on the structure and functions of the skin. Although, UVB (290-320 nm) represents only 5-10% of UV light reaching earth's surface, its contribution towards photoaging is tremendous. In this present study was investigate the photoprotective effect of methanolic extract of the male flower of J. regia L. (MEJR) against UVB induced photoaging in human epidermal keratinocytes (HaCaT). Cells were exposed to UVB-irradiation at a dose of 20 mJ/cm2, induces the activation of several signaling pathways which are associated with oxidative stress and photoaging. A single dose of UVB irradiation increased the protein and mRNA expression of MAPKs, AP-1, MMPs, Smad7 and decreased expression of TIMP-1/2, TGF-ß1, Smad3, procollagen type-1 in HaCaT cells. In contrast, pretreatment of MEJR (80 µg/ml) prior to UVB-irradiation significantly prevented the overexpression of MAPKs, AP-1, MMPs, Smad7 and decreased expression of TIMP-1/2, TGF-ß1, Smad3 and procollagen type-1 in HaCaT cells. Moreover, pretreatment of MEJR (80 µg/ml) prior to UVB-irradiation significantly prevents apoptosis in sub Go-phase. Thus, MEJR protects UVB-mediated photoaging in human skin cells, by modulating the expression of photoaging markers. The protection might be because of the presence of the good amount of bioactive compounds in MEJR.

Protective effect of Juglans regia L. against ultraviolet B radiation induced inflammatory responses in human epidermal keratinocytes.

BACKGROUND: Juglans regia L. has a history of traditional medicinal use for the treatment of various maladies and have been documented with significant antioxidant and antiinflammatory properties. Although all parts of the plant are medicinally important, but male the flower of the plant has not been yet investigated against the photo-damage. PURPOSE: The present study, we sought to determine the photoprotective effect of the male flower of J. regia L. against ultraviolet-B radiation-induced inflammatory responses in human skin cells. METHODS: The profile of pharmacological active compounds present in the male flower of J. regia was analyzed by GC-MS. Then, the antioxidant property of methanolic extract of J. regia (MEJR) was analyzed by in vitro free radical scavenging assays. Further, we analyzed the sun protection factor of this extract by spectrophotometry. Moreover, we investigated the photoprotective effect of MEJR against UVB induced inflammatory signaling in human epidermal cells. Human skin epidermal keratinocytes (HaCaT) were pretreated with the MEJR (80 µg/ml), 30 min prior to UVB-irradiation at a dose of 20 mJ/cm2 and were investigated for lipid peroxidation, enzymatic antioxidants activity, apoptosis and inflammatory markers expression level. RESULTS: The GC-MS results showed the presence of good amount of pharmacologically active compounds in the MEJR. We observed that the MEJR possess significant free radical scavenging activity and it was comparable with standard antioxidants. Further, the MEJR exhibits 8.8 sun-protection-factor (SPF) value. Pretreatment with MEJR, 30 min prior to UVB-irradiation, prevented ROS generation, lipid peroxidation and restored the activity of antioxidant status in HaCaT cells. Moreover, MEJR pretreatment significantly prevented UVB activated inflammatory markers like TNF-α, IL-1, IL-6, NF-κB, COX-2 in HaCaT. CONCLUSION: The present findings suggest that MEJR exhibit photoprotective effects and hence it may be useful for the treatment of inflammation related responses. The pharmacological mechanism of MEJR partly associated with its UV absorbance, modulation of inflammatory signaling as well as due to its free radical scavenging capability.

Juglans regia L. protects against UVB induced apoptosis in human epidermal keratinocytes.

The present study was aimed to investigate the photoprotective effect of the male flower of J. regia L. (MEJR) against ultraviolet-B induced apoptosis in human skin cells. Human skin epidermal keratinocytes were pretreated with the MEJR (80 µg/ml, has been selected after MTT assay), prior to 30 min UVB-irradiation at a dose of 20 mJ/cm2. Mitochondrial membrane potential was evaluated using Rhodamine-123 staining; the % apoptosis by Hoechst staining and acridine orange staining; DNA damage was measured by comet assay. The levels of p53, Bax, Bcl-xL, Bcl-2, Cytochrome c, Caspase-9 and Caspase-3 expression in HaCaT cells were analyzed by western blotting and RT-PCR. Pretreatment with MEJR 80 µg/ml prior to UVB-irradiation significantly prevents apoptotic characteristics, DNA damage and loss of mitochondrial membrane potential. Thus, MEJR protects UVB-mediated human skin cells, by modulating the expression of apoptotic markers and UVB-induced DNA damage in HaCaT cells.

Molecular docking of selected phytoconstituents with signaling molecules of Ultraviolet-B induced oxidative damage.

ABSTRACT: The signaling molecules TNF-α, AP-1, and NF-κB act to integrate multiple stress signals into a series of diverse antiproliferative responses. Disruption of these processes can promote tumor progression and chemoresistance. Naturally occurring plant derived compounds are considered as attractive candidates for cancer treatment and prevention. Phytoconstituents can control and modify various biological activities by interacting with molecules involved in concerned signaling pathways. The aim of this study was to find binding conformations between phytoconstituents and these signaling molecules responsible for multiple stress signals of UVB induced photodamage. Induced fit docking was carried out for understanding the binding interactions of pantothenic acid (vitamin B5); 3,4,5-trihydroxy benzoic acid (gallic acid); madecassic acid and hexadecanoic acid, ethyl ester (palmitic acid) with TNF-α, AP-1, and NF-κB. Favorable binding conformations between these signaling molecules and the four phytoconstituents were observed. A number of poses were generated to evaluate the binding conformations and common interacting residues between the ligands and proteins. Among them, the best ligands against TNF-α, AP-1, and NF-κB are reported. The present investigation strongly suggests the probable use of these flavonoids for the amelioration of UVB induced photodamage.